Seven-membered ring formation through Grewe-cyclization

Article abstract of DOI:10.1016/S0040-4020(01)00497-5

The first example of seven-membered ring formation using Grewe-cyclization of cyclohexene derivatives (3b and c) yielding spiro-substituted benzo[c]azepines (9b and c) is presented.

Full text of DOI:10.1016/S0040-4020(01)00497-5

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 5843±5850
Seven-membered ring formation through Grewe-cyclization
a
Andras Lukacs, Lajos Szabo, Laszlo Hazai, Csaba Szantay, Jr., Marianna Mak, Almos Gorka
b
b
c
c
a
Â
Â
Â
Â
Â
Â
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and Csaba Szantay
Â
a,b,p
Â
a
 Â
Institute of Organic Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Gellert ter 4, Hungary
b
Â
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Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1111 Budapest, Gellert ter 4, Hungary
cSpectroscopic Research Division, Gedeon Richter Ltd., H-1475 Budapest 10, P.O. Box 27, Hungary
Received 15 February 2001; revised 17 April 2001; accepted 3 May 2001
AbstractÐThe ®rst example of seven-membered ring formation using Grewe-cyclization of cyclohexene derivatives 23b and c) yielding
spiro-substituted benzo[c]azepines 29b and c) is presented. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
encountered the problem of cyclizing compounds 4 into the
ring system 9 using Grewe's method.1
The acid-catalyzed cyclization of N-benzyloctahydroiso-
quinolines resulting in morphinan derivatives was ®rst
presented by Grewe.1,2 This type of ring closure reaction
has become known as the `Grewe-cyclization' and has
been widely used as a classical method in the synthesis of
opium alkaloids.3±7 The Grewe-cyclization was performed
under different acidic reaction conditions 2e.g. cc. phos-
phoric acid, cc. sulphuric acid and their mixture, 48%
hydrobromic acid, NH4F´HF in tri¯ic acid) and as a result
six-membered ring closure occurred. A seven-membered
ring-closure under the conditions of the Grewe-cyclization
was attempted only in one case, but failed.8 In the course of
our work aimed at synthesizing some natural products, we
2. Results and discussion
The starting materials were prepared as follows. Condensa-
tion of 4-methoxy-phenethylamine with 3-hydroxy-4-
methoxybenzaldehyde, followed by reduction by sodium
borohydride of the formed imine, gave amine 1a. Methyl-
ation of 1a to 1c was carried out with formylation and
subsequent reduction of the intermediate N-formyl
compound 1b with lithium aluminium hydride. Alterna-
tively, 1c was prepared by allowing 1a to react with
formaldehyde and sodium borohydride.9
Scheme 1.
Keywords: reduction; rearrangement; cyclization; benzazepines.
Corresponding author. Tel.: 136-1-463-1195; fax: 136-1-463-3297; e-mail: szantay.szk@chem.bme.hu
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00497-5

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5844
Birch reduction of amines 1a and 1c was performed with
lithium metal in liquid ammonia in the presence of t-butanol
as the proton source. The reaction gave enolethers 2a and 2c
and the unexpected derivatives 3a and 3c, respectively
2Scheme 1). The overreduction of p-substituted anisole to
a cyclohexene derivative has precedent in the literature.10
Enolether 2a and cyclohexene 3a were conveniently sepa-
rated by column chromatography as N-formyl derivatives
22b and 3b) prepared by formylation with phenyl formate.
Birch reduction of the N-methyl tertiary amine 1c gave
similar results. After demethylation of enol ether 2c by
treatment with aqueous formic acid, ketone 4a and the
cyclohexene derivative 3c were isolated by column chroma-
tography. Similarly, the N-formyl enolether 2b was trans-
formed into ketone 4b.
The next step should have been the acidic cyclization of
ketones 4 under the conditions of the Grewe-cyclization.
We were, however, unsuccessful in that respect although
several acidic systems mentioned above were investigated.
Instead of ring closure, the double bond moved to the
thermodynamically more stable conjugated position, form-
ing compound 5. Rice4 encountered a similar problem
during his synthesis of morphine. His solution to the
problem was the application of a `super-acid' system
2tri¯uoromethanesulfonic acid1ammonium ¯uoride). In
Scheme 2.

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5845
such a system the carbonyl oxygen is assumed to be highly
protonated, thus eliminating the thermodynamic driving
force towards formation of the conjugated system. Unfortu-
nately, in our case the above system did not work: either the
starting material was recovered or the conjugated ketones 5a
and b were obtained. Further on we tried to mask the keto
group by using standard procedures in order to prepare
several derivatives such as oxime 4c, hydroxy derivatives
6a and b, ketals 7a and b and dithioketal 7c. In order to
prevent the isomerization of the b,g-double bond, ketone 4b
was allowed to react with 1,2-ethanedithiol in the presence
of borontri¯uoride etherate11 to give dithiolane 7c in good
yield. Because of the poor solubility of compound 7c in the
mixture of cc. sulphuric acid and cc. phosphoric acid, it was
transformed with aqueous sodium hydroxide into the amino
compound 7d. Under acidic conditions, however, 7d
became deprotected, and subsequently isomerized to 5a
which, after basi®cation, cyclized to 812 isolated as crystal-
line hydrobromide salt.
recorded on a Bruker DRX 500 2compounds 1a±c) and a
Varian INOVA 300 spectrometer 2all other compounds).
Mass spectrometric measurements were performed on a
VG-Trio-2 2EI 70 eV) spectrometer. High-resolution MS
measurements were performed on a Finnigan MAT 95SQ
hybrid tandem mass spectrometer. TLC was carried out
using Kieselgel 60 F254 2Merck) plates.
3.1.1. 2-Methoxy-5-{[2--4-methoxy-phenyl)-ethylamino]-
methyl}-phenol -1a). To a solution of isovanillin 210.00 g,
66 mmol) in dry ethanol 2330 ml), 4-methoxyphenethyl-
Ê
amine 210 g, 66 mmol) and 4 A molecular sieves 262 g)
were added. After stirring overnight the molecular sieves
were ®ltered and washed with dry methanol 2330 ml).
Sodium borohydride 25 g, 132.2 mmol) was added to the
®ltrate at 08C in 6±8 portions, then the reaction mixture
was stirred for 3 h at room temperature. The solvent was
removed in vacuo, the residue was suspended in saturated
NaCl solution 2410 ml), adjusted to pH 8 with 5% aq. HCl
solution 2ca. 80 ml) and was extracted with ethyl acetate
23£200 ml). The combined organic extracts were washed
with 5% aq. HCl solution 22£200 ml) and the combined
acidic extracts were made alkaline 2pH 8) with 40%
2120 ml) and then with 15% 250 ml) aq. NaOH solutions.
After extraction with dichloromethane 24£100 ml), the
combined organic phase was dried over MgSO4, concen-
trated in vacuo giving 1a 216.9 g, 89%) as a white solid,
mp 83±848C 2ethyl acetate). TLC 2dichloromethane±
methanol 10:1) Rf 0.4; IR 2KBr) 3420, 3285, 1605±
1585 cm21 1H NMR 2CDCl3, dTMSˆ0.00 ppm): 2.78 22H,
m, ±CH2CH2N±); 2.85 22H, m, ±CH2CH2N±); 3.7122H, s,
±NCH2Ph); 3.76 23H, s, OCH3); 3.80 23H, s, OCH3); 4.65
22H, broad, OH1NH); 6.74 22H, m, Ar-H-3,4) and 6.86
21H, m, Ar-H-6); 6.79 22H, dm) and 7.07 22H, dm)
2H-o,o0-PhOMe, H-m,m0-PhOMe). MS m/z 2%): 288 20.1,
MH1), 287 2M1), 166 243.0), 137 2100.0), 121 219.0), 94
215.0), 77 212.0), 65 27.0). Anal. Calcd for C17H21NO3
2287.36): C, 71.06; H, 7.37; N, 4.87. Found C, 71.00; H,
7.51; N 5.03.
Subsequently, we investigated the behavior of the amino
compound 6c under similar conditions. The amino
compound 6c was prepared from ketone 4b applying
reductive amination.13,14 The puri®cation of 6c proved to
be dif®cult, therefore 6c was transformed into the diacetyl
derivative 6d by re¯uxing in acetic anhydride. Unfortu-
nately, neither the amine 6c nor its diacetyl derivative 6d
could be cyclized under the mentioned conditions. All these
failures can be rationalized by assuming that: 2a) the
strained seven-membered ring does not form under Grewe's
conditions 2excepting one failed attempt,8 we could not ®nd
any example of a similar reaction in the literature); 2b) the
isomerization of the double bond in ketone 4 is much faster
than the slow seven-membered ring formation, unlike in the
case of the faster six-membered ring formation.
To investigate the problem we repeated the reaction using
compounds 3 2Scheme 2). Performing Grewe-cyclization
both with N-formyl 23b) and N-methyl cyclohexenes 23c)
in the proven acidic system 2a 1:1 vol/vol mixture of cc.
phosphoric acid and cc. sulphuric acid) the ring closure
occurred and we could isolate the spiro-substituted benzo-
[c]azepines 9b 221%) and 9c 221.5%) in addition to the
tertiary alcohols 10b 237%) and 10c 216%). Alcohols 10b
and c were transformed into 9b 255%) and 9c 29.3%),
respectively, under the same conditions. Deformylation of
9b by re¯uxing under alkaline conditions yielded benzo-
[c]azepine 9a 240%).
3.1.2. 2-Methoxy-5--{[2--4-methoxy-phenyl)-ethyl]-methyl-
amino}-methyl)-phenol -1c). Method A. A solution of 1a
212.38 g, 43.14 mmol) in a mixture of formamide 2111 ml)
and formic acid 281ml) was re¯uxed for 2.5 h. The excess
formic acid was removed in reduced pressure and the solu-
tion was poured into ice-water 2300 ml). The precipitate was
®ltered, washed with water and dried in a vacuum desicca-
tor, yielding 12.6 g 293%) of N-formyl derivative 1b as a
crystalline substance, mp 100±1018C 2ethyl acetate). TLC
2dichloromethane±methanol 20:1) Rf 0.6; IR 2KBr) 3100,
1635, 1600 cm21; 1H NMR 2CDCl3, dTMSˆ0.00 ppm) 2a 1:1
mixture of formyl rotamers A and B): 2.71and 2.72 22H, t,
Jˆ7.0 Hz, ±CH2ACH2N±O±CH2BCH2N±); 3.32 and 3.40
22H, t, Jˆ7.0 Hz, ±CH2ACH2N±O±CH2CH2BN±); 3.77
23H, s, OCH3); 3.87 23H, s, OCH3); 4.12 and 4.44 22H, s,
±NCH2APh O±NCH2BPh); 5.93 21H, broad, OH); 6.60±
7.10 27H, m, ArH); 7.92 and 8.23 21H, s,
NCHOAONCHOB); MS m/z 2%) 315 22.0, M1), 181
248.0), 137 2100.0), 121 238.0), 94 211.0), 77 28.0), 65
27.0). Anal. Calcd for C18H21NO4 2315.37): C, 68.55; H,
6.71; N, 4.44. Found C, 68.80; H, 6.75; N, 4.75. To a
suspension of lithium aluminum hydride 25.86 g,
149 mmol) in diethyl ether 2120 ml) a solution of N-formyl
Thus we found the ®rst case of seven-membered ring forma-
tion using Grewe-cyclization. In the literature only a few
relatives of compound 9 are described with analgetic15 or
cholinesterase inhibition activity.16 Derivatives of benzo-
[c]azepine 9 could be a good precursor for the synthesis
of new derivatives with useful biological activity.
3. Experimental
3.1. General
Melting points are uncorrected. IR spectra were recorded on
ZEISS IR 75 and 80 instruments. H NMR spectra were
1

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5846
derivative 21b) 212 g, 38 mmol) in THF 2200 ml) was added
under argon at 2108C with stirring and was heated at 55±
608C oil-bath temperature for 2 h. The reaction mixture was
then decomposed by ethyl acetate 230 ml) and a saturated
solution of Seignette salt 2140 ml) with ice-cooling. After
decantation from solid precipitate the residue was washed
with ethyl acetate 2200 ml). The combined organic solutions
were dried over magnesium sulfate and after evaporation 1c
was obtained 211.2 g, 98%) as white crystals, mp 83±858C.
TLC 2dichloromethane±methanol 10:1) Rf 0.5; IR 2KBr)
2289.38): C, 70.56; H, 8.01; N, 4.84. Found: C, 70.54; H,
8.03; N, 4.86.
3.1.4. N--3-Hydroxy-4-methoxy-benzyl)-N-[2--4-methoxy-
cyclohexa-1,4-dien-1-yl)-ethyl]-formamide -2b) and N--2-
cyclohex-1-enyl-ethyl)-N--3-hydroxy-4-methoxy-benzyl)-
formamide -3b). Crude product of Birch reduction of 1a
23.945 g, ,13 mmol) in a solution of dry ethyl acetate
240 ml) was re¯uxed under Ar with phenyl formate 22.5 g,
20.5 mmol) for 45 min. Reaction mixture was then diluted
with ethyl acetate 230 ml), washed with 2.5% aq. sodium
hydroxide solution 22£40 ml), with water 240 ml) and with
saturated sodium chloride solution 240 ml). After drying
over magnesium sulfate, the solvent was evaporated in
vacuo and products were separated on silica gel by column
chromatography with slight pressure 2ca. 2 bar) using ethyl
acetate±hexane 21:1) yielding 2b 22.45 g, 63%) as white
crystals, mp 90±928C 2ethyl acetate±isopropyl ether 2:5)
and 3b 2289 mg, 8%) as a viscous oil. 2b: TLC 2ethyl
acetate±methanol 1:1) Rf 0.5; IR 2KBr) 3440, 1688, 1644,
3400, 1605, 1590 cm21
;
1H NMR 2CDCl3, dTMS
ˆ
0.00 ppm): 2.25 23H, s, NMe); 2.59 22H, m) and 2.76 22H,
m) 2±CH2CH2N±); 3.46 22H, s, ±NCH2-Ph); 3.77 23H, s,
C240)±OCH3); 3.86 23H, s, C22)±OCH3); 5.88 21H, broad,
OH); 6.75 22H, m H-3,4); 6.87 21H, m, H-6); 6.81 22H, dm)
and 7.09 22H, dm) 2H-o,o0-PhOMe, H-m,m0-PhOMe); MS
m/z 2%) 30120.1, M 1), 300 20.2), 180 258.0), 137 2100.0),
121 212.0), 94 211.0), 77 210.0), 65 27.0). Anal. Calcd for
C18H23NO3 2301.39): C, 71.73; H, 7.69; N, 4.65. Found C,
72.91; H, 7.65; N, 4.71.
1
1536 cm21; H NMR 2DMSO-D6, dTMSˆ0.00 ppm) 2a 1:1
Method B. Secondary amine 1a 2144 mg, 0.5 mmol) was
dissolved in acetonitrile 27 ml) under argon and cooled to
08C. To the solution acetic acid 22 ml) was added and stirred
for 5 min, then sodium borohydride 276 mg, 2 mmol) was
added and the mixture was stirred for 15 min at the above
temperature. The mixture was treated with formaldehyde
23 ml, 37% solution in water) and stirred for 30 min. The
mixture was diluted with water 210 ml) and the pH was
adjusted to 7±8 with saturated aqueous sodium carbonate,
then extracted with chloroform 23£30 ml). The organic
phase was washed with water 220 ml) and dried over
magnesium sulfate. The ®ltrate was evaporated under
reduced pressure to give 1c 2158 mg, 95%) as a crystalliz-
able oil identical with the compound obtained above.
mixture of formyl rotamers A and B): 2.07 and 2.13 22H,
t, Jˆ7.0 Hz, ±CH2ACH2N±O±CH2BCH2N±); 2.55±2.70
24H, m, H2-30,60); 3.15 and 3.20 22H, t, Jˆ7.0 Hz,
±CH2ACH2N±O±CH2BCH2N±); 3.45 and 3.46 23H, s,
C240)OCH3AOC240)OCH3B); 3.74 and 3.75 23H, s,
C24)OCH3AOC24)OCH3B); 4.28 and 4.3122H, s,
±NCH2APh O±NCH2BPh); 4.61and 4.62 2H1 , m, H
-
A
50OHB-50); 5.33 21H, m, H-20); 6.63±6.90 23H, m, ArH);
8.08 and 8.23 21H, s, NCHOAONCHOB); 8.93 and 9.00
21H, s, OHAOOHB); MS m/z 2%): 31721) M, 18122),
1372100), 123234), 9427). Anal. Calcd for C18H23NO4
2317.39): C, 68.11; H, 7.31; N, 4.41. Found C, 68.09; H,
7.31; N, 4.43. 3b: TLC 2ethyl acetate±hexane 1:1) Rf 0.55;
1
IR 2®lm) 3288, 1656, 1592, 1512 cm21; H NMR 2CDCl3,
dTMSˆ0.00 ppm) 2a 1:1 mixture of formyl rotamers A and
B): 1.47±2.13 210H, m, H2-30,40,50,60, ±CH2CH2N±); 3.18
and 3.29 22H, t, Jˆ7.0 Hz, ±CH2CH2AN±O±CH2CH2BN±
); 3.88 and 3.89 23H, s, OCH3AOOCH3B); 4.27 and 4.43
22H, s, ±NCH2APhONCH2BPh); 5.42 21H, m, H-20); 5.77
and 5.80 21H, broad, OHAOOHB); 6.66±6.83 23H, m, ArH);
8.11 and 8.22 21H, s, NCHOAONCHOB); MS m/z 2%):
28927) M, 27122), 181228), 1372100), 12229), 9427), 7926);
HRMS calcd 289.16779, found 289.16790.
3.1.3. Birch-reduction of secondary amine 1a. To a ¯ask
containing absolute THF 245 ml), absolute t-butanol 245 ml)
and liquid ammonia 2280 ml), lithium metal 22.66 g,
0.384 mol) was added portionwise at 2788C under argon.
After stirring for 10 min, compound 1a 24.88 g, 17 mmol)
was added in one portion then the reaction mixture was
stirred between 255 and 2608C for 4 h. The deep blue
color was discharged by addition of solid ammonium
chloride 241g, 0.75 mol) and after evaporation of the
greater part of ammonia the reaction mixture was poured
into saturated aqueous ammonium chloride solution
2200 ml). The separated oil was extracted with chloroform
22£100 ml) and the organic layer washed with water
22£50 ml). The combined organic phase was dried over
magnesium sulfate and after ®ltration the solvent was
evaporated in vacuo. From the crude product 23.5 g, 72%)
a pure sample of 2a was obtained after repeated recrystalli-
zations from ethyl acetate as a white solid, mp 928C. TLC
2dichloromethane±methanol 10:2) Rf 0.2; IR 2KBr) 3290,
3.1.5. Birch reduction of tertiary amine -1c). The reduc-
tion of amine 21c) 210.24 g, 34 mmol) was performed as in
the case of 1a. Crude product of 2c 210.41 g) as a viscous oil
obtained. IR 2KBr) 3400, 1695, 1670, 1590 cm21; 1H NMR
2CDCl3, dTMSˆ0.00 ppm): 2.22 23H, s, NCH3); 2.22 22H, t,
Jˆ7.0 Hz, ±CH2CH2N±); 2.50 22H, t, Jˆ7.0 Hz,
±CH2CH2N±); 2.72 24H, m, H2-30,60); 3.44 22H, s,
±NCH2Ph); 3.54 23H, s, C240)±OCH3); 3.88 23H, s, C22)±
OCH3); 4.6121H, m, H-5 0); 5.40 21H, m, H-20); 6.77±6.81
22H, m, H-3,4); 6.90 21H, m, H-6); MS m/z 2%): 30421)
[M1H], 180293), 1372100), 122217), 94214). HRMS calcd
304.19127 2MH1), found 304.19133.
1695, 1670, 1590 cm21
;
1H NMR 2CDCl3, dTMS
ˆ
0.00 ppm): 2.2122H, t, Jˆ7.0 Hz, ±CH2CH2N±); 2.71
22H, t, Jˆ7.0 Hz, ±CH2CH2N±); 2.7124H, m, H -30,60);
2
3.30 21H, broad, NH); 3.54 23H, s, C240)±OCH3); 3.69 2s,
2H, ±NCH2Ph); 3.86 23H, s, C22)±OCH3); 4.60 21H, m, H-
50); 5.42 21H, m, H-20); 6.74±6.8122H, m, H-3,4); 6.86 21H,
m, H-6); MS m/z 2%): 28921) M, 27424), 166226), 1372100),
122211), 12029), 94217), 77212). Anal. Calcd for C17H23NO3
3.1.6. 4-{2-[-3-Hydroxy-4-methoxy-benzyl)-methyl-amino]-
ethyl}-cyclohex-3-enone -4a) and 5-{[-2-cyclohex-1-enyl-
ethyl)-methyl-amino]-methyl}-2-methoxy-phenol -3c).
The crude product of the Birch reduction of 1c 24.95 g,
,14 mmol) was stirred at room temperature in a mixture

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5847
of formic acid±water 5:1280 ml) for 1h. 10% aqueous
3400±3300 broad, 1590, 1505, 1430, 1270, 790, 750 cm21
;
sodium hydrogen carbonate 2150 ml) was then added and
the pH was adjusted to ,7.5 with addition of solid sodium
hydrogen carbonate. The alkaline mixture was extracted
with chloroform 23£50 ml), the combined organic phases
washed with water 230 ml), dried over magnesium sulfate
and evaporated to dryness. After column chromatography of
the residual oil on silica gel 2benzene±methanol 14:3) with
slight pressure 2ca. 2 bar), ketone 4a 23.05 g, 74%) and
cyclohexene 3c 2423 mg, 11%) were separated as oily
substances. 4a: TLC 2benzene±methanol 14:3) Rf 0.4; IR
2®lm) 3350, 1715, 1690, 1600 cm21; MS m/z 2%): 289212)
M, 180236), 1372100), 122211), 9427). Ketone 4a was used
without any further puri®cation for the next reaction steps.
3c: TLC 2benzene±methanol 14:3) Rf 0.5; IR 2®lm) 2928,
1H NMR 2CDCl3, dTMSˆ0.00 ppm) 2a 4:1mixture of oxime
isomers); major isomer: 2.13±2.24 24H, m, H2-50,60); 2.21
23H, s, NCH3); 2.39 22H, t, Jˆ7.0 Hz, ±CH2CH2N±); 2.46
22H, m, ±CH2CH2N±); 3.06 22H, m, H2-30); 3.43 22H, s,
±NCH2Ph); 3.87 23H, s, OCH3); 5.38 21H, m, H2-20), 6.75±
6.90 23H, m, ArH); MS m/z 2%): 30426) M, 180288),
1372100), 122221), 94237); HRMS calcd 304.17869, found
304.17860.
3.1.9. N--3-Hydroxy-4-methoxy-benzyl)-N-[2--4-oxo-cyclo-
hex-2-enyl)-ethyl]-formamide -5b). In a hard polyethylene
vessel NH4F´HF 21.40 g, 25.9 mmol) was dissolved in
tri¯uoromethanesulphonic acid 25 ml, 8.61g, 57.3 mmol)
under external ice-water cooling and stirring, then enolether
2b 20.41g, 1.30 mmol) was added to the super-acidic
mixture; stirring was continued at the same temperature
for 48 h. Thereafter the reaction mixture was poured into
concentrated ammonium hydroxide 220 ml) containing ice-
water and extracted at pHˆ8.5 with chloroform 23£20 ml).
The combined organic extracts were dried 2magnesium
sulfate), ®ltered and evaporated to dryness under reduced
pressure. The residue 20.32 g) was puri®ed by preparative
;
1620, 1592, 1410, 1270 cm21 1H NMR 2CDCl3,
dTMSˆ0.00 ppm): 1.49±1.67 24H, m, H2-40,50); 1.87±2.02
24H, m, H2-30,60); 2.15 22H, m, ±CH2CH2N±); 2.20 23H, s,
NCH3); 2.46 22H, m, ±CH2CH2N±); 3.42 22H, s,
±NCH2Ph); 3.87 23H, s, OCH3); 5.4121H, m, H-2 0); 6.78
22H, m, H-3,4); 6.89 21H, s, H-6); MS m/z 2%): 27522) M,
180242), 1372100), 12229), 94211); HRMS calcd 275.18852,
found 275.18865.
layer chromatography 2Kieselgel PF2541366
, dichloro-
3.1.7. N--3-Hydroxy-4-methoxy-benzyl)-N-[2--4-oxocyclo-
hex-1-enyl)-ethyl]-formamide -4b). The solution of
enolether 2b 23.26 g, 10.35 mmol) in a mixture of formic
acid 222.0 ml) and water 24.4 ml) was allowed to stand at
room temperature. When the hydrolysis was complete the
reaction mixture was poured into 10% aqueous sodium
hydrocarbonate solution 2100 ml). Under external ice-
water cooling the pH was adjusted to 8 with concentrated
ammonium hydroxide and extracted with chloroform
23x30 ml). After drying over magnesium sulfate, ®ltering
and evaporation in vacuo, the residual oil 23.30 g) was puri-
methane±methanol 20:2). From the least polar layer
120 mg 230.5%) of the title compound was isolated as a
crystalline substance, mp 100±1028C 2ethylacetate). IR
1
2KBr) 3384 2OH), 1680 2COconj.), 1664 2NCHO) cm21; H
NMR 2CDCl3, dTMSˆ0.00 ppm) 2a 2:1mixture of formyl
rotamers A and B): 1.48±2.52 27H, m, ±CH2CH2N,50,60
and H-10); 3.25 and 3.34 22H, m, H2A±CH2CH2AN±O±
CH2CH2BN±); 3.90 and 3.88 23H, s, OCH3AOOCH3B);
4.31s and 4.44
d
14.50
d
22H, ±NCH2A-
PhONCHxBPh1NCHyBPh); 5.82 21H, d, Jˆ11.7 Hz,
H-30); 5.98 21H, m, H-20); 6.66±6.85 23H, m, ArH);
8.28 and 8.2121H, s, NCHO AONCHOB); MS m/z 2%):
30321) M, 28621), 24522), 18225), 14323), 1372100),
122293), 94214); HRMS calcd 303.14706, found
303.14726.
®ed with ¯ash-chromatography 270.0 g of Kieselgel-PF254
,
elution with 400 ml of ethylacetate) to give the title
compound 22.49 g, 79%) as a crystalline product, mp 50±
528C. IR 2KBr) 3312 2OH), 1712 2CO), 1692 2NCHO) 1652
1
2CvC) cm21; H NMR 2CDCl3, dTMSˆ0.00 ppm) 2a 3:2
mixture of formyl rotamers A and B): 2.20±2.50 26H, m,
±CH2CH2N±,50,60); 2.80±2.86 22H, m, H2-30); 3.35 and
3.25 22H, t, Jˆ7.0 Hz, ±CH2CH2AN±O±CH2CH2BN±);
3.90 and 3.88 23H, s, OCH3AOOCH3B); 4.29 and 4.46
22H, s, ±NCH2APh O±NCH2BPh); 5.44 21H, m, H-20);
5.84 and 5.812H1 , s, OH AOOHB); 6.67±6.84 23H, m,
ArH); 8.25 and 8.15 21H, s, NCHOAONCHOB). MS m/z
2%): 30321) M, 28520.5), 18129), 1372100), 122227),
94213); HRMS calcd 303.14706, found 303.14721.
3.1.10. 5--{[2--4-Hydroxy-cyclohex-1-enyl)-ethyl]-methyl-
amino}-methyl)-2-methoxy-phenol -6a). N-Methyl-ketone
4a 22 g, 7 mmol) was dissolved in a mixture of dichloro-
methane 221ml) and methanol 221ml) and was treated with
sodium borohydride 20.53 g, 14 mmol) under ice-cooling.
After stirring at room temperature for 30 min, the reaction
was quenched by adding a few drops of acetic acid, and the
solvent was evaporated under reduced pressure. Water
230 ml) was added to the residue and the pH was adjusted
to 8 by adding 10% aqueous sodium hydrogencarbonate.
The aqueous phase was extracted with chloroform
230 ml), the organic layer was dried over magnesium sul-
fate, ®ltered and evaporated to dryness. After preparative
layer chromatographic separation on silica gel 2chloro-
form±methanol 7:2, Rf 0.2) 1.8 g 288%) of oily product 6a
was obtained. IR 2®lm) 3400 broad, 2920, 2840, 1585, 1505,
3.1.8. 4-{2-[-3-Hydroxy-4-methoxy-benzyl)-methyl-amino]-
ethyl}-cyclohex-3-enone oxime -4c). Ketone 4a 2294 mg,
1mmol) was dissolved in dry ethanol 23 ml), then hydroxyl-
amine hydrochloride 2141 mg, 2 mmol) was added in a solu-
tion of water 20.5 ml). After stirring for 1h at room
temperature, water 210 ml) was added and the pH was
adjusted to 8 by 10% saturated aqueous sodium hydrogen-
carbonate with ice cooling. After extraction with dichloro-
methane 23£10 ml) the organic phase was dried over
magnesium sulfate and the solvent was evaporated under
reduced pressure. After preparative layer chromatography
on silica gel 2chloroform±methanol 7:2, Rf 0.49) 276 mg
289%) of the product 24c) was obtained as an oil. IR 2®lm)
1435, 1275, 790, 750 cm21
;
1H NMR 2CDCl3, dTMS
ˆ
0.00 ppm) 2characteristic signals): 2.23 23H, s, NCH3);
2.47 22H, t, Jˆ7.0 Hz, ±CH2CH2N±); 3.47 22H, s,
±NCH2Ph); 3.88 23H, s, OCH3); 4.20 21H, s, H-40); 5.66
21H, m, H-20); 6.80 22H, m, H-3,4); 6.9121H, s, H-6); MS
m/z 2%): 29121) M, 180218), 1372100), 12228), 9429);
HRMS calcd 291.18344, found 291.16351.

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5848
3.1.11. N-[2--4-Hydroxy-cyclohex-1-enyl)-ethyl]-N--3-
hydroxy-4-methoxy-benzyl)-formamide -6b). N-Formyl-
ketone 24b) 21.55 g, 5 mmol) was reduced by sodium boro-
hydride 2377 mg, 10 mmol) in a mixture of dichloromethane
215 ml) and methanol 215 ml) as described above. Product
26b) 21.05 g, 69%) was obtained as an oil. TLC 2ethyl
acetate±methanol 10:1), Rf 0.5; IR 2KBr) 3400 broad,
CH3AONHCOCH3B); 2.31and 2.30 23H, s, OCOCH 3AOO-
COCH3B); 3.84 and 3.8123H, s, OCH 3AOOCH3B);
4.2514.39 and 4.3914.53 22H, d, Jˆ11.7 Hz,
±NCHxAPh1±NCHyAPh O±NCHxBPh1±NCHyBPh); 5.28
and 5.35 21H, m, HA-20OHB-20); 6.29 and 5.48 21H, broad
NHAONHB); 6.90±7.13 23H, m, ArH); 8.22 and 8.10 21H, s,
NCHOAONCHOB); MS m/z 2%): 38927) MH1, 32924),
23827), 22428), 20928), 179269), 1372100), 12227),
106241); HRMS calcd 389.20765 2MH1), found 389.20782.
1
1640, 1505, 1435, 1270, 795, 750 cm21; H NMR 2CDCl3,
dTMSˆ0.00 ppm) 2a ca. 4:3 mixture of formyl rotamers A
and B): 1.20±2.40 28H, m, ±CH2CH2N±,30,50,60); 3.16±
3.46 22H, m, ±CH2CH2N±); 3.89 and 3.88 23H, s,
OCH3AOOCH3B); 3.93 21H, m, H-40); 4.44 s and 4.24
d14.29 d 22H, ±NCH2BPh O±NCHxAPh1±NCHyAPh);
5.29 21H, m, H-20); 5.73 and 5.69 21H, s, OHAOOHB);
6.66±6.84 23H, m, ArH); 8.22 and 8.11 21H, s,
NCHOAONCHOB); MS m/z 2%): 30522) M, 28721),
181211), 1372100), 12226), 9426); HRMS calcd 305.16279,
found 305.16260.
3.1.14. 5--{[2--1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-ethyl]-
methyl-amino}-methyl)-2-methoxy-phenol -7a). Enol-
ether 22c) 21.165 g, 3.845 mmol) was dissolved in tetra-
hydrofuran 224 ml) and the pH was adjusted to 5 by
addition of methanesulfonic acid 20.34 ml). Ethylene glycol
20.715 g, 11.5 mmol) was then added. After allowing to
stand for 3 h at room temperature the reaction mixture
was made alkaline with cc. ammonium hydroxide and the
solvent was removed in vacuo. The residue was shared
between water 215 ml) and chloroform 230 ml), after separa-
tion the organic phase was extracted with chloroform
22£15 ml). The combined organic phase was dried over
magnesium sulfate, ®ltered and evaporated to dryness.
The product 27a) 2276 mg, 89%) was isolated by preparative
layer chromatography on silica gel 2benzene±methanol
14:5) as a viscous oil, Rf 0.5. IR 2®lm) 3400, 1590, 1510,
1440, 1270, 1230, 850, 795, 750 cm21; 1H NMR 2CDCl3) d
1.79 22H, t, Jˆ7.0 Hz, ±CH2CH2N±); 2.17±2.32 26H, m,
H2-30,50,60); 2.24 23H, s, NMe); 2.50 22H, t, Jˆ7.0 Hz,
CH2CH2N±); 3.44 22H, s, ±NCH2Ph); 3.90 23H, s, OMe);
4.0124H, s, ±OCH 2CH2O±); 5.35 21H, m, H-20); 6.76±6.84
22H, m, H-3,4); 6.94 21H, m, H-6); MS m/z 2%): 33320.3) M,
180248), 1372100), 12227), 9424); HRMS calcd 333.19401,
found 333.19422.
3.1.12. N--3-Hydroxy-4-methoxy-benzyl)-N-[2--4-amino-
cyclohex-1-enyl)-ethyl]-formamide -6c). A solution of
ketone 4b 21.00 g, 3.30 mmol), ammonium acetate
22.50 g, 31.9 mmol) and NaBH3CN 20.26 g, 4.14 mmol) in
30 ml of absolute methanol was stirred for 24 h at 258C.
Concentrated hydrochloric acid was added 2pH 2) and the
methanol was removed under reduced pressure. Water
220 ml) was added to the residue and the acidic solution
was extracted with dichloromethane 23£10 ml). The acidic
aqueous phase was basi®ed with concentrated ammonium
hydroxide, then with 10% aqueous sodium hydrogencarbo-
nate solution 2pH 9) and extracted with dichloromethane
24£20 ml). The combined organic extracts were dried
2magnesium sulfate), ®ltered and evaporated to dryness
under reduced pressure to give 0.65 g 264.8%) of the title
compound as a solid foam. IR 2KBr) 3440 2NH2, OH), 1664
1
2NCHO) cm21; H NMR 2CDCl3, dTMSˆ0.00 ppm) 2a ca.
3.1.15. N-{2--1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-ethyl}-
N--3-hydroxy-4-methoxy)-formamide -7b). Enolether 2b
21.0 g, 3.15 mmol) was dissolved in tetrahydrofuran 220 ml)
containing methanesulfonic acid 20.2 ml) and ethylene
glycol 20.59 g, 9.5 mmol) was added. The reaction mixture
was allowed to stand at room temperature for 1h, the pH
was made alkaline 2pHˆ8) with concentrated ammonium
hydroxide under cooling and evaporated. To the residue
water 220 ml) was added, after extraction with chloroform
22£20 ml) the combined organic phase was washed with
water, dried over magnesium sulfate, ®ltered and the solvent
was evaporated under reduced pressure. The residue was
puri®ed by column chromatography 2silicagel, eluent
dichloromethane±methanol 20:1) under slight pressure
2ca. 2 bar) and 901mg 291.5%) of title compound was
obtained as an oil. IR 2®lm) 3350, 1670, 1620, 1595,
1:1 mixture of formyl rotamers A and B): 1.32±3.20
212H, m, ±CH2CH2N±,30,50,60, NH2); 3.16±3.46 22H, m,
±CH2CH2N±); 3.32 21H, m, H-40); 3.89 and 3.88 23H, s,
OCH3AOOCH3B); 4.44 and 4.28 22H, s, ±NCH2APh O±
NCH2BPh); 5.32 21H, m, H-20); 6.65±6.84 23H, m, ArH);
8.22 and 8.11 21H, s, NCHOAONCHOB); MS m/z 2%):
304216) M, 181212), 1372100), 122211), 94210); HRMS
calcd 304.17869, found 304.17855.
3.1.13. N--3-Acetoxy-4-methoxy-benzyl)-N-[2--4-aceta-
mino-cyclohex-1-enyl)-ethyl]-formamide -6d). The solu-
tion of 6c amine 20.45 g, 1.16 mmol) in acetic anhydride
24.1ml) was re¯uxed at 140 8C for 20 min. After cooling,
water 28.2 ml) was added to the mixture and heated at 1408C
for 5 min to decompose the excess anhydride. Thereafter
under ice-water cooling the mixture was basi®ed with
concentrated ammonium hydroxide to pH 9 and extracted
with dichloromethane 23£20 ml). The combined organic
extracts were dried 2magnesium sulfate), ®ltered, evapo-
rated to dryness under reduced pressure and the residue
was puri®ed by preparative layer chromatography
2Kieselgel PF2541366, dichloromethane±methanol 20:2) to
give 133 mg 229.56%) of the title compound as a viscous
oil. IR 2KBr) 3320 2NH), 1768 2ester CO), 1664 2broad,
1
1505, 1280 cm21; H NMR 2CDCl3) 2a ca. 1:1 mixture of
formyl rotamers A and B): d 1.73±1.76 22H, m,
±CH2CH2N±); 2.12±2.24 26H, m, H2-30,50,60); 3.21and
3.30 22H, t, Jˆ7.0 Hz, ±CH2CH2AN±O±CH2CH2BN±);
3.88 and 3.89 23H, s, OCH3AOOCH3B); 3.97 24H, s,
±OCH2CH2O±); 4.28 and 4.44 22H, s, ±NCH2APh O±
NCH2BPh); 5.31and 5.33 2H1 , m, H A-20OHB-20); 5.78
and 5.82 21H, s, OHAOOHB); 6.67±6.82 23H, m, ArH);
8.13 and 8.22 21H, s, NCHOAONCHOB); MS m/z 2%):
347226) M, 24528), 216212), 181212), 166265), 1372100),
122221), 86227); HRMS calcd 347.17327, found
347.17320.
NCHO and amide CO) cm21
;
1H NMR 2CDCl3,
dTMSˆ0.00 ppm) 2a ca. 2:1mixture of rotamers A and B);
characteristic signals: 2.02 and 1.95 23H, s, NHCO-

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5849
3.1.16. N-{2--1,4-Dithia-spiro[4.5]dec-7-en-8-yl)-ethyl}-
N--3-hydroxy-4-methoxy-benzyl)-formamide -7c). To a
solution of ketone 4b 21.97 g, 6.50 mmol) in dichloro-
methane 227 ml) 1,2-ethanedithiol 20.90 ml, 1.01 g,
10.74 mmol) and borontri¯uoride etherate 20.174 ml,
0.20 g, 1.41 mmol) were added and the mixture was allowed
to stand at room temperature for 14 h. The reaction mixture
was basi®ed with concentrated ammonium hydroxide 2pH
8±9) and evaporated to dryness in vacuum. The residue was
2.52 21H, dd, Jˆ15.3 Hz, 4.8 Hz, Hx-7); 2.59 21H, dd,
Jˆ15.3 Hz, 4.5 Hz, Hy-7); 2.79 21H, dt, Jˆ9.0 Hz, 4.5 Hz,
4.5 Hz 2H-7a); 2.89 21H, m, Hy-2); 3.04 21H, d, Jˆ13.2 Hz,
±NCHxPh); 3.84 21H, d, Jˆ13.2 Hz, ±NCHyPh); 3.86 23H,
s, OCH3); 6.69±6.83 23H, m, ArH); MS m/z 2%): 275237) M,
218256), 20428), 138294), 1372100), 122238), 94252);
HRMS calcd 275.15214, found 275.15238. Hydrobromide
salt of 8, mp 190±1928C 21,2-dichloroethane and 1±2 drops
of methanol). IR 2KBr) 3300 2OH), 1704 2CO) cm21
.
puri®ed by ¯ash chromatography 260 g of Kieselgel-PF254
,
elution with 400 ml of ethylacetate) to yield 1.88 g 276.3%)
of the title compound as white crystals, mp 65±688C. IR
2KBr) 3280 2OH), 1664 2NCHO) cm21; 1H NMR 2CDCl3) 2a
ca. 1:1 mixture of formyl rotamers A and B): d 2.07±2.24
26H, m, ±CH2CH2N,50,60); 2.64 22H, m, H2-30); 3.18±3.38
26H, m, ±CH2CH2N±, ±SCH2CH2S±); 3.88 and 3.89 23H, s,
OCH3AOOCH3B); 4.29 and 4.45 22H, s, ±NCH2APh O±
NCH2BPh); 5.36 and 5.39 21H, m, HA-20OHB-20); 5.67
and 5.7121H, s, OH AOOHB); 6.67±6.84 23H, m, ArH);
8.14 and 8.23 21H, s, NCHOAONCHOB); MS m/z 2%):
379 25.2) M, 351 25.0), 198 211), 181 214), 137 2100), 118
218); HRMS calcd 379.12759, found 379.12767.
3.2. General method for the Grewe-cyclization of
cyclohexenes -3b, c) and tertiary alcohols -10b, c)
Cyclohexene 23b and c) or cyclohexanol 210b and c)
22 mmol), respectively, was dissolved in a 1:1 2vol/vol)
mixture of cc. sulfuric acid and cc. phosphoric acid
240 ml; 20 ml/mmol). After stirring at room temperature
for 2±3 h the reaction mixture was poured into cold cc.
ammonium hydroxide with ice cooling. The alkaline
mixture was then extracted with chloroform, the combined
organic phase was washed with water, dried over magne-
sium sulfate and after ®ltering the solvent was evaporated at
reduced pressure. Products were isolated by preparative
layer chromatography on silica gel.
3.1.17. 5-{[2--1,4-Dithia-spiro[4.5]dec-7-en-8-yl)-ethyl-
amino]-methyl}-2-methoxy-phenol -7d). The solution of
N-formyl-derivate 7c 20.79 g, 2.08 mmol) in 5% aqueous
sodium hydroxide 217 ml) was heated at 1108C under nitro-
gen for 20 h. After cooling the reaction mixture was
adjusted to pH 6 with acetic acid, thereafter basi®ed with
concentrated ammonium hydroxide to pHˆ8.5 and
extracted with chloroform 23£10 ml). The combined
organic extracts were dried 2magnesium sulfate), ®ltered,
evaporated under reduced pressure and the residue
20.67 g) was separated by preparative layer chromatography
2Kieselgel PF2541366, benzene±methanol 14:3, elution with
dichloromethane±methanol 20:4, Rfˆ7c.7d) to give 0.41g
256%) of the title compound as an oil. IR 2KBr) 3300 2broad,
OH, NH), 1592, 1512 cm21; 1H NMR 2CDCl3): d 2.01±2.17
26H, m, ±CH2CH2N±,50,60); 2.58 22H, m, H2-30); 2.64
22H, t, Jˆ7.0 Hz, ±CH2CH2N±); 3.18±3.32 24H, m,
±SCH2CH2S±); 3.65 22H, s, ±NCH2Ph); 3.80 23H, s,
OCH3); 5.37 21H, m, H-20); 6.73 22H, m, H-3,4); 6.83
21H, m, H-6); MS m/z 2%): 35121) M, 32321), 166251),
151211), 1372100), 122227), 105212), 94217); HRMS calcd
351.13267, found 351.13288.
3.2.1. 8-Hydroxy-7-methoxy-spiro[2,3,4,5-tetrahydro-1H-
benzo-c)azepin-5,10-cyclohexane]-2-carbaldehyde -9b).
Viscous oil, yield 21% from 23b) and 55% from 210b).
TLC 2benzene±methanol 14:3), Rf 0.5; IR 2®lm) 3240,
2936, 1660, 1610, 1584, 1516, 1452, 1264, 1200, 1108,
1
1040, 872, 736 cm21; H NMR 2CDCl3) 2a ca. 4:3 mixture
of formyl rotamers A and B): d 1.22±1.92 210H, m, H2-
20,30,40,50,60); 2.07 and 1.96 22H, m, H2A-4OH2B-4); 3.70
and 3.58 22H, m, H2A-3OH2B-3); 3.89 and 3.88 23H, s,
OCH3AOOCH3B); 4.49 and 4.62 22H, s, H2A-1OH2B-1);
5.56 21H, broad, OH); 6.66 and 6.86 21H, s, HA-9OHB-9);
6.99 and 6.94 21H, s, HA-6OHB-6); 8.10 and 8.03 21H, s,
NCHOAONCHOB); MS m/z 2%): 2892100) M, 260222),
246214), 232217), 216213), 201233), 189224), 175221),
137236), 115234); HRMS calcd 289.16779, found 289.16795.
3.2.2. N-[2--1-Hydroxy-cyclohexyl)-ethyl]-N--3-hydroxy-
4-methoxy-benzyl)-formamide -10b). Viscous oil, yield
37%. TLC 2benzene±methanol 14:3) Rf 0.45; IR 2®lm)
3392, 2928, 2866, 1660, 1592, 1440, 1276, 1132, 1028,
1
972, 808, 788, 760 cm21; H NMR 2CDCl3) 2a ca. 4:3
3.1.18. 1--4-Methoxy-3-hydroxy-benzyl)-octahydro-indole-
6-one -8). The solution of compound 7d 20.98 g,
2.79 mmol) in a 1:1 mixture of concentrated sulfuric acid
and 80% phosphoric acid 252 ml) was allowed to stand at
room temperature for 3 h. The reaction mixture was poured
into ice-water 2420 ml) and basi®ed with concentrated am-
monium hydroxide to pH 9 and extracted with chloroform
23£240 ml). The combined organic layers were dried
2magnesium sulfate), ®ltered and evaporated under reduced
pressure. The residue 20.59 g) was separated by preparative
mixture of formyl rotamers A and B): d 1.16±1.6 210H,
m, H2-20,30,40,50,60); 1.61 and 1.65 22H, m, ±CH2ACH2N±
O±CH2BCH2N±); 3.29 and 3.55 22H, m, ±CH2CH2AN±
O±CH2CH2BN±); 3.87 and 3.89 23H, s, OCH3AOOCH3B);
4.29 and 4.43 22H, s, ±NCH2APhO±NCH2BPh); 5.86 and
5.80 21H, broad OHAOOHB); 6.67±6.83 23H, m, ArH); 8.19
and 8.20 21H, s, NCHOAONCHOB); MS m/z 2%): 307214)
M, 28929), 27127), 192213), 181235), 164216), 152211),
1372100), 12229), 94212); HRMS calcd 307.17836, found
307.17821.
layer chromatography 2Kieselgel PF2541366
, dichloro-
methane±methanol 20:2, elution 20:4). From the least
polar layer 95 mg 212.4%) of the title compound could be
isolated as a viscous oil. 1H NMR 2CDCl3): d 1.49 21H, m,
Hx-3); 1.74 21H, m, Hx-5); 1.94 21H, m, Hy-5); 1.97 21H, m,
Hy-3); 2.07 21H, m, Hx-2]; 2.18 21H, ddd, Jˆ18.0 Hz,
6.9 Hz, 4.5 Hz, Hx-4); 2.42±2.52 22H, m, H-3a, Hy-4);
3.2.3. 2-Methyl-7-methoxy-spiro[2,3,4,5-tetrahydro-1H-
benzo-c)azepin-5,10-cyclohexan]-8-ol -9c). Colorless oil,
yield 21.5% from 3c, 9.3% from 10c. TLC 2benzene±
methanol 14:3) Rf 0.4; IR 2KBr) 3400, 2930, 2905 2830,
1600, 1580, 1505, 1450, 1285, 1115, 1030, 880,
770 cm21 1H NMR 2CDCl3): d 1.20±1.76 210H, m,
;

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A. Lukacs et al. / Tetrahedron 57 32001) 5843±5850
5850
H2-20,30,40,50,60); 1.89 22H, m, H2-4); 2.30 23H, s, NCH3);
2.92 22H, m, H2-3); 3.86 22H, s, H2-1); 3.88 23H, s, OCH3);
5.60 21H, broad, OH); 6.61 21H, s, H-9); 6.95 21H, s, H-6);
MS m/z 2%): 275272) M, 274256), 260242), 232212),
192243), 178274), 1372100), 115212); HRMS calcd
275.18853, found 275.18865.
We are grateful for the MS data provided by J. Brlik and
Dr G. Czira, as well as for the NMR technical assistance of
A. FuÈrjes.
References
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3.2.4. 5--{[2--1-Hydroxy-cyclohexyl)-ethyl]-methyl-amino}-
methyl)-2-methoxy-phenol -10c). Viscous oil, yield 16%.
TLC 2benzene±methanol 14:3) Rf 0.45; IR 2KBr) 3400,
1
2910, 2840, 1590, 1510, 1280, 1020, 760 cm21; H NMR
3. Morrison, G. C.; Waite, R. O.; Shavel Jr., J. Tetrahedron Lett.
1967, 4055±4056.
2CDCl3): d 0.72±2.00 212H, m, ±CH2CH2N±,20,30,40,50,60);
2.32 23H, s, ±NCH3); 2.56 22H, m, ±CH2CH2N±); 3.6122H,
s, ±NCH2-Ph); 3.88 23H, s, OCH3); 6.80±7.03 23H, m,
ArH); MS m/z 2%): 29321) M, 180219), 1372100), 122210),
94213); HRMS calcd 293.1991, found 293.2005.
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3.2.5. 7-Methoxy-spiro[2,3,4,5-tetrahydro-1H-benzo-c)-
azepin-5,10-cyclohexan]-8-ol -9a). Compound 29b)
274 mg, 0.256 mmol) was dissolved in a freshly prepared
5% aqueous solution of sodium hydroxide and under Ar
was re¯uxed for 2 h in an oil bath at 110±1158C. After
cooling the pH was adjusted to 6 with diluted acetic acid,
then made alkaline 2pH 8±8.5) by cc. ammonium
hydroxide. After extraction with chloroform 23£5 ml) the
combined organic phase was dried over magnesium sulfate,
®ltered and evaporated to dryness. The crystalline residue
was rubbed with chloroform. After ®ltering and drying in a
vacuum desiccator 27 mg 240%) of product 29a) was
obtained as a crystalline substance, mp 212±2138C 2chloro-
form); TLC 2chloroform±methanol 1:1) Rf 0.2; IR 2KBr)
3440, 3240, 2920, 2840, 1600, 1512, 1312, 1208, 864,
7. Meuzelaar, G. J.; Neeleman, E.; Maat, L.; Sheldon, R. A. Eur.
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Nyulaszi, L.; Szantay, Cs. Heterocycles 1999, 51, 2321±2333.
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1
760 cm21; H NMR 2DMSO-d6): d 1.20±1.86 210H, m,
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 Â
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3.73 23H, s, OCH3); 3.78 22H, s, H2-1); 6.48 21H, s, H-9);
6.85 21H, s, H-6); 6.60 21H, broad, OH); MS m/z 2%):
261289) M, 24427), 232211), 218233), 189231), 178265),
164297), 1372100), 124222), 115232), 91231); HRMS calcd
261.17288, found 261.17270.
Â
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Â
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Acknowledgements
The authors thank Gedeon Richter Ltd for ®nancial support.