Rearrangement of allyl aryl ethers; Part V:1 Reaction of 2,5-dialkoxyhydroquinone with cycloalkanediols

Article abstract of DOI:10.1055/s-2002-35986

Benzo[1,4]dioxines 5 and 6 were prepared in a one pot reaction from 2,5-dialkoxy-hydroquinone 1 and cycloalkane-1,2-diol 2. Acid-catalyzed reaction of 1 and 2 yielded a mixture of cycloalkanobenzofuran 11 and spiro compound 12. The mechanisms of these novel reactions are also discussed.

Full text of DOI:10.1055/s-2002-35986

PAPER
2711
Rearrangement of Allyl Aryl Ethers; Part V:1 Reaction of 2,5-Dialkoxyhydro-
quinone with Cycloalkanediols
R
eaction of 2,5-D
i
l
alkoxyh
i
ydroq
v
uinone with C
é
ycloalkane
r
diols Orovecz,a Péter Kovács,b Pál Kolonits,a László Párkányi,b Éva Szabó,c Lajos Novák*a
a
Institute for Organic Chemistry, Budapest University of Technology and Economics, 1111 Budapest, Gellért tér 4, Hungary
Fax +36(1)4633297; E-mail: lnovak@mail.bme.hu
b
c
Central Research Institute of Chemistry, 1525, Budapest, P.O. Box 17, Hungary
EGIS Pharmaceuticals Ltd., 1475, Budapest 10, P.O. Box 100, Hungary
Received 19 September 2002
that one of the alkoxy groups of the starting hydroquinone
1 was eliminated during the reaction. Furthermore, in the
NMR spectrum of 5a, a multiplet at = 3.68 integrated for
two protons reflecting the annelation protons in the cy-
cloalkano[1,4]dioxine unit.
Abstract: Benzo[1,4]dioxines 5 and 6 were prepared in a one pot
reaction from 2,5-dialkoxy-hydroquinone 1 and cycloalkane-1,2-
diol 2. Acid-catalyzed reaction of 1 and 2 yielded a mixture of cy-
cloalkanobenzofuran 11 and spiro compound 12. The mechanisms
of these novel reactions are also discussed.
Key words: rearrangements, nucleophilic aromatic substitutions,
dioxines, furans, spiro compounds, ethers
The above reaction showed high stereospecificity. Name-
ly, reacting the cis-cycloalkane-1,2-diols 2a,c with com-
pounds 1 we got the cis-fused compounds 6. Similarly, the
reaction of trans-cycloalkane-1,2-diols 2b,d with com-
pounds 1 afforded the trans-fused dioxines 5. Besides the
main product, dihydroxy compounds 5b,e and 6b,e were
also isolated. The latter compounds were apparently
formed by the cleavage of an alkoxy group of the major
product, during these forcing conditions.
Recently we have investigated the acid-catalyzed reaction
of trimethylhydroquinone with cycloalkane-1,2-diols.
These one-pot reactions afforded cycloalkanobenzofurans
and/or spiro compounds.1 To explore the scope and gen-
erality of these new reactions we have examined the reac-
tion of 2,6-dialkoxyhydroquinones with cycloalkane-1,2-
diols and the results are reported in the present paper.
Since spectral data did not provide a final distinction be-
tween the stereostructure of 5 and 6 (the signals for 5a-H
as well as 9 or 10a-H in compounds 5d,e and 6d,e in the
1H NMR spectra appeared very closed to each other in the
range of = 3.7–4.2), crystals of 5c and 6b were submit-
ted for X-ray diffraction analysis. The ORTEP diagrams
of compounds 5c and 6b are shown in Figure 1, and pro-
vide irrevocable proof for their stereostructures.
The acid-catalyzed reactions between 2,5-dialkoxyhydro-
quinones 1 (Scheme 1) and cycloalkane-1,2-diols 2 were
rather slow and surprisingly afforded unexpected prod-
ucts. On the basis of IR, NMR, and mass spectral data,
benzo[1,4]dioxine structures 5,6 were assigned to these
new compounds. For instance, the NMR spectra showed
Scheme 1
Synthesis 2002, No. 18, Print: 19 12 2002.
Art Id.1437-210X,E;2002,0,18,2711,2716,ftx,en;P05202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2712
O. Orovecz et al.
PAPER
Figure 1 ORTEP-plot of molecular structures of 6b and 5c in the crystals (the crystallographic numbering does not reflect the systematic
numbering)
A plausible scheme for the formation of compounds 5 and lowed by 1,3-rearrangement afforded a 1:1 mixture of in-
6 is based on two consecutive aromatic nucleophilic sub- termediates 8 and 9, and then the former underwent acid-
stitutions. In the initial step the cycloalkane-1,2-diol 2, catalyzed intramolecular cyclization. (In some experi-
forms a bond with the substrate (probably with the conju- ments we could isolate and characterize intermediate 3.)
gated acid of 1), and the water or alcohol molecule de- Finally, aromatization of the product 10 resulted in the
parts. In this way intermediate 3 or 4 is obtained, which formation of cycloalkanobenzofuran 11 under forceful
then undergoes an intramolecular SNAr reaction to yield 5 conditions (40–80 h at the boiling point of toluene).
or 6.
The spiro compound 12 can also be derived from the in-
The proposed mechanism was clearly confirmed by our termediate 8. Acid-catalyzed elimination of the hydroxyl
result with an optically active diol. If the mechanism was group of the cycloalkane moiety with simultaneous ring
correct, in an optically active diol the chirality should be contraction followed by 1,2-H shift on the resulting cat-
preserved. Actually, the reaction between 1a and (1S)- ion, and cyclization yielded the minor product 12.
trans-cyclohexane-1,2-diol [(S,S)-2b] afforded (S,S)-
hexahydrodibenzo[1,4]dioxine [(S,S)-5a].
In summary, benzo[1,4]dioxine derivatives 5 and 6 are
prepared in one operation from 2,5-dialkoxyhydroquino-
Under similar conditions, the reaction between compound ne 1 and cycloalkane-1,2-diol 2. The new method is effi-
1 and cycloalkane-1,2-diol 2, with continuous separation cient in terms of ready availability of the starting material
of water formed, gave the expected cycloalkanobenzofu- and high stereospecificity. Beside the new synthesis we
ran 11 (Scheme 2) as the major product, along with the could extend our recently discovered reactions of hydro-
spiro compound 12, as a minor one. The reactions leading quinone derivative and diol 2, affording cycloalkano-
to the formation of 11 and 12 presumably proceed by a benzofuran and spiro compound, to 2,5-di-
similar mechanism to the one we suggested earlier,1–3 alkoxyhydroquinone 1, by continuous separation of water
namely, initial acid-catalyzed formation of ethers 3, fol- formed in the reaction. The mechanisms of these novel re-
Scheme 2
Synthesis 2002, No. 18, 2711–2716 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Reaction of 2,5-Dialkoxyhydroquinone with Cycloalkanediols
135.35 (C-4a), 136.67 (C-10a), 140.70 (C-2), 142.01 (C-3).
2713
actions are also discussed. The new compounds are of po-
tential biological interest.
MS: m/z (%) = 236 (M+, 90), 221 (M+ – CH3 , 25), 167 (18), 156
+
(28), 141 (32), 81 (C6H9 , 100).
Anal. Calcd for C13H16O4 (236.3): C, 66.08; H, 6.83. Found: C,
65.82; H, 6.80.
Solvents were used as received from commercial vendors and no
further attempts were made to purify or dry them. Mps were deter-
mined on a Büchi apparatus and are uncorrected. IR spectra were re-
corded on Zeiss Specord M 80 spectrophotometer. 1H and 13C NMR
spectra were obtained on a Bruker DRX-500 spectrometer. All
NMR spectra are reported in ppm relative to TMS. MS measure-
ments were carried out on a VG-TRIO-1000 GC/MS instrument.
Only selected peaks from the infrared and mass spectra are quoted.
Merck precoated silica gel 60 F254 plates were used for TLC and
Kieselgel 60 for column chromatography. Solvents were mixed on
a v/v basis.
2,5-Dimethoxyhydroquinone (1a),4,5 2,5-diethoxyhydroquinone
(1b),4,6 cis-cyclohexane-1,2-diol (2a),7 trans-cyclohexane-1,2-diol
(2b),8 cis-cycloheptane-1,2-diol (2c),9 trans-cycloheptane-1,2-diol
(2d),9 and (S)-trans-cyclohexane-1,2-diol10 were prepared by liter-
ature procedures.
(5aS, 9aS)-Enantiomer of 5a
This was prepared from 1a and (S)-trans-cyclohexane-1,2-diol fol-
lowing the general procedure, with a reaction time 16 h.
Yield: 55%; mp 175–176 °C; [ ]D20 – 124.8 (c 0.3, MeOH).
The spectral data of this compound matched in all aspects the data
of 5a reported above.
trans-5a,6,7,8,9,9a-Hexahydrodibenzo[1,4]dioxine-2,3-diol (5b)
IR (KBr): 3500, 3390, 1635, 1540, 1460, 1370, 1250, 1190 cm–1.
1H NMR (DMSO-d6): = 1.31 (2 H, m, CH2), 1.35 (2 H, m, CH2),
1.70 (2 H, br s, CH2), 2.04 (2 H, m, CH2), 3.57 (2 H, m, 2 CH), 6.24
(2 H, s, aromatic-H), 8.40 (2 H, s, 2 OH).
13C NMR (DMSO-d6): = 23.44 (C-7 and C-8), 29.85 (C-6 and C-
9), 76.08 (C-5a and C-9a), 104.15 (C-1 and C-4), 135.49 (C-4a and
C-10-a), 139.32 (C-2 and C-3).
Benzo[1,4]dioxine 5 and 6; General Procedure
To a stirred suspension of hydroquinone 1 (0.02 mol) and the appro-
priate cycloalkane-1,2-diol 2 (0.02 mol) in anhyd toluene (400 mL)
was added TsOH H2O (3.8 g; 0.02 mol) and the resulting mixture
was refluxed for the time indicated (Table 1). After cooling, the re-
action mixture was washed with H2O, dried (MgSO4) and the sol-
vent was evaporated in vacuo. The residue was subjected to column
chromatography (hexane–acetone, 5:2).
MS: m/z (%) = 222 (M+, 90), 153 (42), 142 (100), 113 (24), 81 (56).
Anal. Calcd for C12H14O4 (222.2): C, 64.85; H, 6.35. Found: C,
64.56; H, 6.70.
cis-3-Methoxy-5a,6,7,8,9,9a-hexahydrodibenzo[1,4]dioxin-2-ol
(6a)
IR (KBr): 3450, 1525, 1440, 1220, 1200, 1155 cm–1.
Table 1 Reaction of 2,5-Dialkoxyhydroquinone 1 with Cyclo-
alkanediols 2
1H NMR (CDCl3): = 1.41 (2 H, m, CH2), 1.66 (2 H, m, CH2), 1.68
(2 H, m, CH2), 1.92 (2 H, m, CH2), 3.80 (3 H, s, OCH3), 4.11 (2 H,
m, 2 CH), 4.90 (1 H, br s, OH), 6.43 (1 H, s, aromatic-H), 6.48 (1
H, s, aromatic-H).
Starting
Material Time (h)
Reaction
Product Yield
Mp
(ºC)
TLCa
(Rf)
(s)
(%)
13C NMR (CDCl3): = 21.38 (C-7), 21.57 (C-8), 27.78 (C-6), 27.98
(C-9), 56.47 (OCH3), 72.05 (C-5a), 72.15 (C-9a), 100.80 (C-4),
103.53 (C-1), 134.68 (C-4a), 135.77 (C-10a), 139.69 (C-2), 140.71
(C-3).
1a,2b
1a,2a
1a,2d
18
16
15
5a
and
5b
53
and
25
177–178
and
221–223
0.56
and
0.3
6a
and
6b
55
and
21
81–84
and
142–144
0.48
and
0.31
MS: m/z (%) = 236 (M+, 26), 221 (M+ – CH3, 10), 156 (18), 141
+
(22), 127 (20), 81 (C6H9 , 100).
Anal. Calcd for C13H16O4 (236.3): C, 66.08; H, 6.83. Found: C,
65.92; H, 6.94.
5d
and
5e
24
and
9
134–136
and
167–168
0.64
and
0.36
cis-5a,6,7,8,9,9a-Hexahydrodibenzo[1,4]dioxine-2,3-diol (6b)
IR (KBr): 3480, 3410, 1625, 1535, 1460, 1300, 1220, 1160 cm–1.
1a,2c
1b,2b
14
24
5d
22
96–97
0.36
1H NMR (DMSO-d6): = 1.36 (2 H, m, CH2), 1.53 (2 H, m, CH2),
1.56 (2 H, m, CH2), 1.72 (2 H, m, CH2), 4.08 (2 H, m, 2CH), 6.22
(2 H, s, aromatic-H), 8.34 (2 H, s, OH).
13C NMR (DMSO-d6): = 21.16 (C-7 and C-8), 27.50 (C-6 and C-
9), 71.31 (C-5a and C-9a), 104.29 (C-1 and C-4), 133.81 (C-4a and
C-10a), 139.20 (C-2 and C-3).
5c
and
5e
19
and
2
122
and
226–227
0.5
and
0.2
1b,2a
28
3c
and
6b
18
and
15
89–93
and
156–157
0.34
and
0.63
MS: m/z (%) = 222 (M+, 78), 179 (15), 153 (8), 142 (100), 112 (16),
81 (72).
a Hexane–acetone (5:2).
Anal. Calcd for C12H14O4 (222.2): C, 64.85; H, 6.35. Found: C,
64.61; H, 6.62.
trans-3-Methoxy-5a,6,7,8,9,9a-hexahydrodibenzo[1,4]dioxin-2-
ol (5a)
trans-3-Ethoxy-5a,6,7,8,9,9a-hexahydrodibenzo[1,4]dioxin-2-ol
IR (KBr): 3520, 1530, 1440, 1360, 1200, 1155 cm–1.
(5c)
IR (KBr): 3400, 1505, 1455, 1380, 1220, 1150 cm–1.
H NMR (CDCl3): = 1.35 (4 H, m, 2 CH2), 1.72 (2 H, m, CH2), 2.06
(2 H, m, CH2), 3.61 (2 H, m, 2 CH), 3.65 (3 H, s, OCH3), 6.29 (1 H,
s, aromatic-H), 6.46 (1 H, s, aromatic-H), 8.51 (1 H, s, OH).
13C NMR (CDCl3): = 23.41 (C-7 and C-8), 29.77 (C-6), 56.44
(CH3), 76.07 (C-5a), 76.18 (C-9a), 102.30 (C-4), 104.27 (C-1),
1H NMR (CDCl3) : = 1.38 (3 H, t, J = 7 Hz, CH3), 1.40 (4 H, m, 2
CH2), 1.82 (2 H, m, CH2), 2.17 (2 H, m, CH2), 3.64 (2 H, m, 2 CH),
3.99 (2 H, q, J = 7 Hz, CH2O), 5.35 (1 H, br s, OH), 6.43 (1 H, sm,
aromatic-H), 6.49 (1 H, s, aromatic-H).
Synthesis 2002, No. 18, 2711–2716 ISSN 0039-7881 © Thieme Stuttgart · New York

2714
O. Orovecz et al.
PAPER
13C NMR (CDCl3): = 14.92 (CH3), 23.85 (C-7 and C-8), 30.10 (C-
9), 30.15 (C-6), 65.10 (CH2O), 76.51 (C-9a), 76.54 (C-5a), 101.67
(C-1), 103.34 (C-4a), 136.22 (C-10a), 137.39 (C-4a), 139.89 (C-3),
140.05 (C-4a).
Anal. Calcd for C14H18O4 (250.3): C, 67.18; H, 7.25. Found: C,
66.89; H, 7.50.
Benzofurans 11 and Spiro[benzofuran-2(3H),1 -cycloalkanes]
12; General Procedure
+
MS: m/z (%) = 250 (M+, 36), 221 (20), 141 (22), 81 (C6H9 , 100).
To a stirred suspension of dialkoxyhydroquinone 1 (0.02 mol) and
the corresponding cycloalkanediol 2 (0.02 mol) in anhyd toluene
(400 mL) was added TsOH H2O (3.8 g, 0.02 mol) and the resultant
mixture was refluxed with continuous separation of water for the
time indicated (Table 2). After cooling the reaction mixture was
washed with water and then dried (MgSO4). Evaporation of the sol-
vent in vacuo gave an oily mixture of compounds 11 and 12 which
was separated by column chromatography. The eluents used are
listed in Table 2.
Anal. Calcd for C14H18O4 (250.3): C, 67.18; H, 7.25. Found: C,
66.87; H, 7.40.
Benzoate of 5c
This compound was prepared by standard procedure.
Yield: 75%; mp 130–132 °C; TLC Rf 0.5 (hexane–acetone, 5:2).
1H NMR (CDCl3): = 1.25 (3 H, t, J = 7 Hz, CH3), 1.42 (4 H, m,
CH2), 1.84 (2 H, m, CH2), 2.22 (2 H, m, CH2), 3.72 (2 H, m, 2 CH),
3.95 (2 H, q, J = 7Hz, OCH2), 6.56 (1 H, s, aromatic-H), 6.71 (1 H,
s, aromatic-H), 7.49 (2 H, t, J = 7.6 Hz, aromatic-H), 7.61 (1 H, t,
J = 7.5 Hz, aromatic-H), 8.19 (2 H, d, J = 7.6 Hz, aromatic-H).
13C NMR (CDCl3): = 14.81 (CH3), 23.81 (C-7 and C-8), 30.05 (C-
6), 30.10 (C-9), 65.25 (CH2O), 76.40 (C-5a), 76.77 (C-9a), 103.46
(C-1), 111.44 (C-4), 128.45 (C-3 and C-5 ), 129.68 (C-1 ), 130.22
(C-2 and C-6 ), 133.29 (C-4 ), 133.96 (C-4a), 137.15 (C-10a),
141.59 (C-2), 144.84 (C-3), 165.07 (CO).
5-Hydroxy-6-methoxyspiro[benzofuran-2(3H),1 -cyclopen-
tane] (12a)
IR (KBr): 3410, 1510, 1455, 1360, 1250, 1200, 1160 cm–1.
1H NMR (CDCl3): = 1.70 (2 H, m, CH2), 1.72 (2 H, m, CH2), 1.86
(2 H, m, CH2), 2.07 (2 H, m, CH2), 3.08 (2 H, s, CH2), 3.82 (3 H, s,
OCH3), 5.15 (1 H, br s, OH), 6.37 (1 H, s, aromatic-H), 6.72 (1H, s,
aromatic-H).
13C NMR (CDCl3): = 23.80 (C-2 and C-3 ), 39.33 (C-1 and C-4 ),
40.15 (C-3), 56.17 (OCH3), 94.15 (C-7), 97.34 (C-2), 110.63 (C-4),
118.13 (C-3a), 139.20 (C-5), 145.98 (C-6), 152.26 (C-7a).
trans-3-Methoxy-6,7,8,9,10,10a-hexahydro-5aH-5,11-dioxacy-
clohepta[b]naphthalen-2-ol (5d)
IR (KBr): 3520, 1525, 1450, 1380, 1250, 1200, 1160 cm–1.
Anal. Calcd for C13H16O3 (220.3): C, 70.89; H, 7.32. Found: C,
70.55; H, 7.58.
1H NMR (CDCl3): = 1.58 (2 H, m, CH2), 1.61 (2 H, m, CH2), 1.70
(2 H, m, CH2), 1.77 (2 H, m, CH2), 2.05 (2 H, m, CH2), 3.72 (2 H,
m, CH2), 3.79 (3 H, s, OCH3), 5.23 (1 H, br s, OH), 6.45 (1 H, s, ar-
omatic-H), 6.49 (1 H, s, aromatic-H).
Table 2 Reaction of 2,5-Dialkoxyhydroquinone 1 with Cyclo-
alkanediols 2 with Continuous Separation of Water
13C NMR (CDCl3): = 22.02 (C-7 and C-9), 27.12 (C-8), 30.17 (C-
6), 30.27 (C-10), 56.48 (CH3O), 79.26 (C-5a), 79.27 (C-10a),
100.47 (C-4), 103.23 (C-1), 136.37 (C-4a), 137.44 (C-11a), 139.68
(C-2), 140.71 (C-3).
Starting Reaction Product Yield Mp
TLC
(Rf)
Eluentd
Material Time (h) (s)
(%)
(ºC)
1a,2b
1a,2a
1a,2d
48
48
84
12a
3a
15
87–93
80–82
0.56a
0.34b
I
MS: m/z (%) = 250 (M+, 88), 235 (M+ 15, 12), 167 (32), 156 (52),
16
II
I
141 (68), 127 (42), 95 (C7H11+, 100).
12c
and
11c
22
and
9
55–62
and
oil
0.53a
and
Anal. Calcd for C14H18O4 (250.3): C, 67.18; H, 7.25. Found: C,
66.90; H, 7.43.
0.55a
trans-6,7,8,9,10,10a-Hexahydro-5aH-5,11-dioxacyclohep-
ta[b]naphthalene-2,3-diol (5e)
1a,2c
48
12c
and
11c
21
and
8
61–65
and
oil
0.5a
and
I
IR (KBr): 3480, 3400, 1600, 1535, 1460, 1240, 1170 cm–1.
0.53a
1H NMR (DMSO-d6): = 1.52 (4 H, m, 2 CH2), 1.61 (2 H, m, CH2),
1.64 (2 H, m, CH2), 1.92 (2 H, m, CH2), 3.63 (2 H, m, CH2), 6.23 (2
H, s, aromatic-H), 8.39 (2 H, s 2 OH).
13C NMR (DMSO-d6): = 21.57 (C-7 and C-9), 26.74 (C-8), 29.85
(C-6 and C-10), 78.74 (C-5a and C-10a), 103.94 (C-1 and C-4),
135.51 (C-4a and C-11a), 139.24 (C-2 and C-3).
1b,2a
1b,2d
42
39
3c
35
93–95
0.36b
II
12d
and
11d
17
and
7
87–88
and
0.57c
and
III
134–135 0.55c
1b,2c
41
12d
and
11d
19
and
7
91–93
and
0.55c
and
III
Anal. Calcd for C13H16O4 (236,3): C, 66.08: H, 6.83. Found: C,
65.82; H, 7.08.
128–130 0.58c
a Hexane–EtOAc (2:1).
b Hexane–acetone (5:2).
cis-3-Methoxy-6,7,8,9,10,10a-hexahydro-5aH-5,11-dioxacyclo-
hepta[b]naphthalen-2-ol (6d)
IR (KBr): 3450, 1525, 1455, 1370, 1240, 1200, 1160 cm–1.
c Toluene–hexane–EtOAc (12:4:1).
d I, hexane–EtOAc (4:1); II, hexane–acetone (5:1); III, toluene–hex-
ane–EtOAc (24:4:1).
1H NMR (CDCl3): = 1.48 (2 H, m, CH2), 1.60 (2 H, m, CH2), 1.77
(2 H, m, CH2), 1.79 (2 H, m, CH2), 1.98 (2 H, m, CH2), 3.79 (3 H,
s, OCH3), 4.20 (2 H, m, CH2), 5.25 (1 H, br s, OH), 6.43 (1 H, s,
aromatic-H), 6.47 (1 H, s, aromatic-H).
13C NMR (CDCl3): = 21.46 (C-7), 21.62 (C-9), 27.32 (C-8), 28.94
(C-6), 29.19 (C-10), 56.48 (OCH3), 75.31 (C-5a), 75.48 (C-10a),
100.72 (C-4), 103.45 (C-1), 135.31 (C-4a), 136.31 (C-11a), 139.64
(C-2), 140.64 (C-3).
cis-4-(2-Hydroxycyclohexyloxy)-2,5-dimethoxyphenol (3a)
IR (KBr): 3450, 1520, 1455, 1420, 1360, 1260, 1180, 1150 cm–1.
1H NMR (CDCl3): = 1.32 (1 H, m, CH2), 1.34 (1 H, m, CH2), 1.49
(1 H, m, CH2), 1.67 (1 H, m, CH2), 1.69 (1 H, m, CH2), 1.77 (1 H,
m, CH2), 1.89 (1 H, m, CH2), 1.99 (1 H, m, CH2), 2.80 (1 H, br s,
OH), 3.79 (1 H, m CHOH), 3.80 (3 H, s, OCH3), 3.83 (3 H, s,
MS: m/z (%) = 250 (M+, 32), 156 (38), 141 (30), 95 (68), 41 (100).
Synthesis 2002, No. 18, 2711–2716 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Reaction of 2,5-Dialkoxyhydroquinone with Cycloalkanediols
2715
OCH3), 3.92 (1 H, m, CHO), 5.50 (1 H, br s, OH), 6.59 (1 H, s, ar-
omatic-H), 6.64 (1 H, s, aromatic-H).
MS: m/z (%) = 246 (M+, 46), 217 (M+ – Et, 100), 189 (10), 115 (13),
91 (20), 69 (24).
13C NMR (CDCl3): = 20.80 (C-4 ), 22.69 (C-5 ), 27.45 (C-6 ),
30.24 (C-3 ), 56.52 (OCH3), 56.75 (OCH3), 67.88 (C-2 ), 83.84 (C-
1 ), 100.60 (C-6), 106.58 (C-3), 139.15 (C-4), 140.19 (C-2), 141.82
(C-1), 146.33 (C-5).
Anal. Calcd for C15H18O3 (246.3): C, 73.15; H, 7.37. Found: C,
72.92; H, 7.58.
5-Hydroxy-6-ethoxyspiro[benzofuran-2(3H),1 -cyclohexane]
(12d)
Anal. Calcd for C14H20O5 (268.3): C, 62.67; H, 7.51. Found: C,
62.52; H, 7.84.
IR (KBr): 3480, 1640, 1520, 1490, 1380, 1250, 1180 cm–1.
1H NMR (CDCl3): = 1.41 (3 H, t, J = 7Hz, CH3), 1.47 (4 H, m, 2
CH2), 1.65 (2 H, m, CH2), 1.75 (2 H, m, CH2), 1.78 (2 H, m, CH2),
2.88 (2 H, s, CH2), 4.00 (1 H, br s, OH), 4.04 (2 H, q, J = 7 Hz,
OCH2), 6.37 (1 H, s, aromatic-H), 6.71 (1 H, s, aromatic-H).
13C NMR (CDCl3): = 14.92 (CH3), 23.11 (C-2 and C-4 ), 25.23
(C-3 ), 37.11 (C-1 and C-5 ), 41.14 (C-3), 64.73 (OCH2), 88.76 (C-
2), 95.10 (C-7), 110.81 (C-4), 117.53 (C-3a),139.29 (C-5), 145.13
(C-6), 152.07 (C-7a).
cis-4-(2-Hydroxycyclohexyloxy)-2,5-diethoxyphenol (3c)
1H NMR (CDCl3): = 1.33 (1 H, m, CH2), 1.36 (1 H, m, CH2), 1.41
(3 H, t, J = 7 Hz, CH3), 1.42 (3 H, t, J = 7 Hz, CH3), 1.49 (1 H, m,
CH2), 1.66 (1 H, m, CH2), 1.69 (1 H, m, CH2), 1.77 (1 H, m, CH2),
1.88 (1 H, m, CH2), 2.00 (1 H, m, CH2), 3.18 (1 H, br s, OH), 3.78
(1 H, m, CH), 3.89 (1 H, m, CH), 4.00 (2 H, m, OCH2), 4.03 (2 H,
m, OCH2), 5.20 (1 H, br s, OH), 6.58 (1 H, s, aromatic-H), 6.63 (1
H, s, aromatic-H).
13C NMR (CDCl3): = 4.77 (CH3), 14.97 (CH3), 20.84 (C-4 ),
22.69 (C-5 ), 27.56 (C-6 ), 30.21 (C-3 ), 65.07 (OCH2), 65.43
(OCH2), 67.84 (C-2 ), 84.12 (C-1 ), 101.46 (C-6), 107.80 (C-3),
139.35 (C-4), 139.42 (C-2), 142.08 (C-1), 145.62 (C-5).
MS: m/z (%) = 248 (M+, 62), 167 (54), 139 (100).
Anal. Calcd for C15H20O3 (248.3): C, 72.55; H, 8.12. Found: C,
72.41; H, 7.96.
X-Ray Crystallographic Analysis of 5c and 6b
Anal. Calcd for C16H24O5 (296.4): C, 64.84; H, 8.16. Found: C,
64.55; H, 8.28.
The determination of the unit-cell parameters and intensity data col-
lections were performed on an Enraf-Nonius CAD4 diffractometer
using monochromated MoK (0.7107 Å, 5c) and CuK (1.5418 Å,
6b) radiation, /2 scans at 293 K. Both structures were solved by
direct methods (SHELXS97)11 and refined by anisotropic least-
squares (SHELXL97).12
2-Methoxy-6,7,8,9-tetrahydro-5H-10-oxabenzo[a]azulen-3-ol
(11c)
IR (KBr): 3490, 1600, 1510, 1480, 1450, 1360, 1190, 1180 cm–1.
1H NMR (CDCl3): = 1.76 (4 H, m, 2 CH2), 1.82 (2 H, m, CH2),
2.61 (2 H, m, CH2), 2.86 (2 H, m, CH2), 3.90 (3 H, s, OCH3), 4.85
(1 H, br s, OH), 6.89 (1 H, s aromatic-H), 6.92 (1 H, s, aromatic-H).
13C NMR (CDCl3): = 23.34 (C-5), 26.48 (C-8), 28.33 (C-6), 29.15
(C-9), 30.56 (C-7), 56.48 (OCH3), 94.37 (C-1), 102.56 (C-4),
115.75 (C-4b), 123.35 (C-4a), 142.11 (C-3), 144.13 (C-2), 147.15
(C-10a), 155.55 (C-9a).
Compound 5c
Formula C12H14O4, formula weight 222.23; monoclinic, P21/c,
Z = 4, a = 9.420(1) Å, b = 10.536(1) Å, c = 11.089(1) Å,
= 112.77(1)°, V = 1014.80(17) Å3 dcalc = 1.455 Mg/m3, unique re-
flections 4347 [2479 I > 2 (I)], number of parameters 148, final
R1 = 0.0405, R1(all data) = 0.0929, R2w = 0.1198.
Selected bond lengths (Å): C2–C3 1.388(1), C3–O4 1.387(1), C3–
C12 1.391(1), O4–C5 1.451(1), C5–C6 1.510(1), C5–C10 1.521(1),
C6–C7 1.526(1), C7–C8 1.521(1), C8–C9 1.523(2), C9–C10
1.522(1), C10–O11 1.443(1), O11–C12 1.371(1), C12–
C13;1.393(1).
Anal. Calcd for C14H16O3 (232.3): C, 72.39; H, 6.94. Found: C,
72.22; H, 7.13.
5-Hydroxy-6-methoxyspiro[benzofuran-2(3H),1 -cyclohexane]
(12c)
IR (KBr): 3450, 1510, 1455, 1360, 1200, 1170 cm–1.
Selected bond angles (°): C2–C3–C12 120.41(8), C3–O4–C5
112.44(6), O4–C5–C6 110.85(7), O4–C5–C10 110.19(7), C6–C5–
C10 112.71(7), C5–C6–C7 111.44(8), C8–C7–C6 111.36(8), C7–
C8–C9 111.54(8), C10–C9–C8 112.23(8), O11–C10–C5
110.19(7), O11–C10–C9 106.96(8), C5–C10–C9 111.10(8), C12–
O11–C10 115.29(7), O11–C12–C3 122.70(8), O11–C12–C13
118.11(7).
1H NMR (CDCl3): = 1.47 (4 H, m, 2 CH2), 1.67 (2 H, m, CH2),
1.77 (2 H, m, CH2), 1.80 (2 H, m, CH2), 2.81 (2 H, s, CH2), 3.82 (3
H, s, OCH3), 4.50 (1 H, br s, OH), 6.39 (1 H, s, aromatic-H), 6.71 (1
H, s, aromatic-H).
13C NMR (CDCl3): = 23.10 (C-2 and C-4 ), 25.22 (C-3 ), 37.11
(C-5 ), 41.14 (C-3), 56.16 (OCH3), 88.81 (C-2), 94.24 (C-7), 110.93
(C-4), 117.55 (C-3a), 139.09 (C-5), 145.99 (C-6), 152.15 (C-7a).
Hydrogen bonds: O1–H.O4[–x + 1, y – 1/2, –z + 1/2], O–H 0.90,
H.O 2.16, O.O 2.847(1) Å, O–H.O 132.9°; O2–H.O1 [x, –y+1/2, z–
1/2] O–H 0.90, H.O 2.04, O.O 2.940(1) Å, O–H.O 175.9°.
Anal. Calcd for C14H18O3 (234.3): C, 71.77; H, 7.74. Found: C,
71.51; H, 7.82.
Compound 6b
2-Ethoxy-6,7,8,9-tetrahydro-5H-10-oxabenzo[a]azulen-3-ol
(11d)
Formula C14H18O4, formula weight 250.28, rhombohedral, R–3,
a = 34.377(1) Å, c = 6.213(1) Å, V = 6358.7(11) Å3, T = 293(2) K,
Z = 18, dcalc = 1.176 Mg/m3, 2722 unique reflections [1797
I>2 (I)], 165 parameters, final R1 = 0.0750, R1(all data) = 0.0988,
R2w = 0.2514.
IR (KBr): 3450, 1480, 1460, 1380, 1280, 1150, 1140 cm–1.
1H NMR (CDCl3): = 1.46 (3 H, t, J = 7Hz, CH3), 1.78 (4 H, m, 2
CH2), 1.81 (2 H, m, CH2), 2.61 (2 H, m, CH2), 2.86 (2 H, m, CH2),
4.11 (2 H, q, J = 7 Hz, OCH2), 5.54 (1 H, br s, OH), 6.89 (1 H, s,
aromatic-H), 6.90 (1 H, s, aromatic-H).
13C NMR (CDCl3): = 14.86 (CH3), 23.33 (C-5), 26.48 (C-8),
28.33 (C-6), 29.15 (C-9), 30.56 (C-7), 65.13 (OCH2), 95.30 (C-1),
102.44 (C-4), 115.75 (C-4b), 123.33 (C-4a), 142.31 (C-3), 143.20
(C-2), 147.11 (C-10a), 155.50 (C-9a).
Selected bond lengths (Å): C2–C3,1.391(3), C3–O4 1.371(3), C3–
C12 1.375(3), O4–C5 1.413(3), C5–C6 1.492(4), C5–C10 1.426(5),
C6–C7 1.510(4), C7–C8 1.419(5), C8–C9,1.494(4), C9–C10
1.489(3), C10–O11,1.422(3), O11–C12 1.382(3), C12–
C13,1.388(3).
Selected bond angles (°): C2–C3–C12 119.6(2), C3–O4–C5
114.2(2), O4–C5–C10 116.8(3), C6–C5–C10 116.7(3), C5–C6–C7
Synthesis 2002, No. 18, 2711–2716 ISSN 0039-7881 © Thieme Stuttgart · New York

2716
O. Orovecz et al.
PAPER
111.9(2), C8–C7–C6 117.9(3), C7–C8–C9 116.0(3), C10–C9–C8
113.2(2), O11–C10–C5 113.9(3), O11–C10–C9 111.2(2), C5–
C10–C9 114.8(3), C12–O11–C10 113.8(2), O11–C12–C3
122.3(2), O11–C12–C3 122.3(2), O11–C12–C13 118.1(2).
References
(1) For Part IV, see: Novák, L.; Kovács, P.; Kolonits, P.;
Orovecz, O.; Fekete, J.; Szántay, C. Synthesis 2000, 809.
(2) Novák, L.; Kovács, P.; Pirok, G.; Kolonits, P.; Hanania, M.;
Donáth, K.; Szántay, C. Tetrahedron 1997, 53, 9789.
(3) Novák, L.; Kovács, P.; Kolonits, P.; Hanania, M.; Fekete, J.;
Szabó, E.; Szántay, C. Synthesis 1997, 909.
Hydrogen bond: O1–H.O11 [x – y, x, –z], O–H 0.92, H.O 1.97, O.O
2.813(2) Å, O–H.O 150.6°; O–H 0.92, H.O 2.28, O.O 2.703(2) Å,
O–H.O 107.5.
(4) Nietzki, R.; Rechberg, F. Chem. Ber. 1890, 23, 1216.
(5) Scholl, R.; Dahll, P. Chem. Ber. 1924, 57, 83.
(6) Knoevenagel, E.; Bückel, G. Chem. Ber. 1901, 34, 3993.
(7) Littler, J. S. Tetrahedron 1971, 27, 81.
(8) Carey, B. N.; Slayton, E. A. J. Org. Chem. 1981, 46, 3361.
(9) Oven, L. N.; Saharia, G. S. J. Chem. Soc. 1953, 2582.
(10) Kazlauskas, R. J.; Caron, G. J. Org. Chem. 1991, 56, 7251.
(11) Sheldrick, G. M. SHELXS-97 Program for Crystal Structure
Solution; University of Göttingen: Germany, 1997.
Acknowledgement
Generous support by the Hungarian OTKA Foundation (T 29014)
and NKFP programme contract 1/047 (Hungarian Ministry of Edu-
cation) is gratefully acknowledged.
(12) Sheldrick, G. M. SHELXL-97 Program for Crystal Structure
Refinement; University of Göttingen: Germany, 1997.
Synthesis 2002, No. 18, 2711–2716 ISSN 0039-7881 © Thieme Stuttgart · New York