Synthesis of bulky 1,2-dialkoxy- and 1,2,3-trialkoxy-arenes

Article abstract of DOI:10.1016/j.tet.2011.06.013

A large series of bulky 1,2-dialkoxy- and 1,2,3-trialkoxy-benzenes was efficiently prepared via Williamson etherification. Preparation of their contiguous bromine-containing derivatives was also achieved.

Full text of DOI:10.1016/j.tet.2011.06.013

Tetrahedron 67 (2011) 6308e6315
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Synthesis of bulky 1,2-dialkoxy- and 1,2,3-trialkoxy-arenes
,
b
, ,
y
a,b,
ꢀ ꢀ b
Michel Stephan a
, Borut Zupancic , Barbara Mohar
*
*
a En-Fist Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
b National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
A large series of bulky 1,2-dialkoxy- and 1,2,3-trialkoxy-benzenes was efficiently prepared via Wil-
liamson etherification. Preparation of their contiguous bromine-containing derivatives was also
achieved.
Received 1 March 2011
Received in revised form 20 May 2011
Accepted 6 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 14 June 2011
Keywords:
Dialkoxy-benzene
Trialkoxy-benzene
Dialkoxy-naphthalene
1. Introduction
2. Results and discussion
1,2-Dimethoxy- and 1,2,3-trimethoxy-benzene units are present
in a variety of organic molecules, which possess interesting
chemical and biological properties.1 For example, many represen-
tative members of the naturally occurring isoquinoline alkaloid and
flavone families contain the first unit, and some cytotoxic lignans
(e.g., podophyllotoxin, steganone), and alkaloids (e.g., reserpine)
contain the second. A comprehensive literature survey revealed
that the bulk of the starting syntheses of 1,2-di(linear alkoxy)arenes
rely heavily on Williamson etherification of catechols or on an
oxidationehydrolysis sequence of 1-alkoxyarene-2-carboxalde-
hydes and subsequent etherification of the resulting aromatic OH
group.2 However, the few known sterically hindered analogues are
prepared by inconvenient procedures or are poorly characterized,
and the bulky trialkoxy-arenes are especially less well encountered
in the literature and constitute a particular synthetic challenge.
As part of our continuous research focus on polyalkoxy-aryl-
containing phosphine ligands for transition metal-catalyzed
transformations,3 we present herein the practical synthesis on
a preparative scale of series of bulky 1,2-dialkoxy-benzenes and
naphthalenes, and also of isomeric trialkoxy-benzenes.
2.1. Preparation of bulky 1,2-dialkoxy-arenes
A series of 1,2-dialkoxy-benzenes 1aej was prepared under
improved procedures starting from catechol and the appropriate
alkyl halide via Williamson etherification in acetone, followed by
hydrogenation of the pendent olefinic group when required
(Scheme 1, Table 1).4 Various primary and secondary alkyl groups
with branching on the first or second carbon atom were suc-
cessfully introduced under mild conditions demonstrating the
suitability of this method for the incorporation of the relatively
sensitive b-methallyl (b-Met), 2-cyclohexenyl (c-Hexen-2-yl) and
cyclohexyl (Cy) groups, which were appended taking advantage
of the corresponding activated halide on allylic position toward
nucleophilic substitution, thus avoiding harsh alkylation condi-
tions.5 Following, PtO2-catalyzed hydrogenation under low H2
pressures of the olefinic groups proceeded smoothly but partial
over-reduction, i.e., partial hydrogenolysis to the corresponding
phenol, occurred at higher H2 pressures or upon longer expo-
sures. The o-alkoxyphenol could be conveniently eliminated from
the 1,2-dialkoxy-arene by basic workup (washing with aq NaOH
and/or distillation over NaH).
* Corresponding authors. Fax: þ33 148283011 (M.S); tel.: þ386 14760250; fax:
þ386 14760300 (B.M); e-mail addresses: mstephan@phosphoenix.com (M. Stephan),
barbara.mohar@ki.si (B. Mohar).
y
ꢁ
Present address: PhosPhoenix SARL, 115 rue de l’Abbe Groult, 75015 Paris,
Scheme 1. Preparation of bulky 1,2-dialkoxy-benzenes 1aej.
France.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.013

M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
6309
Table 1
Bulky 1,2-dialkoxy-benzenes 1aej prepared via Scheme 1
1
R1
R2
Conditionsa
Isolated
yield %
a
b
c
d
eb
f
i-Pr
i-Pr
i-Bu
H
i-Pr
H
i-PrBr (1 equiv), K2CO3 (2.5 equiv), reflux in acetone
i-PrI (3 equiv), K2CO3 (3.5 equiv), reflux in acetone
i-BuI (1.5 equiv), K2CO3 (2.5 equiv), reflux in acetone
b-Methallyl chloride (3 equiv), KI (cat.), K2CO3 (4 equiv), reflux in acetone
H2 (1 bar), PtO2 (cat.), rt in EtOH
TMSCH2I (2.2 equiv), K2CO3 (4 equiv), 85 ꢀC in DMF
t-BuCH2I (2.2 equiv), K2CO3 (4 equiv), 90 ꢀC in DMF
c-PenBr or c-PenI (3 equiv), K2CO3 (3.5 equiv), reflux in acetone
2-Cyclohexenyl bromidec (2.5 equiv), K2CO3 (3 equiv), rt in acetone
H2 (1 bar), PtO2 (cat.), rt in EtOH
88
94
80
86
95
85
67
92
86
86
b-Met
b
-Met
i-Bu
i-Bu
TMSCH2
H
c-Pen
c-Hexen-2-yl
Cy
TMSCH2
Neopentyl
c-Pen
c-Hexen-2-yl
Cy
g
h
i
jd
a
Reactions were carried out with catechol using the appropriate alkyl halide under the mentioned conditions; the 1,2-dialkoxy-benzenes were distilled and displayed >99%
chemical purity by 1H NMR (see Experimental section).
b
Prepared from 1d.
Another nomenclature is 3-bromocyclohexene.
Prepared from 1i.
c
d
The nature of both alkyl chain (bulkiness) and halogen atom
(especially iodine vs bromine) of the alkyl halide proved to dictate
the proper choice of the reaction conditions, which in turn affected
the reaction rate and yield. Whereas use of i-PrBr (1 equiv) or i-BuI
(1e2 equiv) furnished mostly the corresponding o-alkoxyphenol,
i-PrI (>2 equiv) afforded the targeted 1,2-diisopropoxybenzene in
very high yield (after 2 day reflux in acetone). And while practically
no O-alkylation of catechol in acetone in the presence of K2CO3 with
the bulky neopentyl group occurred, using either its iodide or
tosylate, mono-O-alkylation was complete in DMF at 90 ꢀC using the
iodide (even with>2 equiv) and O,O0-dialkylation could only be
achieved as described in the literature.4b Bycontrast, under the same
reaction conditions in DMF, bis(TMSCH2)-alkylated product was
obtained in good yield using TMSCH2I. As expected, use of i-PrI and
cyclopentyl iodide (c-PenI) in place of the often used corresponding
bromides reduced significantly the reaction times. For example,
using i-PrI led to cleaner and wtwofold faster formation of 1b.
We were also interested in the preparation of 1,2-diisopro-
poxynaphthalene (1k). Its synthesis was accomplished in a good
overall yield (71%) starting from 2-isopropoxynaphthalene as
depicted in Scheme 2. Noteworthy, the relatively sensitive formate
intermediate ensuant from the BaeyereVilliger oxidation of the
aromatic carboxaldehyde was directly used in the subsequent
transformation and its saponified product was O-alkylated in situ.
bromineelithium exchange of the suitably-placed bromine atom.
This is a must in some problematic cases where the direct ortho-
lithiation is not complete with remaining transmetallating agent still
present in the medium,7 or when utilizing unsymmetrical 1,2-
dialkoxy-arenes with two non-equivalent and competing free or-
tho-positions. In such cases, in order to avoid side reactions from
competing different organolithiums with the electrophile, access to
the bromo-derivative in a predictable manner is crucial and permits
the regioselective formation of the desired aryllithium in high yield.8
For example, bromoarenes 2a and 2b (Chart 1) were obtained in
56% and 64% isolated yield, respectively, following o-lithiation with
n-BuLi/TMEDA of the corresponding arene and quench with 1,2-
dibromoethane. Also, the contiguous bromine atom-containing
1,2-dialkoxy-arenes 2cee (Scheme 3) were prepared in good
yields by etherification of the resulting o-bromo-hydroxyarene
obtained byortho-regioselective ring bromination (t-BuNH2/Br29) of
the o-alkoxyphenol.10 In particular, 3-bromocatechol acetonide (2c)
was prepared in good overall yield starting from guaiacol. Thus, the
3-bromocatechol derived from 2-hydroxy-3-bromoanisole treat-
ment with BBr3, furnished 2c (86% yield) under acid-catalyzed
ketalization using PCl3/acetone in benzene.11 Such regioselective
incorporation of bromine atom at an adjacent requisite position
facilitates lithiation or prevents the subsequent lithiation in the
‘wrong sense’.12
Chart 1. Prepared bromine-containing 1,2-dialkoxy-arenes.
Scheme 2. Synthesis of 1,2-diisopropoxynaphthalene (1k).
2.2. Preparation of 1-bromo-2,3-dialkoxy-arenes
While 1,2-dialkoxy-arenes can be, in general, directly ring ortho-
lithiated with butyllithiums due to the ortho-directing ability of
the alkoxy group,6 the generation of the ortho-lithiated species
can be conveniently facilitated under mild conditions via
Scheme 3. Synthesis of 2cee.

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M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
2.3. Preparation of bulky isomeric trialkoxy-benzenes
Also, deprotonation with NaH in THF at 0 ꢀC followed by addition of
2-cyclohexenyl bromide did not improve the latter case in view of
the targeted formation of 1,2,3-tri(2-cyclohexenyloxy)benzene. The
greater steric demands, reactivity and sensitivity of the 2-
cyclohexenyl group seem to prevent this access route. Gratify-
ingly, the preparation of the 1,2,3-tricyclohexyloxybenzene (3f)
was cleanly achieved from 1,2-dicyclohexyloxybenzene (1j) by
stepwise incorporation as outlined in Scheme 5. Thus, the recourse
to activated allylic halides allowed the efficient preparation of
3b,c,e,f. The PtO2-catalyzed hydrogenation of the pendent olefinic
groups in 3b,e proceeded smoothly at 1 bar H2, however operating
at higher H2 pressures or upon longer exposure times to H2, partial
hydrogenolysis to the phenol occurred as observed with the 1,2-
dialkoxy-benzene counterparts.
The series of 1,2,3- (3aed) and 1,3,5-trialkoxy-benzenes (4a,d)
were prepared starting from pyrogallol and phloroglucinol, re-
spectively, via Williamson etherification with the appropriate alkyl
halide (Scheme 4, Table 2). Though pyrogallol is structurally more
congested than phloroglucinol, here again various alkyl groups
with branching on the first or second carbon atom were success-
fully incorporated in acetone. Interestingly, while monitoring pe-
riodically by 1H NMR the pyrogallol O,O0,O00-trialkylation progress,
it was noticed that the unsymmetrical 2,3-dialkoxyphenol (not
isolated) was the major intermediate formed and not the expected
2,6-dialkoxyphenol. Electronic effects seem to favor such a situa-
tion. In view of the clean formation of 1,2,3-triisopropoxy- (3a) and
1,2,3-tricyclopentoxybenzene (3d) in high yields, i-PrI and c-PenBr/
c-PenI were used, respectively, however still 5e6-day reaction time
was required.
While O,O0,O00-trialkylation of phloroglucinol at 60 ꢀC in DMF
using i-PrBr afforded the desired compound 4a,13 surprisingly no
product was formed using i-PrI in refluxing acetone. This may be
explained by the ability of phloroglucinol to form a keto tautomer
under basic conditions.14
Further on, 1,2,3-tricyclohexyloxybenzene (3f) with its three
contiguous and spacially close CyO groups was prepared in an in-
direct method starting from 1,2-dicyclohexyloxybenzene (1j)
(Scheme 5). Thus, application of the O-alkylationehydrogenation
sequence on 2,3-dicyclohexyloxyphenol furnished 3f in 75% overall
yield. The 1,2,4-tricyclohexyloxybenzene (6) isomer could be pre-
pared from 1j via formylation under VilsmeiereHaack conditions (N-
methylformanilide/POCl3) followed by BaeyereVilliger oxidation
and saponification of the resulting formate, which furnished the 3,4-
dicyclohexyloxyphenol. Its O-alkylation with 3-bromocyclohexene
afforded 5 in 76% overall yield. Finally, hydrogenation of 5 under
1 barH2 provided 6, whilethethermalClaisen rearrangementof 5 led
to the 2-(2-cyclohexenyl)-4,5-dicyclohexyloxyphenol.
Scheme 4. Preparation of bulky 1,2,3- (3aed) and 1,3,5-trialkoxy-benzenes (4a,d).
Table 2
Bulky 1,2,3- (3aed) and 1,3,5-trialkoxy-benzenes (4a,d) prepared via Scheme 4
R
Conditionsa
Isolated
yield %
2.3.1. Preparation of 1-bromo-2,3,4-trialkoxy-benzenes. As in the
case of 1,2-dialkoxy-arenes,1,2,3-trialkoxy-arenes can be directly o-
lithiated with butyllithiums owing to the ortho-directing ability of
the alkoxy group, though the latter require harsher conditions.2c,7a
Therefore, the generation of the ortho-lithiated species can be
facilitated under mild conditions via the bromineelithium exchange
procedure of the suitably-placed bromine atom. The 1-bromo-
2,3,4-trialkoxy-benzenes 7a,c,d,f were conveniently prepared in
high yields via an ortho-regioselective bromination procedure using
NaBr/aq H2O2 in acetic acid15 (Scheme 6).
3a
3b
i-Pr
i-PrI (4 equiv), K2CO3 (5 equiv), reflux in acetone
b-Methallyl chloride (5 equiv), KI (cat.), K2CO3
(5 equiv), reflux in acetone
91
95
b-Met
3cb i-Bu
3d
4a
4d
H2 (1 bar), PtO2 (cat.), rt in EtOH
79
c-Pen
i-Pr
c-Pen
c-PenBr (5 equiv), K2CO3 (6 equiv), reflux in acetonec 76
i-PrBr (6 equiv), K2CO3 (6 equiv), 60 ꢀC in DMF
c-PenBr (6 equiv), K2CO3 (6 equiv), 60 ꢀC in DMF
64
71
a
Reactions were carried out with pyrogallol or phloroglucinol using the appro-
priate alkyl halide under the mentioned conditions; the products were distilled and
displayed >99% chemical purity by 1H NMR (see Experimental section).
b
Prepared from 3b.
c-PenI (1 equiv) added after 3 days for higher conversion.
c
3. Conclusion
Notably, whereas three
ded to pyrogallol using
pound 3b (within 2e3 days), the use of 2-cyclohexenyl bromide led
to an unidentifiable complex mixture under various conditions.
b
-Met groups were successfully appen-
In summary, a large series of bulky 1,2-dialkoxy- and 1,2,3-
trialkoxy-benzenes was efficiently prepared. ortho-Regioselective
incorporation of a bromine atom into these compounds was carried
out, which would allow facile generation of the corresponding
b
-methallyl chloride, resulting in com-
Scheme 5. Synthesis of 1,2-dicyclohexyloxybenzene (1j) derivatives.

M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
6311
(ESI): m/z calcd for C10H13O2 [MþꢂH] 165.092, found 165.091. 1H
NMR is in accordance with the literature data.2a
4.2.4. 1,2-Bis(
similar procedure as for 1b using
b
-methallyloxy)benzene (1d). Prepared following
-methallyl chloride (3-chloro-2-
b
methylpropene) (27.2 g, 300 mmol, 3 equiv), KI (cat.), and K2CO3
(55.3 g, 400 mmol, 4 equiv) in acetone (200 mL) refluxing for 2
days. The residue was purified on silica gel eluting with petroleum
ether 40e60/EtOAc 9:1 (Rf 0.7) affording a colorless liquid (18.8 g,
Scheme 6. Bromination of 1,2,3-trialkoxy-benzenes.
aryllithiums under mild conditions. Preparation of some pure iso-
meric 1,3,5- and 1,2,4-trialkoxy-benzenes was achieved as well.
Their application in P-stereogenic phosphine synthesis will be
communicated in due time.
86%); nmax 2915, 1592, 1500, 1451, 1247, 1204, 1123 cmꢂ1
; dH
1.82e1.85 (6H, m, Me), 4.47e4.50 (4H, m, 2CH2), 4.95e4.98 (2H, m,
2CHaHb), 5.10e5.12 (2H, m, 2CHaHb), 6.87e6.90 (4H, m); dC 19.3,
72.7, 112.3, 114.3, 121.2, 141.0, 148.8; m/z (ESI) 219.1 (100, MHþ);
HRMS (ESI): MHþ, found 219.138. C14H19O2 requires 219.139.
4. Experimental section
4.2.5. 1,2-Diisobutoxybenzene (1e). A mixture of 1d (18.0 g,
82.5 mmol) and PtO2 (40.0 mg) in EtOH (96%, 75 mL) was hydro-
genated with a Parr hydrogenator at rt under 1 bar of H2 for 2 h.
Following, it was filtered through Celite and the filtrate concen-
trated. Kugelrohr distillation (115 ꢀC, 0.04 mbar) over NaH afforded
a faint yellow-colored oil (17.2 g, 95%); Rf (hexane/toluene 1:1) 0.6;
4.1. General considerations
3-Bromocyclohexene (2-cyclohexenyl bromide)16 and 2,2-
dimethyl-2,3-dihydrobenzofuran-7-ol are commercially available.
2-Bromo-6-methoxyphenol and 2-bromo-6-isopropoxyphenol17
were prepared according to literature. 1H (300 MHz, internal
Me4Si) and 13C (75 MHz, internal CDCl3) NMR spectra were recor-
ded for solutions in CDCl3. IR spectra were recorded using a Specac
Golden Gate ATR cell equipped with a diamond crystal.
nmax 2957, 1592, 1501, 1470, 1452, 1251, 1224, 1121 cmꢂ1
; dH 1.04
(12H, d, J 6.7 Hz, 4Me), 2.12 (2H, tsept, J 6.6, 6.7 Hz, 2CH), 3.74 (4H, d,
J 6.6 Hz, 2CH2), 6.85e6.88 (4H, m); dC 19.2, 28.4, 75.6, 114.1, 120.9,
149.4; m/z (ESI) 223.2 (100, MHþ); HRMS (ESI): MHþ, found
223.169. C14H23O2 requires 223.170.
4.2.6. 1,2-Bis(trimethylsilylmethoxy)benzene (1f). A mixture of cate-
chol (1.10 g, 10.0 mmol), (iodomethyl)trimethylsilane (4.70 g,
22.0 mmol), and K2CO3 (5.50 g, 40.0 mmol) in DMF (40 mL) was
stirred at 85 ꢀC for 2 days. Following, H2O (100 mL) was added and
the product extracted with Et2O (3ꢁ100 mL). The organic layer was
washed with H2O (4ꢁ50 mL), dried (Na2SO4), and concentrated
affording a brown-colored oil, which was purified on silica gel
eluting with hexane/CH2Cl2 9:1 (Rf 0.4); colorless liquid (2.40 g,
4.2. Detailed synthetic protocols
4.2.1. 2-Isopropoxyphenol (1a). A mixture of catechol (11.0 g,
100 mmol), 2-bromopropane (9.40 mL, 100 mmol), and K2CO3
(34.5 g, 250 mmol) in acetone (100 mL) was refluxed for 1 day and
the reaction progress monitored by TLC. The salts were filtered off
rinsing with acetone and the filtrate concentrated. The residue
was partitioned between diluted aq HCl (100 mL) and Et2O
(80 mL), and the product extracted with Et2O (2ꢁ80 mL). The
organic layer is dried (Na2SO4) and concentrated. Kugelrohr dis-
tillation (120 ꢀC, 10 mbar) afforded a colorless liquid (13.4 g, 88%);
dH 1.35 (6H, d, J 6.1 Hz, 2Me), 4.56 (1H, sept, J 6.1 Hz, CH), 5.77
(1H, s, OH), 6.77e6.96 (4H, m). 1H NMR is in accordance with the
literature data.2b,17c
85%); nmax 2957, 1590, 1497, 1429, 1248, 1231, 1216, 1116 cmꢂ1
; dH
0.20 (18H, s, 9Me), 3.61 (4H, s, 2CH2), 6.87e6.93 (2H, m), 6.96e7.02
(2H, m); dC ꢂ3.1, 61.4,112.0, 120.3,151.5; m/z (ESI) 283.2 (100, MHþ);
HRMS (ESI): MHþ, found 283.155. C14H27O2Si2 requires 283.155.
4.2.7. 2-Neopentoxyphenol (1g). Prepared following similar pro-
cedure as for 1f using neopentyl iodide (1-iodo-2,2-
dimethylpropane) (2.92 mL, 22.0 mmol, 2.2 equiv) and heating at
90 ꢀC for 3 days. The resulting mixture was diluted with H2O
(50 mL), acidified and extracted with Et2O (3ꢁ10 mL). The organic
layer was washed with H2O (3ꢁ10 mL), dried (Na2SO4), and con-
centrated affording a brown oil, which was purified on silica gel
eluting with hexane/toluene 9:1 (Rf 0.2): yellowish syrup (1.21 g,
67%); dH 1.06 (9H, s, 3Me), 3.68 (2H, s, CH2), 5.62 (1H, s, OH),
6.81e6.89 (3H, m), 6.91e6.96 (1H, m); dC 26.6, 31.9, 78.6, 111.7,
114.4, 120.1, 121.3, 145.8, 146.2; m/z (ESI) 181.1 (100, MHþ); HRMS
(ESI): MHþ, found 181.122. C11H17O2 requires 181.123.
4.2.2. 1,2-Diisopropoxybenzene (1b). A mixture of catechol (11.0 g,
100 mmol), 2-iodopropane (30.0 mL, 300 mmol), and K2CO3
(48.5 g, 351 mmol) in acetone (100 mL) was refluxed for 2 days
and the reaction progress monitored by TLC. The salts were fil-
tered off rinsing with acetone and the filtrate concentrated. The
residue was partitioned between H2O (100 mL) and Et2O (80 mL),
and the product extracted with Et2O (2ꢁ80 mL). The organic layer
was washed with 1 M NaOH (50 mL), dried (Na2SO4), and con-
centrated. Kugelrohr distillation (120 ꢀC, 10 mbar) afforded a col-
orless liquid (18.3 g, 94%); Rf (toluene) 0.6; dH 1.33 (12H, d, J 6.1 Hz,
4Me), 4.46 (2H, sept, J 6.1 Hz, 2CH), 6.87e6.96 (4H, m); dC 22.2,
72.1, 118.4, 121.7, 149.2. 1H NMR is in accordance with the litera-
ture data.18
4.2.8. 1,2-Dicyclopentoxybenzene (1h). Prepared following similar
procedure as for 1b using bromocyclopentane (29.0 mL, 270 mmol,
3 equiv) or iodocyclopentane (3 equiv). Kugelrohr distillation
(90 ꢀC, 0.04 mbar) over NaH afforded
a
colorless liquid
(20.4e20.6 g, 92e93%); Rf (toluene) 0.7; nmax 2959, 2971, 1590,
1494, 1452, 1251, 1218, 1168 cmꢂ1
dH 1.53e1.66 (4H, m, 2CH2),
4.2.3. 2-Isobutoxyphenol (1c). Prepared following similar pro-
cedure as for 1a using isobutyl iodide (1-iodo-2-methylpropane)
(17.3 mL, 150 mmol, 1.5 equiv) and K2CO3 (34.5 g, 250 mmol,
2.5 equiv) refluxing for 3 days. The residue was purified on silica gel
eluting with hexane/toluene 95:5 affording a colorless liquid,
which solidified upon standing (13.3 g, 80%); mp 50e51 ꢀC; dH 1.03
(6H, d, J 6.7 Hz, 2Me), 2.11 (1H, tsept, J 6.6, 6.7 Hz, CH2CH), 3.79 (2H,
d, J 6.6 Hz, CH2), 5.67 (1H, s, OH), 6.81e6.88 (3H, m), 6.90e6.95 (1H,
m); dC 19.2, 28.2, 75.1, 111.6, 114.4, 120.0, 121.3, 145.8, 146.0; HRMS
;
1.75e1.96 (12H, m, 6CH2), 4.71e4.77 (2H, m, 2 OCH), 6.84e6.92 (4H,
m); dC 23.7, 32.6, 80.8, 116.9, 121.0, 148.8; m/z (EI) 246 (60, Mþ);
HRMS (EI): Mþ, found 246.163. C16H22O2 requires 246.162.
4.2.9. 1,2-Di(2-cyclohexenyloxy)benzene (1i). A mixture of catechol
(22.0 g, 200 mmol), 2-cyclohexenyl bromide (80.5 g, 0.50 mol,
2.5 equiv), and K2CO3 (82.9 g, 0.60 mol, 3 equiv) in acetone

6312
M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
(250 mL) was stirred at rt for 1 day. The salts were filtered off
rinsing with acetone and the filtrate concentrated. The residue was
partitioned between H2O (200 mL) and Et2O (150 mL), and the
product extracted with Et2O (2ꢁ150 mL), dried (Na2SO4) and con-
centrated. Kugelrohr distillation (85 ꢀC, 0.04 mbar) afforded a col-
orless liquid (46.5 g, 86%); Rf (hexane/EtOAc 9:1) 0.5; nmax 2934,
7.21 (1H, d, J 9.0 Hz), 7.33 (1H, ddd, J 1.3, 6.8, 8.2 Hz), 7.42 (1H, ddd, J
1.4, 6.8, 8.5 Hz), 7.50e7.54 (1H, m), 7.72e7.76 (1H, m), 8.13e8.18
(1H, m); dC 22.5, 22.8, 72.3, 75.1, 119.6, 122.3, 123.4, 124.1, 125.5,
127.3, 130.1, 130.8, 142.8, 146.5; m/z (EI) 244 (15, Mþ); HRMS (EI):
Mþ, found 244.147. C16H20O2 requires 244.146.
1590, 1492, 1451, 1247, 1205, 1110 cmꢂ1
;
dH 1.60e2.17 (12H, m,
4.2.14. 7-Isopropoxy-2,2-dimethyl-2,3-dihydrobenzofuran. Prepared
following similar procedure as for 1b from 2,2-dimethyl-2,3-
dihydrobenzofuran-7-ol (16.4 g, 100 mmol) and 2-iodopropane
(12.0 mL, 0.12 mol). Kugelrohr distillation (70 ꢀC, 0.04 mbar)
afforded a colorless liquid (19.2 g, 93%); Rf (toluene/EtOAc 9:1) 0.7;
6CH2), 4.69e4.75 (2H, m, 2 OCH), 5.85e5.96 (4H, m, 2CH]CH),
6.86e7.00 (4H, m); dC 18.9, 19.0, 25.1, 28.49, 28.52, 73.1, 118.75,
118.78, 121.9, 127.0, 131.36, 131.38, 149.23, 149.24; m/z (EI) 270 (30,
Mþ); HRMS (EI): Mþ, found 270.163. C18H22O2 requires 270.162.
nmax 2974, 1594, 1481, 1459, 1370, 1299, 1261, 1242, 1136, 1111 cmꢂ1
;
4.2.10. 1,2-Dicyclohexyloxybenzene (1j). A mixture of 1,2-di(2-
cyclohexenyloxy)benzene (1i) (40.5 g, 150 mmol) and PtO2
(100 mg) in EtOH (96%, 100 mL) was hydrogenated with a Parr
hydrogenator at rt under 1 bar of H2 for 6 h. Following, it was fil-
tered through Celite and the filtrate concentrated. Kugelrohr dis-
tillation (130 ꢀC, 0.04 mbar) over NaH afforded a colorless liquid
(35.1 g, 86%), which crystallized upon standing; mp 40e42 ꢀC; Rf
(toluene/EtOAc 9:1) 0.4; nmax 2933, 1855, 1593, 1492, 1449, 1252,
dH 1.34 (6H, d, J 6.1 Hz, CHMe2), 1.49 (6H, s, CMe2), 3.00 (2H, s, CH2),
4.58 (1H, sept, J 6.1 Hz, OCH), 6.71e6.77 (3H, m); dC 22.0, 27.9, 43.0,
71.2, 86.5, 115.9, 117.5, 120.0, 128.3, 142.3, 148.5; m/z (ESI) 207 (60,
MHþ); HRMS (ESI): MHþ, found 207.138. C13H19O2 requires 207.139.
4.2.15. 6-Bromo-7-isopropoxy-2,2-dimethyl-2,3-dihydrobenzofuran
(2a). To
a
solution
of
7-isopropoxy-2,2-dimethyl-2,3-
dihydrobenzofuran (0.62 g, 3.00 mmol) and TMEDA (0.45 mL,
3.00 mmol) in Et2O (5 mL) was added under stirring n-BuLi (2 M in
cyclohexane,1.50 mL, 3.00 mmol). The resulting mixture was stirred
at rt for 4 h, cooled to ꢂ40 ꢀC and 1,2-dibromoethane (0.26 mL,
3.00 mmol) was added. After stirring at rt overnight, the reaction
mixturewas quenched with H2O (1 mL). The residue was partitioned
between H2O (10 mL) and CH2Cl2 (10 mL), and the product extracted
with CH2Cl2 (2ꢁ10 mL), dried (Na2SO4) and concentrated. Purifica-
tion on silica gel eluting with hexane/toluene 7:3 afforded a colorless
oil (0.48 g, 56%); Rf (hexane/toluene 1:1) 0.4; nmax 2975, 2930, 1589,
1204, 1111 cmꢂ1
; dH 1.27e1.46 (6H, m, 3CH2), 1.49e1.71 (6H, m,
3CH2), 1.73e1.89 (4H, m, 2CH2), 1.91e2.02 (4H, m, 2CH2), 4.14e4.24
(2H, m, 2 OCH), 6.85e6.97 (4H, m); dC 23.6, 25.6, 31.9, 77.0, 118.4,
121.5, 148.9; m/z (EI) 274 (10, Mþ); HRMS (EI): Mþ, found 274.194.
C18H26O2 requires 274.193.
4.2.11. 2-Isopropoxy-1-naphthaldehyde. To a cold (0 ꢀC) mixture of
2-isopropoxynaphthalene19b (10.0 g, 53.7 mmol) and N-methyl-
formanilide (7.20 mL, 58.0 mmol) was added POCl3 (5.30 mL,
58.0 mmol). Then it was heated at 75 ꢀC for 12 h. The mixture was
suspended in 2 M NaOH (90 mL) and extracted with Et2O
(3ꢁ100 mL). The organic layer was washed with 1 M HCl (50 mL),
dried (Na2SO4), filtered through a bed of silica gel, and the filtrate
concentrated. Crystallization from hexane afforded yellow crystals
(11.3 g, 98%): dH 1.42 (6H, d, J 6.0 Hz, 2Me), 4.79 (1H, sept, J 6.0 Hz,
CH), 7.24 (1H, d, J 9.2 Hz), 7.39 (1H, ddd, J 1.1, 6.9, 7.9 Hz), 7.41 (1H,
ddd, J 1.5, 7.0, 8.5 Hz), 7.70e7.77 (1H, m), 7.98 (1H, d, J 9.2 Hz),
9.25e9.30 (1H, m), 10.89 (1H, s); dC 22.2, 72.4, 115.2, 118.0, 124.7,
124.8, 128.1, 128.4, 129.6, 131.6, 137.2, 162.9, 192.5. 1H NMR is in
accordance with the literature data.19
1448, 1371, 1313, 1101 cmꢂ1
; dH 1.32 (6H, d, J 6.2 Hz, CHMe2),1.47 (6H,
s, CMe2), 2.94 (2H, d, J 1.1 Hz, CH2), 4.65 (1H, sept, J 6.2 Hz, OCH), 6.68
(1H, td, J 1.1, 7.9 Hz), 6.96 (1H, d, J 7.9 Hz); dC 22.4, 28.0, 42.8, 74.9, 88.1,
115.9,120.0,124.1,128.5,139.5,151.5; m/z (ESI) 285 (25, MHþ); HRMS
(ESI): MHþ, found 285.050. C13H1879BrO2 requires 285.049.
4.2.16. 3-Bromo-1,2-diisopropoxynaphthalene (2b). Prepared from
1,2-diisopropoxynaphthalene (1k) (4.88 g, 20.0 mmol) following
similar procedure as for 2a. Purification on silica gel eluting with
hexane/toluene 8:2 afforded a colorless oil (4.14 g, 64%); Rf (hexane/
toluene 1:1) 0.8; dH 1.32 and 1.36 (12H, 2d, J 6.2 Hz, 4Me), 4.75 and
4.83 (2H, 2sept, J 6.2 Hz, 2CH), 7.37e7.49 (2H, m), 7.64e7.70 (1H, m),
7.84 (1H, s), 8.08e8.15 (1H, m); dC 22.4, 22.6, 75.1, 75.6,122.6,125.77,
125.78,126.5,126.8,130.2,131.3,133.6,143.9,146.2; m/z (EI) 322 (25,
Mþ); HRMS (EI): Mþ, found 322.058. C16H1979BrO2 requires 322.057.
4.2.12. 2-Isopropoxy-1-naphthyl formate. To a cold (0 ꢀC) solution
of 2-isopropoxy-1-naphthaldehyde (10.0 g, 46.7 mmol) in CH2Cl2
(100 mL) was added under stirring m-CPBA (70%, 60.7 mmol,
15.0 g). The mixture was stirred at rt for 1 h then concentrated. The
residue was triturated with hexane (70 mL), insolubles were fil-
tered off, and the filtrate concentrated yielding the product as
a yellow oil (10.2 g, 95%; contains <5% m-CBA); dH 1.37 (6H, d, J
6.1 Hz, 2Me), 4.67 (1H, sept, J 6.1 Hz, CH), 7.32 (1H, d, J 9.1 Hz), 7.40
(1H, ddd, J 1.2, 6.8, 8.2 Hz), 7.51 (1H, ddd, J 1.3, 6.8, 8.4 Hz), 7.71e7.76
(1H, m), 7.78e7.82 (1H, m), 7.84e7.88 (1H, m), 8.42 (1H, s, CHO); dC
22.2, 72.6, 116.9, 120.2, 124.5, 127.1 (2C), 127.7, 127.9, 129.3, 134.0,
145.8, 159.9; m/z (EI) 230 (40, Mþ); HRMS (EI): Mþ, found 230.094.
C14H14O3 requires 230.094.
4.2.17. 1-Bromo-2,3-dihydroxybenzene (3-bromocatechol). To a cold
(ꢂ78 ꢀC) solution of 2-bromo-6-methoxyphenol (8.00 g,
39.4 mmol) in dry CH2Cl2 (40 mL) was added slowly BBr3 (1 M in
CH2Cl2, 43.1 mmol, 43.0 mL). After stirring at rt for 1 h, the mixture
was poured onto ice-water, stirred for 30 min and extracted with
CH2Cl2 (3ꢁ30 mL). The organic layer was dried (MgSO4) then
concentrated affording the title product as a brownish oil (6.90 g,
93%); Rf (toluene/EtOAc 9:1) 0.2; dH 5.60 (1H, br s, OH), 5.69 (1H, br
s, OH), 6.72 (1H, dd, J 8.1, 8.1 Hz), 6.87 (1H, dd, J 1.5, 8.1 Hz), 7.00 (1H,
dd, J 1.5, 8.1 Hz); dC 109.5, 114.9, 121.9, 123.3, 140.3, 144.5. 1H NMR is
in accordance with the literature data.20
4.2.13. 1,2-Diisopropoxynaphthalene (1k). To
a solution of 2-
isopropoxy-1-naphthyl formate (10.0 g, 43.4 mmol) in acetone/
MeOH 8:2 (100 mL) was added K2CO3 (12.0 g, 86.8 mmol). The
mixture was stirred at rt for 1 h then 2-iodopropane (11.1 g,
65.1 mmol) was added and heated at 75 ꢀC for 3 days. The con-
centrated residue was partitioned between Et2O (3ꢁ100 mL) and
H2O (200 mL), and the organic layer dried (Na2SO4) then concen-
trated. Kugelrohr distillation (105 ꢀC, 0.04 mbar) afforded a yellow
oil (8.60 g, 81%); Rf (hexane/toluene 1:1) 0.6; nmax 2974, 2931, 1594,
4.2.18. 3-Bromo-(isopropylidenedioxy)benzene (2c). To a cold (0 ꢀC)
solution of 3-bromocatechol (6.00 g, 31.7 mmol) and acetone
(2.80 mL, 38.1 mmol) in benzene (25 mL) was added dropwise PCl3
(1.11 mL, 12.7 mmol). The reaction mixture was stirred at rt until
HCl evolution ceased, then H2O (100 mL) was added. Extraction
with CH2Cl2 (3ꢁ30 mL), drying (Na2SO4), and purification of the
residue on silica gel eluting with toluene afforded a colorless oil
(6.24 g, 86%); Rf (toluene) 0.5; dH 1.72 (6H, s, 2Me), 6.67 (2H, 2d, J
4.7 Hz), 6.91 (1H, dd, J 4.7, 4.7 Hz); dC 25.9, 100.7, 107.5, 118.7, 122.1,
1467, 1378, 1371, 1262, 1237, 1106 cmꢂ1
4Me), 4.64 (1H, sept, J 6.1 Hz, OCH), 4.73 (1H, sept, J 6.1 Hz, OCH),
; dH 1.35 (12H, d, J 6.1 Hz,

M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
6313
124.3, 145.7, 147.7; m/z (ESI) 229.0 (100, MHþ); HRMS (ESI): MHþ,
198 mmol, 5 equiv) refluxing for 6 days (with the addition of
1 equiv of iodocyclopentane after 3 days for higher conversion).
Kugelrohr distillation (145 ꢀC, 0.04 mbar) afforded yellowish crys-
tals (10.0 g, 76%); Rf (toluene) 0.7; mp 30e32 ꢀC; nmax 2958, 1593,
found 228.987. C9H1079BrO2 requires 228.986.
4.2.19. 1-Bromo-2-isopropoxy-3-methoxybenzene
following similar procedure as for 1b from 2-bromo-6-
methoxyphenol (1.00 g, 4.92 mmol), 2-iodopropane (850 L,
(2d). Prepared
1466, 1248, 1167 cmꢂ1
; dH 1.50e1.69 (8H, m, 4CH2), 1.74e1.98 (16H,
m
m, 8CH2), 4.66e4.72 (1H, m, CH), 4.72e4.79 (2H, m, 2CH), 6.51 (2H,
d, J 8.2 Hz), 6.87 (1H, t, J 8.2 Hz); dC 23.4, 23.7, 32.66, 32.68, 79.9,
84.2, 108.0, 122.4, 138.4, 152.4; m/z (EI) 330 (15, Mþ); HRMS (EI):
Mþ, found 330.220. C21H30O3 requires 330.219.
9.85 mmol, 2 equiv), and K2CO3 (1.36 g, 9.85 mmol). Colorless liquid
(1.12 g, 93%); Rf (toluene) 0.6; nmax 2976,1572,1473,1450,1435,1259,
1232,1102 cmꢂ1
; dH 1.33 (6H, d, J 6.2 Hz, 2Me), 3.83 (3H, s, OMe), 4.55
(1H, sept, J 6.2 Hz, OCH), 6.83 (1H, dd, J 1.8, 8.3 Hz), 6.89 (1H, dd, J 7.7,
8.3Hz), 7.13 (1H, dd, J 1.8, 7.7Hz); dC 22.5, 56.0, 75.9,111.6,118.8,124.3,
125.0,144.7,154.1.1HNMRisinaccordancewiththeliteraturedata.17c
4.2.25. 1,3,5-Triisopropoxybenzene (4a). A mixture of phlor-
oglucinol dihydrate (11.35 g, 70.0 mmol), 2-bromopropane (40.0 mL,
0.42 mol, 6 equiv), and K2CO3 (58.0 g, 0.42 mol, 6 equiv) in DMF
(150 mL) was heated at 60 ꢀC for 1 day. Following, H2O (100 mL) was
added and the product was extracted with Et2O (3ꢁ100 mL). The
organic layer was washed with H2O (4ꢁ50 mL), dried (Na2SO4), and
concentrated. Purification on silica gel eluting with hexane/CH2Cl2
9:1 followed by Kugelrohr distillation (90 ꢀC, 0.04 mbar) afforded
a colorless liquid (11.3 g, 64%); nmax 2976, 1588, 1464, 1183, 1147,
4.2.20. 1-Bromo-3-isopropoxy-2-methoxybenzene
(2e). Prepared
following similar procedure as for 1b from 2-bromo-6-
isopropoxyphenol (6.70 g, 29.0 mmol), MeI (3.60 mL, 58.0 mmol,
2 equiv), and K2CO3 (8.00 g, 58.0 mmol, 2 equiv). Colorless liquid
(6.7 g, 94%); Rf (hexane/EtOAc 9:1) 0.6; dH 1.36 (6H, d, J 6.1 Hz, 2Me),
3.86 (3H, s, OMe), 4.54 (1H, sept, J 6.1 Hz, OCH), 6.83e6.92 (2H, m),
7.12 (1H, dd, J 2.6, 6.9 Hz); dC 22.1, 60.4, 71.6, 115.4, 117.9, 124.7,
125.0, 147.8, 152.1; m/z (ESI) 267.0 (75, MNaþ); HRMS (ESI): MNaþ,
found 266.999. C10H1379BrO2Na requires 267.000.
1111 cmꢂ1
; dH 1.310 (18H, d, J 6.1 Hz, 6Me), 4.47 (3H, sept, J 6.1 Hz,
3OCH), 6.03 (3H, s); dC 22.1, 69.7, 96.1, 159.7; m/z (ESI) 253.2 (100,
MHþ); HRMS (ESI): MHþ, found 253.180. C15H25O3 requires 253.180.
4.2.21. 1,2,3-Triisopropoxybenzene (3a). A mixture of pyrogallol
(25.2 g, 0.20 mol), 2-iodopropane (80 mL, 0.80 mol), and K2CO3
(138 g, 1.00 mol) in acetone (300 mL) was refluxed for 5 days mon-
itoring the reactionprogress by TLC. The salts were filtered off rinsing
with acetone and the filtrate concentrated. The residue was parti-
tioned between H2O (300 mL) and CH2Cl2 (100 mL), and the product
extractedwithCH2Cl2 (2ꢁ100mL),dried(Na2SO4), andconcentrated.
Kugelrohr distillation (125 ꢀC, 10 mbar) afforded a light yellow-
colored liquid (45.9 g, 91%); Rf (toluene/EtOAc 9:1) 0.6; nmax 2975,
4.2.26. 1,3,5-Tricyclopentoxybenzene (4d). Prepared following sim-
ilar procedure as for 4a using bromocyclopentane (32.0 mL,
0.30 mol, 6 equiv) heating for 2 days. Purification on silica gel
eluting with hexane/CH2Cl2 9:1 followed by Kugelrohr distillation
(190 ꢀC, 0.04 mbar) afforded a yellowish liquid (11.7 g, 71%), which
crystallized upon standing; mp 31e33 ꢀC; nmax 2962, 1591, 1463,
1349, 1149 cmꢂ1
; dH 1.51e1.66 (6H, m, 3CH2), 1.69e1.96 (18H, m,
9CH2), 4.64e4.72 (3H, m, 3 OCH), 5.99 (3H, s); dC 24.0, 32.9, 79.2,
95.5, 159.8; m/z (ESI) 331.2 (100, MHþ); HRMS (ESI): MHþ, found
331.228. C21H31O3 requires 331.227.
1584,1468,1382,1372,1244,1109 cmꢂ1
; dH 1.30 (6H, d, J 6.2 Hz, 2Me),
1.32 (12H, d, J 6.1 Hz, 4Me), 4.33 (1H, sept, J 6.2 Hz, OCH), 4.52 (2H,
sept, J 6.1 Hz, 2 OCH), 6.55 (2H, d, J 8.3Hz), 6.88 (1H, t, J 8.3 Hz); dC 21.8,
22.3, 70.7, 74.8,109.3,122.4,139.2,152.2; m/z (ESI) 253.2 (100, MHþ);
HRMS (ESI): MHþ, found 253.180. C15H25O3 requires 253.180.
4.2.27. 2,3-Dicyclohexyloxyphenol. To
a solution of 1,2-dicyclo-
hexyloxybenzene (1j) (10.0 g, 36.5 mmol) in cyclohexane
(100 mL) was added under stirring t-BuLi (1.5 M in pentane,
29.2 mL, 43.8 mmol). The resulting mixture was heated at 60 ꢀC for
4 h, cooled to ꢂ30 ꢀC, and B(OMe)3 (8.14 mL, 73.0 mmol) was slowly
added. After stirring at rt for 15 min, the reaction mixture was
hydrolyzed with 1 M HCl (200 mL), extracted with CH2Cl2
(3ꢁ50 mL), and dried (Na2SO4). The residue was taken in THF
(250 mL) and 0.5 M NaOH (150 mL) was added followed by slow
addition of 30% aq H2O2 (100 mL). The reaction mixture was stirred
at rt overnight, cooled to 0 ꢀC and Na2S2O5 slowly added portion-
wise until evolution of oxygen ceased. This was acidified to pH w2
with 1 M HCl and extracted with CH2Cl2 (3ꢁ50 mL), dried (Na2SO4),
and concentrated. Purification on silica gel eluting with hexane/
toluene 6:4 afforded a yellowish oil (8.69 g, 82%); Rf (hexane/EtOAc
95:5) 0.4; dH 1.13e1.64 (12H, m, 6CH2), 1.69e1.85 (4H, m, 2CH2),
1.90e2.09 (4H, m, 2CH2), 4.20e4.31 (2H, m, 2 OCH), 5.87 (1H, br s,
OH), 6.45 (1H, dd, J 1.4, 8.4 Hz), 6.55 (1H, dd, J 1.4, 8.2 Hz), 6.84 (1H,
t, J 8.3 Hz); dC 23.5, 24.3, 25.4, 25.5, 31.8, 32.8, 75.9, 80.7, 107.1, 107.4,
123.2, 134.3, 150.3, 150.4; m/z (EI) 290 (50, Mþ); HRMS (EI): Mþ,
found 290.190. C18H26O3 requires 290.188.
4.2.22. 1,2,3-Tris(
b-methallyloxy)benzene (3b). Prepared following
similar procedure as for 3a using
b-methallyl chloride (3-chloro-2-
methylpropene) (22.6 g, 250 mmol, 5 equiv), and KI (85.0 mg)
refluxing for 2e3 days. Purification on silica gel eluting with hex-
ane/CH2Cl2 8:2 afforded a colorless oil (13.7 g, 95%); Rf (hexane/
CH2Cl2 7:3) 0.4; nmax 2916, 1598, 1490, 1473, 1451, 1249 cmꢂ1
; dH
1.82e1.85 (6H, m, 2Me), 1.88e1.91 (3H, m, Me), 4.43e4.46 (6H, m,
3CH2), 4.90e4.93 (1H, m, CH), 4.94e4.98 (2H, m, 2CH), 5.08e5.12
(3H, m, 3CH), 6.56 (2H, d, J 8.3 Hz), 6.90 (1H, dd, J 8.0, 8.6 Hz); dC
19.4, 19.7, 72.8, 76.9, 107.4, 112.4, 112.7, 123.2, 138.2, 141.0, 142.3,
153.0; m/z (ESI) 289.2 (100, MHþ); HRMS (ESI): MHþ, found
289.180. C18H25O3 requires 289.180.
4.2.23. 1,2,3-Triisobutoxybenzene (3c). A mixture of 3b (12.0 g,
41.6 mmol) and PtO2 (35.0 mg) in EtOH (96%, 50 mL) was hydroge-
nated with a Parr hydrogenator at rt under 1 bar of H2 for 72 h.
Following, it was filtered through Celite and the filtrate concen-
trated. Kugelrohr distillation (150 ꢀC, 0.04 mbar) over NaH afforded
a colorless liquid (9.68 g, 79%); Rf (hexane/toluene 2:8) 0.6; nmax
4.2.28. 2,3-Dicyclohexyloxy-(2-cyclohexenyloxy)benzene
(3e).
2957,1597,1463,1250 cmꢂ1
;
dH 1.03 (12H, d, J 6.8 Hz, 4Me),1.04 (6H,
Prepared following similar procedure as for 1i from 2,3-
dicyclohexyloxyphenol (8.50 g, 29.3 mmol), 3-bromocyclohexene
(7.10 g, 43.9 mmol, 1.5 equiv), and K2CO3 (8.10 g, 58.6 mmol,
2 equiv) stirring at rt for 3 days. Kugelrohr distillation (60 ꢀC,
0.04 mbar) afforded a yellow-colored syrup (10.1 g, 94%); Rf (hex-
d, J 6.8 Hz, 2Me), 2.07 (1H, tsept, J 6.7, 6.7 Hz, CH), 2.11 (2H, tsept, J 6.7,
6.7 Hz, 2CH), 3.73 (4H, d, J 6.4 Hz, 2CH2), 3.74 (2H, d, J 6.4 Hz, CH2),
6.53 (2H, d, J 8.4 Hz), 6.90 (1H, t, J 8.4 Hz); dC 19.3, 19.4, 28.5, 29.2,
75.4, 79.7, 106.6, 123.1, 138.3, 153.5; m/z (ESI) 295.2 (100, MHþ);
HRMS (ESI): MHþ, found 295.226. C18H31O3 requires 295.227.
ane/EtOAc 95:5) 0.4; nmax 2932, 2856, 1583, 1466, 1239 cmꢂ1
; dH
1.15e1.41 (6H, m, 3CH2), 1.45e2.17 (20H, m, 10CH2), 4.00e4.10 (1H,
m, OCH), 4.17e4.27 (1H, m, OCH), 4.73e4.79 (1H, m, OCH),
5.88e5.92 (2H, m, 2CH), 6.54e6.61 (2H, m), 6.86 (1H, t, J 8.2 Hz); dC
4.2.24. 1,2,3-Tricyclopentoxybenzene (3d). Prepared following sim-
ilar procedure as for 3a using bromocyclopentane (21.0 mL,

6314
M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
19.0, 23.8, 24.16, 24.19, 25.1, 25.6, 25.7, 28.5, 31.98, 32.01, 32.69,
32.73, 72.3, 76.6, 80.7, 109.9, 110.0, 122.5, 126.9, 133.4, 139.6, 152.4,
152.5; m/z (EI) 370 (55, Mþ); HRMS (EI): Mþ, found 370.252.
C24H34O3 requires 370.251.
Colorless syrup (11.7 g, 92%); Rf (hexane/EtOAc 7:3) 0.9; nmax 2932,
2855, 1511, 1420, 1182, 1167 cmꢂ1
dH 1.21e1.40 (6H, m, 3CH2),
;
1.44e1.67 (7H, m, 3CH2, CH), 1.70e2.19 (13H, m, 6CH2, CH),
3.96e4.06 (1H, m, OCH), 4.14e4.24 (1H, m, OCH), 4.64e4.71 (1H, m,
OCH]CH), 5.82e5.89 (1H, m, CH]CH), 5.91e5.99 (1H, m, CH]CH),
6.41 (1H, dd, J 2.8, 8.7 Hz), 6.54 (1H, d, J 2.8 Hz), 6.83 (1H, d, J
8.7 Hz); dC 18.9, 23.6, 23.8, 25.0, 25.6, 25.7, 28.2, 31.83, 31.84, 32.2,
71.2, 76.6, 78.7, 106.6, 106.9, 120.7, 126.5, 131.8, 142.5, 150.3, 151.1;
m/z (ESI) 371.3 (100, MHþ); HRMS (ESI): MHþ, found 371.259.
C24H35O3 requires 371.259.
4.2.29. 1,2,3-Tricyclohexyloxybenzene (3f). A mixture of 3e (10.0 g,
27.0 mmol) and PtO2 (50.0 mg) in EtOH (96%, 50 mL) was hydro-
genated with a Parr hydrogenator at rt under 1 bar of H2 for 1 h.
Following, it was filtered through Celite and the filtrate concen-
trated affording a colorless oil (9.75 g, 97%): nmax 2931, 2855, 1497,
1210, 1166 cmꢂ1
; dH 1.18e1.65 (18H, m, 9CH2), 1.72e1.87 (6H, m,
3CH2), 1.91e2.08 (6H, m, 3CH2), 4.00e4.11 (1H, m, OCH), 4.17e4.27
(2H, m, 2 OCH), 6.54 (2H, d, J 8.3 Hz), 6.84 (1H, t, J 8.3 Hz); dC 23.7,
24.2, 25.6, 25.7, 32.0, 32.7, 76.5, 80.6, 109.5, 122.4, 139.4, 152.3; m/z
(EI) 372 (25, Mþ); HRMS (EI): Mþ, found 372.268. C24H36O3 requires
372.266.
4.2.34. 1,2,4-Tricyclohexyloxybenzene (6). Prepared from 5 (10.0 g,
27.0 mmol) following similar procedure as for 3f. Colorless oil
(9.65 g, 96%); Rf (toluene) 0.7; nmax 2931, 2855, 1497, 1210,
1167 cmꢂ1
; dH 1.22e1.64 (18H, m, 9CH2), 1.73e1.86 (6H, m, 3CH2),
1.90e2.03 (6H, m, 3CH2), 3.96e4.06 (1H, m, OCH), 4.05e4.15 (1H,
m, OCH), 4.15e4.25 (1H, m, OCH), 6.39 (1H, dd, J 2.9, 8.8 Hz), 6.51
(1H, d, J 2.9 Hz), 6.82 (1H, d, J 8.8 Hz); dC 23.8, 23.9, 24.0, 25.6, 25.67,
25.7, 31.97, 31.99, 32.3, 76.1, 76.9, 78.8, 107.1, 107.5, 120.7, 142.6,
150.3, 153.2; m/z (ESI) 373.3 (40, MHþ); HRMS (ESI): MHþ, found
373.274. C24H37O3 requires 373.274.
4.2.30. 3,4-Dicyclohexyloxybenzaldehyde. To a cold (0 ꢀC) solution
of 1j (14.6 g, 53.4 mmol) in NMFA (8.66 g, 64.1 mmol, 7.91 mL) was
added POCl3 (9.83 g, 64.1 mmol, 5.87 mL). After overnight stirring
at 70 ꢀC, the reaction was quenched with 2 M NaOH (100 mL) and
the product extracted with Et2O (3ꢁ50 mL). The organic layer was
dried (Na2SO4) and concentrated affording a yellow oil (15.5 g,
96%); Rf (toluene) 0.4; dH 1.28e1.47 (6H, m, 3CH2), 1.49e1.71 (6H, m,
3CH2), 1.74e1.89 (4H, m, 2CH2), 1.90e2.03 (4H, m, 2CH2), 4.23e4.33
(1H, m, OCH), 4.34e4.44 (1H, m, OCH), 6.99 (1H, d, J 8.1 Hz), 7.42
(1H, dd, J 2.0, 8.1 Hz), 7.44 (1H, d, J 2.0 Hz), 9.82 (1H, s, CHO); dC 23.3,
23.4, 25.4, 25.5, 31.4, 31.6, 76.5, 77.2, 114.9, 116.3, 126.2, 129.8, 148.7,
154.8, 190.7; m/z (EI) 302 (20, Mþ); HRMS (EI): Mþ, found 302.189.
C19H26O3 requires 302.188.
4.2.35. 2-(2-Cyclohexenyl)-4,5-dicyclohexyloxyphenol. Heating
5
(1.00 g, 2.70 mmol) at 150 ꢀC for 1e2 h afforded the pure title
compound (0.75 g, 75%); Rf (toluene/EtOAc 95:5) 0.5; mp
150e152 ꢀC; dH 1.20e1.39 (6H, m, 3CH2), 1.42e1.69 (8H, m, 4CH2),
1.70e1.85 (5H, m, CH, 2CH2), 1.87e2.01 (5H, m, CH, 2CH2),
2.06e2.14 (2H, m, CH2), 3.34e3.46 (1H, m, CH), 3.92e4.05 (1H, m,
OCH), 4.08e4.22 (1H, m, OCH), 5.33 (1H, br s, OH), 5.78 (1H, m, CH),
6.00 (1H, m, CH), 6.41 (1H, s), 6.68 (1H, s); dC 21.3, 23.7, 24.0, 25.0,
25.6, 25.7, 30.2, 31.9, 32.3, 37.4, 76.8, 79.1, 105.7, 121.9, 122.9, 130.0,
130.6, 141.6, 148.6, 149.1; m/z (ESI) 371.3 (100, MHþ); HRMS (ESI):
MHþ, found 371.259. C24H35O3 requires 371.259.
4.2.31. 3,4-Dicyclohexyloxyphenyl formate. To a cold (0 ꢀC) solution
of 3,4-dicyclohexyloxybenzaldehyde (15.0 g, 49.6 mmol) in CH2Cl2
(100 mL) was added under stirring m-CPBA (70%, 64.5 mmol,
15.9 g). The mixture was stirred at rt for 1 h then concentrated. The
residue was triturated with hexane (50 mL), insolubles were fil-
tered off, and the filtrate concentrated yielding the product as
a yellow oil (14.4 g, 91%); Rf (hexane/EtOAc 9:1) 0.7; nmax 2933,
4.2.36. 1-Bromo-2,3,4-triisopropoxybenzene (7a). To a mixture of
3a (5.00 g, 19.8 mmol), NaBr (2.00 g, 19.8 mmol) in acetic acid
(20 mL)/CH2Cl2 (20 mL) was added dropwise 30% aq H2O2 (2.00 mL)
at rt and the reaction progress was followed by TLC. After 2 h, H2O
(30 mL) was added and the product extracted with CH2Cl2
(3ꢁ50 mL). The organic layer was dried (Na2SO4), concentrated and
the residue purified on silica gel eluting with hexane/toluene 3:2 to
afford a colorless liquid (6.23 g, 95%); Rf (hexane/toluene 1:1) 0.5;
2857, 1740, 1498, 1210, 1158 cmꢂ1
; dH 1.24e1.42 (6H, m, 3CH2),
1.48e1.65 (6H, m, 3CH2),1.73e1.87 (4H, m, 2CH2),1.89e2.01 (4H, m,
2CH2), 4.09e4.25 (2H, m, 2 OCH), 6.64 (1H, dd, J 2.6, 8.7 Hz), 6.70
(1H, d, J 2.6 Hz), 6.91 (1H, d, J 8.7 Hz), 8.28 (1H, s, CHO); dC 23.6, 23.7,
25.5, 25.6, 31.7, 32.0, 77.2, 78.1, 110.5, 113.1, 119.1, 144.2, 146.9, 149.8,
159.7; m/z (ESI) 319.2 (40, MHþ); HRMS (ESI): MHþ, found 319.191.
C19H27O4 requires 319.191.
nmax 2976, 1462, 1434, 1382, 1372, 1103 cmꢂ1
; dH 1.28 (6H, d, J 6.1 Hz,
2Me), 1.31 (6H, d, J 6.1 Hz, 2Me), 1.34 (6H, d, J 6.1 Hz, 2Me), 4.42 (1H,
sept, J 6.1 Hz, OCH), 4.50 (1H, sept, J 6.1 Hz, OCH), 4.72 (1H, sept, J
6.1 Hz, OCH), 6.54 (1H, d, J 9.0 Hz), 7.15 (1H, d, J 9.0 Hz); dC 2.0, 22.4,
22.5, 70.9, 75.5, 75.7, 109.7, 111.1, 126.4, 142.8, 149.8, 152.1; m/z (EI)
330 (25, Mþ); HRMS (EI): Mþ, found 330.084. C15H2379BrO3 requires
330.083.
4.2.32. 3,4-Dicyclohexyloxyphenol. To a solution of 3,4-dicyclo-
hexyloxyphenyl formate (14.0 g, 44.0 mmol) in MeOH (100 mL)
was added under stirring K2CO3 (12.2 g, 88.0 mmol). The mixture
was stirred at rt for 1 h, concentrated, and the residue partitioned
between H2O (200 mL) and CH2Cl2 (100 mL), and the product
extracted with CH2Cl2 (2ꢁ100 mL). The organic layer was dried
(Na2SO4), concentrated, and the residue crystallized from hexane to
afford a white powder (12.1 g, 95%); Rf (hexane/EtOAc 9:1) 0.3; mp
96e98 ꢀC; nmax 3455, 2935, 2857, 1605, 1508, 1449, 1203,
4.2.37. 1-Bromo-2,3,4-triisobutoxybenzene (7c). Prepared from 3c
(5.89 g, 20.0 mmol) following similar procedure as for 7a. Colorless
oil (6.94 g, 93%); Rf (hexane/CH2Cl2 85:15) 0.5; dH 1.03 (6H, d, J
6.8 Hz, 2Me), 1.04 (6H, d, J 6.8 Hz, 2Me), 1.06 (6H, d, J 6.8 Hz, 2Me),
2.07 (1H, tsept, J 6.5, 6.8 Hz, CH), 2.12 (1H, tsept, J 6.5, 6.8 Hz, CH),
2.13 (1H, tsept, J 6.5, 6.8 Hz, CH), 3.69 (2H, d, J 6.5 Hz, CH2), 3.76 (2H,
d, J 6.5 Hz, CH2), 3.81 (2H, d, J 6.5 Hz, CH2), 6.53 (1H, d, J 9.0 Hz), 7.15
(1H, d, J 9.0 Hz); dC 19.28, 19.31, 19.4, 28.4, 29.17, 29.20, 75.3, 80.22,
80.24, 108.5, 109.3, 126.5, 143.2, 150.6, 153.1; m/z (ESI) 273.1 (30,
MHþ); HRMS (ESI): MHþ, found 373.137. C18H3079BrO3 requires
373.138.
1168 cmꢂ1
; dH 1.19e1.37 (6H, m, 3CH2), 1.42e1.59 (6H, m, 3CH2),
1.70e1.83 (4H, m, 2CH2), 1.87e2.01 (4H, m, 2CH2), 3.94e4.04 (1H,
m, OCH), 4.13e4.23 (1H, m, OCH), 5.88 (1H, br s, OH), 6.29 (1H, dd, J
2.9, 8.5 Hz), 6.43 (1H, d, J 2.9 Hz), 6.77 (1H, d, J 8.5 Hz); dC 23.7, 24.0,
25.58, 25.63, 31.8, 32.2, 76.7, 79.4, 104.8, 107.0, 121.4, 141.7, 150.3,
151.4; m/z (ESI) 291.2 (100, MHþ); HRMS (ESI): MHþ, found 291.195.
C18H27O3 requires 291.196.
4.2.38. 1-Bromo-2,3,4-tricyclopentoxybenzene (7d). Prepared from
3d (6.61 g, 20.0 mmol) following similar procedure as for 7a. Col-
orless liquid (7.29 g, 89%); Rf (hexane/toluene 1:1) 0.7; nmax 2959,
4.2.33. 3,4-Dicyclohexyloxy-(2-cyclohexenyloxy)benzene
Prepared from 3,4-dicyclohexyloxyphenol (10.0 g, 34.4 mmol) fol-
lowing similar procedure as for 3e and stirring at rt for 2e3 days.
(5).
1463,1432,1289,1208 cmꢂ1
; dH 1.51e1.73 (10H, m, 5CH2),1.76e1.99

M. Stephan et al. / Tetrahedron 67 (2011) 6308e6315
6315
4. (a) Our results regarding attempts to prepare 1,2-di-tert-butoxybenzene will be
published as a separate full study as they are in disagreement with the reported
ones in Ref. 2c. Therein, also the preparation of 1b (48% yield) and 1e (42%
yield) has been reported using the corresponding alkyl bromides refluxing in
acetone for 8 days; (b) Preparation of 1,2-dineopentoxybenzene was achieved
using neopentyl tosylate (>2 equiv) and KOH under phase transfer catalysis in
HMPA. For this, see: Khanamiryan, A. K.; Bhardwaj, N.; Leznoff, C. C. J. Por-
phyrins Phthalocyanines 2000, 4, 484e490.
(14H, m, 7CH2), 4.67e4.74 (1H, m, OCH), 4.74e4.80 (1H, m, OCH),
5.02e5.08 (1H, m, OCH), 6.51 (1H, d, J 9.0 Hz), 7.14 (1H, d, J 9.0 Hz);
dC 23.6, 23.7, 24.0, 32.7, 32.8, 80.0, 84.8, 85.2, 109.2, 110.2, 126.3,
142.3, 149.7, 152.3; m/z (EI) 408 (10, Mþ); HRMS (EI): Mþ, found
408.131. C21H2979BrO3 requires 408.130.
5.
For other particular procedures for preparing o-(2-cyclohexyloxy)- or o-(2-
cyclohexenyloxy)phenol, see: (a) Melis, S.; Piras, P. P.; Plumitallo, A.; Sotgiu, F.
J. Heterocycl. Chem. 1983, 20, 1413e1414; (b) Tietze, L. F.; Lohmann, J. K.; Stadler,
C. Synlett 2004, 1113e1116.
6. (a) Wakefield, B. J. Organolithium Methods; Academic: London, 1990; (b) Clay-
den, J. Organolithiums: Selectivity for Synthesis; Elsevier Science Ltd: Oxford,
2002.
7. For effects of MeO groups on benzene metallation, see: (a) Maggi, R.; Schlosser,
M. Tetrahedron Lett. 1999, 40, 8797e8800; (b) The low-yield direct o-lithiation
of (isopropylidenedioxy)benzene was not successful in our hands as described
in the literature. For the latter, see: Huang, D.-S.; Ting, S.-H. J. Chem. Res., Synop.
1994, 12, 500e501.
8. The radical halogenation of 1,2-dialkoxy-arenes leads to the corresponding 4-
halo derivatives. For an example, see: James, C. A.; Snieckus, V. J. Org. Chem.
2009, 74, 4080e4093.
4.2.39. 1-Bromo-2,3,4-tricyclohexyloxybenzene (7f). Prepared from
3f (7.45 g, 20.0 mmol) following similar procedure as for 7a. Col-
orless oil (8.03 g, 89%); Rf (hexane/EtOAc 95:5) 0.6; nmax 2932, 2856,
1462,1449,1434,1206 cmꢂ1
; dH 1.16e1.65 (m,18H; 9CH2),1.71e1.87
(6H, m, 3CH2), 1.90e2.06 (6H, m, 3CH2), 4.05e4.15 (1H, m, OCH),
4.15e4.25 (1H, m, OCH), 4.31e4.42 (1H, m, OCH), 6.53 (1H, d, J
9.3 Hz), 7.13 (1H, d, J 9.3 Hz); dC 23.8, 24.3, 24.4, 25.56, 25.62, 31.8,
32.67, 32.7, 76.2, 81.1, 81.4,109.4, 110.7,126.2,142.5, 149.6,151.9; m/z
(EI) 450 (45, Mþ); HRMS (EI): Mþ, found 450.178. C24H3579BrO3
requires 450.177.
Acknowledgements
9. For ortho-bromination of phenols, see: Pearson, D. E.; Wysong, R. D.; Breder, C.
V. J. Org. Chem. 1967, 32, 2358e2360.
10. Interestingly, 2-bromo-6-trimethylsilylanisole was prepared by selective
transmetallation of 2,6-dibromophenol followed by reaction with TMSCl and
etherification with MeI. For this, see Ref. 3a (Supporting Information).
11. For a ketalization of catechols with acetone, see: Ivanov, A. V.; Svinareva, P. A.;
Tomilova, L. G.; Zefirov, N. S. Russ. Chem. Bull., Int. Ed. 2001, 50, 919e920.
12. For an example of bromineelithium exchange using 2e, see Ref. 3b.
13. Chaumeil, H.; Signorella, S.; Le Drian, C. Tetrahedron 2000, 56, 9655e9662 and
personal communication from the corresponding author.
14. Note, 1,3-diisopropoxybenzene could be prepared in >95% yield under stan-
dard Williamson etherification of resorcinol using i-PrI in acetone. For a study
of preparation of phloroglucinol linear ethers, see: Touchstone, J. C.; Ashmore,
J.; Huffan, M. N. J. Am. Chem. Soc. 1956, 78, 5643e5645.
15. Yang, J.; Weng, L.; Zheng, H. Synth. Commun. 2006, 2401e2405.
16. This reagent can be prepared as described in: Ponomarev, N. E.; Stambirskii, M.
V.; Dvorko, G. F.; Bazil’chuk, A. V. Russ. J. Org. Chem. 2004, 40, 489e496.
17. (a) Bungard, C. J.; Morris, J. C. Synthesis 2001, 5, 741e744; (b) Ishizaki, M.; Ozaki,
K.; Kanematsu, A.; Isoda, T.; Hoshino, O. J. Org. Chem. 1993, 58, 3877e3885; (c)
Kissau, L.; Stahl, P.; Mazitschek, R.; Giannis, A.; Waldmann, H. J. Med. Chem.
2003, 46, 2917e2931.
18. Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1980, 102, 3056e3062.
19. (a) Pansare, S. V.; Ravi, R. G. Synlett 1994, 823e824; (b) Barbasiewicz, M.;
Szadkowska, A.; Makal, A.; Jarzembska, K.; Wozniak, K.; Grela, K. Chem.dEur. J.
2008, 14, 9330e9337 (we used acetone instead of MeCN for the preparation of
2-isopropoxynaphthalene).
This work was supported by the Ministry of Higher Education,
Science, and Technology of the Republic of Slovenia (Grant No. P1-
242) and by EN-FIST Centre of Excellence, Dunajska 156, SI-1000
ꢀ
Ljubljana, Slovenia. E. Jeretin, A. Vizintin, and M. Brvar are ac-
knowledged for their partial assistance with this work.
References and notes
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K. J. Org. Chem. 2007, 77, 8308e8318.
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2261e2272; (c) For an example of preparation of some 1,2-dialkoxy- and 1,2,3-
trialkoxy-benzenes, see: Horner, L.; Simons, G. Phosphorus and Sulfur 1983, 14,
189e209.
ꢀ ꢀ
3. (a) Zupancic, B.; Mohar, B.; Stephan, M. Adv. Synth. Catal. 2008, 350,
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2024e2032; (b) Zupancic, B.; Mohar, B.; Stephan, M. Tetrahedron Lett. 2009, 50,
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