Syntheses of isochromane analogues of the michellamines and korupensamines

Article abstract of DOI:10.1039/a908367g

Syntheses of the oxygen analogues 6, 7 and 8 of the michellamines 1 and korupensamines 2 are described. Racemic 5-iodo-6,8-dimethoxy-trans-1,3-dimethylisochromane 10 was synthesised in eleven steps from 2,4-dimethoxybenzaldehyde in an overall yield of 51%

Full text of DOI:10.1039/a908367g

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Syntheses of isochromane analogues of the michellamines and
korupensamines
Charles B. de Koning,* Joseph P. Michael and Willem A. L. van Otterlo
1
Centre for Molecular Design, Department of Chemistry, University of the Witwatersrand,
PO Wits 2050, South Africa
Received (in Cambridge, UK) 19th October 1999, Accepted 15th December 1999
Syntheses of the oxygen analogues 6, 7 and 8 of the michellamines 1 and korupensamines 2 are described. Racemic
5-iodo-6,8-dimethoxy-trans-1,3-dimethylisochromane 10 was synthesised in eleven steps from 2,4-dimethoxybenz-
aldehyde in an overall yield of 51%. The isopropoxy analogue 11 was synthesised in a similar manner. Isochromane
10 was coupled using Suzuki methodology with 4-isopropoxy-5-methoxy-7-methylnaphthalene-1-boronic acid 9
to produce 7 in 96% yield. This was converted in good yield into the desired product 6 by oxidative dimerisation
followed by reduction of the cross-conjugated ene-dione intermediate 45.
Introduction
The michellamines (e.g., michellamine B, 1) are a growing class
of novel naphthylisoquinoline alkaloids isolated from the trop-
ical liana Ancistrocladus korupensis, found in the Cameroon.1
These compounds are of interest to the scientific community as
they show activity against the Human Immunodeficiency Virus
(HIV).2 In addition, as a result of their intriguing structures,
chemists have been interested in the synthesis of these mole-
cules and a number of groups have published total syntheses or
approaches to their synthesis.3
Most of the published syntheses rely on the dimerisation of a
(5)-naphthylisoquinoline such as 2, which in turn is constructed
from a suitably protected tetrahydroisoquinoline precursor, e.g.
3. Isoquinoline 3 is invariably made by means of a Bischler–
Napieralski cyclisation.4 The bromonaphthalene 4 is a key
intermediate in several reported syntheses.3e,p,5 The biaryl axis is
then formed between 3 and various naphthalene boronic acids
such as 5, which are themselves prepared from the brominated
precursor 4. The formation of the biaryl axis has been accom-
plished using both Suzuki3a–d,h–j,l,o,q and Stille3e,p coupling pro-
cedures, with the Suzuki methodology6 used more frequently.
Removal of R2 from the diastereoisomeric biaryl products 2,
dimerisation and deprotection of the remaining phenolic
groups result in formation of the michellamines, e.g. 1. The
biaryl products 2, the ‘monomers’ of the michellamines, are
also found in Nature and are known as the korupensamines.7
They do not show activity against the HIV, but do show bio-
logical activity against the malaria parasite, Plasmodium
falciparum.
As a result of the activities associated with natural products
such as the michellamines, the National Cancer Institute (NCI)
of the USA has encouraged researchers to synthesise analogues
of these naturally occurring compounds,8 and several have been
reported.9 Most of the analogues prepared have unnatural
biaryl linkages in which the isoquinoline and naphthalene
moieties are joined at sites other than those found in 1. In this
paper we report in full on a synthesis of racemic methoxy-
and isopropoxy-isochromane analogues of the korupensamines
(7 and 8) as well as the methoxylated michellamine oxygen
analogue 6. Preliminary details have previously appeared in a
communication.10
the target into account, and leads to 7. This important inter-
mediate was in turn disconnected to give isochromane 10 and
the naphthalene 9. In 10, the phenolic groups are protected as
their methyl ethers, but we also chose to prepare the analogue
11 possessing isopropyl protecting groups, as it was hoped that
these groups could be selectively removed when required to
afford phenolic analogues of 6.11
We elected to synthesise the desired isochromanes 10 and 11
from 1-allyloxy-2,4-dimethoxybenzene 13 and its isopropoxy
analogue 14. The bromide analogue 12 was also prepared from
Results and discussion
Retrosynthesis of 6 takes the obvious structural symmetry of
DOI: 10.1039/a908367g
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
This journal is © The Royal Society of Chemistry 2000
799

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location of the acetyl group in both products was unambigu-
1
ous, as the H NMR spectra showed, inter alia, two singlets
(i.e., no ortho or meta coupling) at δ 7.45 and 6.50 for 19 and
δ 7.44 and 6.50 for 20.
Efficient conversion (ca. 80%) of both 19 and 20 into 21 and
22, respectively, was achieved by heating the compounds neat at
160 ЊC (to induce a Claisen rearrangement) and protecting the
resulting phenols as benzyl ethers. Reduction of 21 and 22 gave
the racemic alcohols 23 and 24 (both in 93–94% yield).
Utilising methodology developed by Giles et al.,16 we
converted both of these alcohols into the desired racemic trans-
1,3-dimethylisochromanes 25 and 26 by treatment with potas-
sium tert-butoxide in DMF at 75 ЊC. Evidence for the formation
of the trans-product in both cases was again obtained from the
1H NMR spectra. It has been shown that 3-H for trans-1,3-
dimethylisochromanes occurs upfield (δ ≈ 4) in relation to the
1
cis-isomer (δ ≈ 3.8).17 In these examples, the H NMR spectra
showed 3-H for 25 as a multiplet at δ 3.99–3.91, and for the
isopropyl analogue 26 as a multiplet at δ 3.98–3.93. The relative
stereochemistry was confirmed by an X-ray crystal-structure
determination on compound 36, prepared later in the synthetic
sequence.
The naphthalene 9 required for the coupling with the iso-
chromane moiety was synthesised using standard method-
ology. 2-Bromo-5-isopropoxybenzaldehyde18 was treated with
dimethyl succinate in the presence of potassium tert-butoxide to
give the intermediate Stobbe condensation product 27 as a
mixture of geometrical isomers (60:40). This was treated
with acetic anhydride and sodium acetate19 to give the naph-
thalene 28. The overall yield of this two-step sequence was 49%.
13. 1-Allyloxy-2,4-dimethoxybenzene 13 was synthesised either
from vanillin through the intermediacy of 15 and 16 or from
2,4-dimethoxybenzaldehyde12 via 17;13 both routes involve
Baeyer–Villiger oxidation of the aldehyde group as shown in
Scheme 1. Although vanillin is cheaper, the second route was
Following
a
series of functional-group manipulations3e
(28 → 29 → 30 → 31 → 32), 5-bromo-8-isopropoxy-
1-methoxy-3-methylnaphthalene 4 was obtained. Conversion
into the corresponding naphthaleneboronic acid 9 was accom-
plished in high yield by sequential treatment of 4 with
n-butyllithium at Ϫ78 ЊC and triisopropyl borate followed by
hydrolysis as outlined in Scheme 2.
Scheme 1 Reagents and conditions: For 15 → 16 → 13 (i) MMPP
(magnesium monoperoxyphthalic acid hexahydrate) silica gel, MeOH
(64%); (ii) (MeO)2SO2, K2CO3, Me2CO (92%); (iii) H2C᎐CHCH2Br,
᎐
K2CO3, Me2CO (96%) (17 → 13) (or 94%) (18 → 14); (iv) AcOH,
TFAA, CH2Cl2 (66%) (13 → 19) (or 94%) (14 → 20); (v) (a) 160 ЊC;
(b) PhCH2Br, K2CO3, Me2CO (2 steps) (82%) (19 → 21) (or 79%)
(20 → 22); (vi) LiAlH4, Et2O (94%) (21 → 23) (or 93%)
(22 → 24); (vii) KOBut, DMF, (94%) (23 → 25) (or 85%)
(24 → 26).
the method of choice as the intermediate products were formed
in higher yields and were easier to handle. Compound 14 was
synthesised from 2,4-diisopropoxybenzaldehyde, which is
readily made by Vilsmeier–Haack formylation of 1,3-diiso-
propoxybenzene.14 Following the same steps as outlined for the
formation of 13, 2,4-diisopropoxybenzaldehyde was converted
into 14 via 18 in good overall yields (62%). With both 13 and 14
in hand, the acetyl functionality was introduced by treatment
with a mixture of acetic acid and trifluoroacetic anhydride at
ambient temperature to yield 19 (66%) and 20 (94%).15 The
Scheme 2 Reagents and conditions: (i) Ac2O, NaOAc (74%); (ii) KOH–
MeOH (95%); (iii) (MeO)2SO2, K2CO3, Me2CO (99%); (iv) LiAlH4,
Et2O (98%); (v) (CBrCl2)2, PPh3, CH2Cl2 (86%); (vi) L-Selectride,
CH2Cl2 (100%); (vii) (a) n-BuLi, THF, Ϫ78 ЊC; (b) B(OPri)3, aq. NH4Cl,
not purified.
800
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With the synthesis of both the isochromane skeleton and the
naphthalene accomplished, it was necessary to modify func-
tional groups to allow for efficient coupling of the two moieties.
In particular, the benzyl ether at C-5 in both isochromanes 25
and 26 must be converted into a functional group suitable for
coupling with the naphthalene 9. While the specific choice of
functional group was not obvious at this stage, it was clear that
hydrogenolysis of the benzyl group was an essential first step.
Removal of the benzyl protecting group was accomplished with
either 10% palladium on charcoal or palladium black under a
hydrogen atmosphere to give a quantitative yield of both 33 and
34. The isochromane ring, itself a benzylic ether, was unaffected
during this reaction.
The stage was now set to couple the halogenated iso-
chromanes 10–12 with the substituted naphthaleneboronic acid
9 using the palladium-mediated Suzuki reaction.6 However, we
considered it prudent to optimise reaction conditions by first
performing some model reactions with readily accessible
aromatic boronic acids before committing our more valuable
naphthaleneboronic acid 9. Treatment of bromoisochromane 12
with 1-naphthylboronic acid 40 in the presence of 10 mol%
tetrakis(triphenylphosphine)palladium(0) in toluene and of aq.
sodium bicarbonate3f under argon gave a 28% yield of the
desired product 43 as a mixture of diastereoisomers (ratio:
66:34), which arise from the creation of a stereogenic axis.
Clear evidence for the formation of two diastereoisomers came
from the 1H and 13C NMR spectra, which showed doubling of
virtually all the signals. In addition, the high-resolution mass
spectrum showed the expected molecular ion at Mϩ 348.1717
(C23H24O3 requires M, 348.1725). As the yield of 43 was low the
reaction was repeated using the method of Coudret.26 Reaction
of 12 with 1-naphthylboronic acid pinacol ester 4127 and
dichloro-[1,1Ј-bis(diphenylphosphino)ferrocene]palladium(0)
gave a very disappointing yield (14%) of the desired product 43.
Hence, at this stage it was decided that all future work on these
reactions would be done on the iodinated isochromanes 10
and 11, as literature precedent indicated that iodine is the best
halogen for Suzuki coupling reactions.3f
Phenol 33 was converted into triflate 35 by treatment with
triflic anhydride in the presence of pyridine (Scheme 3).
After much experimentation, iodoisochromane 10 and naph-
thylboronic acid 9 were treated with 20 mol% tetrakis(triphenyl-
phosphine)palladium(0) in DMF under argon with tribasic
potassium phosphate28 to give the desired biaryl compound 7 in
1
an excellent yield of 96%. Doubling of signals in both the H
NMR and 13C NMR spectra showed clearly that the product
had been formed as a mixture of two diastereoisomers (59:41).
The 1H NMR spectrum showed a number of differences on the
isochromane moiety as compared with that of the precursor 10,
the most significant being the shift of the aromatic singlet (7-H)
from δ 6.34 to δ 6.99 and 6.97 for the diastereomeric products.
Additionally, the two 4-H protons, which appeared as double
doublets at δ 2.74 and 2.35 in 10, appeared in the product 7 as
multiplets at δ 2.15–2.03 and 1.88–1.81.
Under the same conditions, coupling 11 with 9 gave the
desired product 8 in a disappointing yield of 15%. Even in the
presence of an oxygen scavenger, 2,6-di-tert-butyl-4-methyl-
phenol,29 the yield could not be improved. Nevertheless,
compounds 7 and 8 are both oxygen analogues of the koru-
pensamines—the first on record.
Selective removal of the isopropyl group of 7 with boron
trichloride yielded the naphthol 44. This was treated with
silver() oxide to afford 45 (Scheme 4). This purple compound
was not characterised fully, but subjected to hydrogenation
on a palladium–charcoal catalyst to yield the desired oxygen
analogue of the michellamines 6 in good yield. The product was
produced as a mixture of racemic diastereoisomers. This repre-
sents the first synthesis of an isochromane analogue of the
michellamines. We are currently investigating the separation of
these six possible diastereoisomers, after which biological
evaluation of these new michellamine analogues will be under-
taken. Furthermore, synthesis of the isochromane building
blocks as pure enantiomers will also reduce the number of
diastereoisomeric options in the final product, and this com-
paratively straightforward task is also under investigation.
Scheme 3 Reagents and conditions: (i) 10% Pd/C, MeOH, H2 (100%)
(25 → 33) and (26 → 34); (ii) Tf2O, CHCl3, pyridine (88%); (iii)
(EtO)2POCl, NaH, THF (100%) (33 → 36) (or 81%) (34 → 37);
(iv) K, NH3, Ϫ78 ЊC (100%) (36 → 38) (or 91%) (37 → 39); (v)
Ag2SO4, I2, EtOH (94%) (38 → 10) and (39 → 11); or Br2, AcOH–
CHCl3 (93%) (38 → 12).
Attempted coupling reactions with two model systems,
1-naphthylboronic acid 4020 and tributyl-(4-methoxyphenyl)-
stannane 42,21 were unsuccessful. This is probably due to the
electron-rich nature of the isochromane, which makes it more
difficult for palladium(0) to be inserted between the triflate
oxygen and carbon in the aromatic ring.22 Hence we chose to
replace the benzyloxy group with a halogen before attempt-
ing coupling reactions. For isochromane 25, this was done by
using an uneventful high yielding deoxygenation sequence,23
25 → 33 → 36 → 38, which proceeded overall in quanti-
tative yield. An X-ray crystal structure24 of 36 provided conclu-
sive evidence of the structure of the molecule and verified the
1,3-trans-dimethyl stereochemistry of the pyran ring. Iso-
chromane 38 was converted into both the bromide 12 and iodide
10 using bromine in acetic acid or iodine and silver() sulfate25
in yields of 93 and 94%, respectively. A similar sequence of
reactions was used for converting the isopropoxyisochromane
34 into iodide 11 via 37 and 39. The regiochemistry of all three
products 10, 11 and 12 was confirmed by NOE experiments.
Irradiation of the single aromatic proton showed enhancement
of both methoxy groups in 10 and 12, while irradiation of 11
showed enhancement of both isopropoxy groups.
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192 (Mϩ, 100%), 177 (6), 151 (63), 95 (43), 77 (19), 65 (10) and
41 (32).
4-Allyloxy-3-methoxyphenol 16
Magnesium monoperoxyphthalic acid hexahydrate (MMPP)
(51.0 g, 0.10 mol) was added to a solution of the benzaldehyde
15 (16.6 g, 0.086 mol) in dry methanol (200 cm3), under a nitro-
gen atmosphere at 0 ЊC. The reaction mixture was allowed to
warm up to room temperature and stirred under nitrogen for 55
h, during which time a pink precipitate formed. An additional
portion of MMPP (10 g) was added and the reaction mixture
was stirred for a further 15 h. The solvent was removed in vacuo
and the residue was purified by column chromatography (20%
ethyl acetate–hexane), to afford the phenol 16 as a dark
red-brown oil (9.91 g, 64%) (Found: Mϩ, 180.0774. C10H12O3
requires M, 180.0786); νmax(film)/cmϪ1 3417br (OH), 3086m
(᎐CH ), 2844m (OCH ), 1601s and 1510m (ArC᎐C), 1211s and
᎐
᎐
2
3
1016m (C–O–C) and 994s (᎐CH); δ (200 MHz; CDCl ; Me Si)
᎐
H
3
4
6.74 (1H, d, J 8.6, 5-H), 6.46 (1H, d, J 2.8, 2-H), 6.33 (1H, dd,
J 8.6 and 2.8, 6-H), 6.17–5.95 (2H, m, 2Ј-H and OH), 5.40–5.19
(2H, m, 3Ј-H2), 4.51 (2H, br dt, J 5.6 and 1.4, 1Ј-H2) and 3.76
(3H, s, OCH3); δC (50.32 MHz; CDCl3) 150.9, 150.4 and 141.5
(3 × ArC–O), 133.6 (2Ј-C), 117.8 (3Ј-C), 115.6 (5-C), 106.0
(2-C), 100.8 (6-C), 71.1 (1Ј-C) and 55.6 (OCH3); m/z (EI) 180
(Mϩ, 34%), 139 (100), 111 (26), 93 (12), 69 (6), 65 (8) and 41 (11).
1-Allyloxy-2,4-dimethoxybenzene 13
Dimethyl sulfate (11.8 cm3, 0.13 mol) and potassium carbonate
(20.0 g, 0.14 mol) were added to a solution of 4-allyloxy-3-
methoxyphenol 16 (5.45 g, 0.03 mol) in distilled acetone (250
cm3). The reaction mixture was heated at reflux under a nitro-
gen atmosphere for 18 h. The acetone was removed in vacuo
after which water (100 cm3) and diethyl ether (100 cm3) were
added. The organic phase was separated, and washed succes-
sively with aq. ammonia (10% v/v; 3 × 100 cm3), water (100
cm3), hydrochloric acid (10% v/v; 100 cm3) and water (100 cm3).
The organic solvent was dried (MgSO4), and removed in vacuo
to yield the crude material, which was purified by column
chromatography (5% ethyl acetate–hexane) to give the triether
13 (5.39 g, 92%) as a clear oil (Found: Mϩ, 194.0934. C11H14O3
requires M, 194.0943); νmax(film)/cmϪ1 2820m (OCH3), 1610m
Scheme 4 Reagents and conditions: (i) BCl3, Ϫ78 ЊC, CH2Cl2 (51%);
(ii) Ag2O, 0.2% Et3N, CHCl3 (100%); (iii) H2, Pd/C (75%).
Experimental
1H and 13C NMR spectra were recorded either on a Bruker
AC-200 or Bruker DRX 400 spectrometer at the frequency
indicated. DEPT, CH-correlated and HMBC spectra were run
on some samples to enable complete assignments of all the
signals. J-Values are given in Hz. NMR spectroscopic assign-
ments with the same superscript may be interchanged. IR
spectra were recorded on either a Bruker IFS 25 Fourier Trans-
form spectrometer or on a Bruker Vector 22 Fourier Transform
spectrometer. Mass spectra were recorded on a Kratos MS 9/50,
VG 70E MS or a VG 70 SEQ mass spectrometer. Elemental
analyses were performed on a Perkin-Elmer 2400 CHN
Elemental Analyser. Macherey-Nagel Kieselgel 60 (particle
size 0.063–0.200 mm) was used for conventional silica gel
chromatography, and Macherey-Nagel Kieselgel 60 (particle
size 0.040–0.063 mm) was used for preparative flash chromato-
graphy. All solvents used for reactions and chromatography
were distilled prior to use.
and 1583m (ArC᎐C), 1503m (C᎐C), 1210vs and 1043s (C–O–C)
᎐
᎐
and 983s and 917m (᎐CH); δ (200 MHz; CDCl3; Me4Si) 6.81
᎐
H
(1H, d, J 8.7, 6-H), 6.51 (1H, d, J 2.9, 3-H), 6.36 (1H, dd, J 8.7
and 2.9, 5-H), 6.18–5.95 (1H, m, 2Ј-H), 5.37 (1H, dd, J 17.3 and
1.5, 3Ј-H), 5.25 (1H, dd, J 10.5 and 1.5, 3Ј-H), 4.53 (2H, br dt,
J 5.5 and 1.5, 1Ј-H2) and 3.84 and 3.75 (each 3H, s, OCH3);
δC (50.32 MHz; CDCl3; Me4Si) 154.6, 150.5 and 142.1 (3 ×
ArC–O), 133.7 (2Ј-C), 117.5 (3Ј-C), 114.8 (6-C), 102.9 (3-C),
100.3 (5-C), 70.7 (1Ј-C) and 55.7 and 55.4 (2 × OCH3); m/z (EI)
194 (Mϩ, 32%), 153 (100), 125 (40) and 91 (28).
4-Allyloxy-3-methoxybenzaldehyde 15
Allyl bromide (39.8 g, 0.33 mol) and potassium carbonate (90.0
g, 0.65 mol) were added to a solution of vanillin (22.0 g, 0.145
mol) in dry DMF (500 cm3). The reaction mixture was heated
under nitrogen at 70 ЊC for 50 h. After filtration and removal
of the solvent in vacuo, the reside was purified by column
chromatography (10% ethyl acetate–hexane) to give the product
15 as a clear yellow oil (27.5 g, 99%) which solidified (mp 27–
29 ЊC) (Found: Mϩ, 192.0793. C11H12O3 requires M, 192.0786);
νmax(film)/cmϪ1 3080m (᎐CH ), 3030m (᎐CH), 1683s (C᎐O),
2,4-Dimethoxyphenol 17
Magnesium monoperoxyphthalic acid hexahydrate (26.8 g,
0.054 mol) was added portionwise to a solution of 2,4-
dimethoxybenzaldehyde (6.00 g, 0.036 mol) in methanol
(250 cm3), under a nitrogen atmosphere at 0 ЊC. The reaction
mixture was warmed to room temperature and stirred under
nitrogen for 48 h, during which time the mixture went a bright
pink colour. The reaction mixture was then filtered to remove
the precipitate. The precipitate was washed with an excess of
ethyl acetate and then the organic filtrates were combined and
the solvent removed in vacuo. The crude residue was purified by
column chromatography (10–20% ethyl acetate–hexane) to
afford the phenol 17 (4.90 g, 88%) as a yellow oil (bp 129 ЊC, 10
mmHg; lit.,13 129 ЊC, 10 mmHg); δH (200 MHz; CDCl3; Me4Si)
6.82 (1H, d, J 8.6, 6-H), 6.49 (1H, d, J 2.8, 3-H), 6.38 (1H, d,
J 8.6 and 2.8, 5-H), 5.53 (1H, br s, OH) and 3.84 and 3.75 (each
᎐
᎐
᎐
2
1586s (ArC᎐C), 1267s and 1032m (C–O–C) and 995s (᎐CH);
᎐
᎐
δH (200 MHz; CDCl3; Me4Si) 9.85 (1H, s, CHO), 7.43 (1H,
dd, J 8.7 and 1.9, 6-H), 7.41 (1H, d, J 1.9, 2-H), 6.98 (1H, d,
J 8.7, 5-H), 6.16–6.02 (1H, m, 2Ј-H), 5.50–5.31 (2H, m, 3Ј-H2),
4.71 (2H, br dt, J 5.4 and 1.4, 1Ј-H2) and 3.94 (3H, s, OCH3);
δC (50.32 MHz; CDCl ) 190.7 (C᎐O), 153.3, 149.7 (2 ×
᎐
3
ArC–O), 132.1 (2Ј-C), 130.0 (1-C), 126.4 (6-C), 118.6 (3Ј-C),
111.8 (2-C), 109.1 (5-C), 69.6 (1Ј-C) and 55.8 (OCH3); m/z (EI)
802
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3H, s, OCH3); δC (50.32 MHz; CDCl3) 153.5, 147.0 and 139.7
(3 × ArC–O), 114.1 (6-C), 104.2 (3-C), 99.4 (5-C) and 55.8 and
55.7 (2 × OCH3).
(COCH3) and 30.5 (1Ј-C); m/z (EI) 326 (Mϩ, 14%), 235 (100),
217 (37), 91 (57) and 43 (83).
1-(2-Allyl-3-benzyloxy-4,6-dimethoxyphenyl)ethanol 23
1-Allyloxy-2,4-dimethoxybenzene 13 (alternative preparation)
Lithium aluminium hydride (0.53 g, 0.014 mol) was added to a
solution of ketone 21 (2.27 g, 6.96 mmol) in dry diethyl ether
(40 cm3) and the reaction mixture was stirred under argon for
18 h. Methanol (10 cm3) was added carefully, followed by water
(40 cm3), and the aqueous phase was extracted with ethyl
acetate (3 × 20 cm3). The organic layer was dried (MgSO4) and
the solvent removed in vacuo, after which the residue was puri-
fied by column chromatography (10% ethyl acetate–hexane), to
yield the alcohol 23 as a clear oil (2.14 g, 94%) (Found: Mϩ,
328.1666. C20H24O4 requires M, 328.1675); νmax(film)/cmϪ1
Allyl bromide (18.6 cm3, 26.0 g, 0.21 mol) and potassium
carbonate (29.7 g, 0.21 mol) were added to a solution of 2,4-
dimethoxyphenol 17 (13.3 g, 0.086 mol) in dry acetone (200
cm3). The reaction mixture was heated at reflux under nitrogen
for 18 h. The potassium carbonate was removed by filtration
and the solvent was removed in vacuo. Purification by column
chromatography (10–20% ethyl acetate–hexane) afforded the
product 13 as a clear yellow oil (16.01 g, 96%). Spectral data
of this compound were identical to those obtained from
4-allyloxy-3-methoxyphenol 16.
3600br (OH), 1600s (ArC᎐C) and 1000s (᎐CH); δ (200 MHz;
᎐
᎐
H
CDCl3; Me4Si) 7.48–7.29 (5H, m, Ph), 6.49 (1H, s, 5-H), 6.00–
5.82 (1H, m, 2Ј-H), 5.02 (1H, dd, J 10.2 and 1.6, 3Ј-H), 4.94 (1H,
dd,J17.2and1.6,3Ј-H),4.87and4.91(each1H,d,J10.9,OCH2),
3.88 and 3.87 (each 3H, s, OCH3), 3.88–3.81 (1H, br m,
CHCH3), 3.50–3.43 (2H, m, 1Ј-H2) and 1.51 (3H, d, J 6.6, CH3);
δC (50.32 MHz; CDCl3) 154.1, 151.9 and 140.1 (3 × ArC–O),
137.9 (ArC–C), 136.8 (2Ј-C), 131.3 (ArC–C), 128.3, 127.9 and
127.7 (3 × PhC), 124.0 (ArC–C), 115.4 (3Ј-C), 96.2 (5-C), 74.9
(OCH2), 67.0 (CHOH), 55.9 and 55.5 (2 × OCH3), 30.3 (1Ј-C)
and 23.7 (CH3); m/z (EI) 328 (Mϩ, 19%) 237 (66), 219 (100) and
91 (45).
5-Allyloxy-2,4-dimethoxyacetophenone 19
Trifluoroacetic anhydride (TFAA) (3.3 cm3, 4.9 g, 0.023 mol)
and glacial acetic acid (1.3 cm3, 1.4 g, 0.023 mol) were
pre-mixed in a glass vial and the mixture added to a solution of
1-allyloxy-2,4-dimethoxybenzene 13 (3.49 g, 0.018 mol) in dry
dichloromethane (100 cm3). The reaction mixture was then
stirred under nitrogen for 60 h. Water (50 cm3) was added and
solid sodium hydrogen carbonate was added portionwise until
effervescence had decreased. The reaction mixture was then
stirred for 1 h before being extracted with dichloromethane
(3 × 30 cm3), and the organic layer was dried (MgSO4), and
concentrated in vacuo. Column chromatography (20% ethyl
acetate–hexane) yielded the ketone 19 as a white crystalline
material (2.80 g, 66%), mp 82.5–83.5 ЊC (from hexane–ethyl
acetate) and starting material (0.59 g, 17% recovery) (Found:
Mϩ, 236.1036. C, 66.02; H, 6.76. C13H16O4 requires M,
236.1049. C, 66.07; H, 6.83%); νmax(KBr pellet)/cmϪ1 2835w
(OCH ), 1760s (C᎐O), 1667s and 1613s (ArC᎐C), 1507 (C᎐C),
5-Benzyloxy-6,8-dimethoxy-trans-1,3-dimethylisochromane 25
Sublimed potassium tert-butoxide (1.50 g, 13.4 mmol) was
added to a solution of the alcohol 23 (1.10 g, 3.35 mmol) in dry
DMF (50 cm3). The reaction mixture was stirred under argon at
75 ЊC for 90 min. Water (20 cm3) and diethyl ether (20 cm3) were
added and the mixture was extracted sequentially with diethyl
ether (3 × 50 cm3), dichloromethane (3 × 40 cm3) and ethyl
acetate (20 cm3). The organic solvents were combined, dried
(MgSO4) and evaporated under vacuum. Subsequent purifi-
cation by column chromatography (5% ethyl acetate–hexane)
afforded the isochromane 25 (1.03 g, 94%) as a clear oil (Found:
Mϩ, 328.1681. C20H24O4 requires M, 328.1675); νmax(film)/cmϪ1
᎐
᎐
᎐
3
1287s and 1027s (C–O–C) and 975m (᎐CH); δ (200 MHz;
᎐
H
CDCl3) 7.45 (1H, s, 6-H), 6.50 (1H, s, 3-H), 6.16–5.96 (1H,
m, 2Ј-H), 5.41 (1H, dd, J 17.3 and 1.5, 3Ј-H), 5.28 (1H, dd,
J 10.4 and 1.5, 3Ј-H), 4.58 (2H, br dt, J 5.5 and 1.5, 1Ј-H), 3.94
and 3.91 (each 3H, s, OCH3) and 2.58 (3H, s, COCH3);
δC (50.32 MHz; CDCl3) 197.0 (CO), 155.7, 154.4 and 141.8
(3 × ArC–O), 133.1 (2Ј-C), 119.0 (1-C), 118.1 (3Ј-C), 114.9
(6-C), 96.4 (3-C), 70.2 (1Ј-C), 56.0 and 56.0 (2 × OCH3) and
32.0 (COCH3); m/z (EI) 236 (Mϩ, 41%), 195 (100), 43 (58) and
41 (18).
2842m (OCH ), 1604s and 1568m (ArC᎐C), 1230m, 1088s and
᎐
3
808m (C–O–C); δH (200 MHz; CDCl3; Me4Si) 7.48–7.30 (5H, m,
Ph), 6.39 (1H, s, 7-H), 5.04 (1H, q, J 6.5, 1-H), 4.91 (2H, s,
OCH2), 3.99–3.91 (1H, m, 3-H), 3.87 and 3.80 (each 3H, s,
OCH3), 2.78 (1H, dd, J 17.0 and 3.3, 4-H pseudo-equatorial),
2.28 (1H, dd, J 17.0 and 10.8, 4-H pseudo-axial), 1.47 (3H, d,
J 6.5, 1-CH3) and 1.27 (3H, d, J 6.1, 3-CH3); δC (50.32 MHz;
CDCl3) 151.7, 151.1 and 138.7 (3 × ArC–O), 138.0 and 128.7
(2 × ArC–C), 128.3, 128.1 and 127.8 (3 × PhC), 120.3 (ArC–C),
94.8 (7-C), 74.3 (OCH2), 68.0 (1-C), 62.4 (3-C), 56.1 and 55.4
(2 × OCH3), 30.8 (4-C), 21.9 (1-CH3) and 19.7 (3-CH3); m/z
(EI) 328 (Mϩ, 18%), 237 (100), 193 (88), 165 (17) and 91 (13).
2-Allyl-3-benzyloxy-4,6-dimethoxyacetophenone 21
5-Allyloxy-2,4-dimethoxyacetophenone 19 (3.29 g, 0.014 mol)
was heated at 160 ЊC for 23 h under a nitrogen atmosphere. An
NMR spectrum of the crude product confirmed that conver-
sion to the phenol had occurred. The reaction mixture was
cooled to room temperature and acetone (200 cm3), potassium
carbonate (9.6 g, 0.070 mol) and benzyl bromide (8.3 cm3, 0.070
mol) were added. The reaction mixture was then heated under
nitrogen at reflux for 18 h. After cooling, filtration of the
inorganic solids and evaporation of the solvent under vacuum,
the residue was purified by column chromatography (5–10%
ethyl acetate–hexane) to afford the ketone 21 as a clear, colour-
less oil (3.71 g, 82%) (Found: Mϩ, 326.1512. C20H22O4 requires
M, 326.1518); νmax(film)/cmϪ1 3004m (᎐CH), 2840m (OCH ),
2,4-Diisopropoxyphenol 18
DMF (13.1 cm3, 12.4 g, 0.17 mol) and anhydrous phosphoryl
trichloride (7.9 cm3, 13.0 g, 0.085 mol) were added to a solution
of 1,3-diisopropoxybenzene14 (16.4 g, 84.6 mmol) in toluene
(15 cm3). The reaction mixture was stirred at 0 ЊC for 30 min
and the bright yellow mixture was then heated at 120 ЊC for 2 h
under nitrogen. During this time the colour of the reaction
changed from yellow to deep red. The reaction mixture was
poured into aq. sodium hydroxide (250 cm3 of 10% NaOH and
100 cm3 of ice) with stirring and the mixture was subsequently
extracted with dichloromethane (3 × 100 cm3). The organic
phase was washed with water (2 × 100 cm3), dried (MgSO4) and
evaporated in vacuo. The resultant black residue was purified by
silica gel column chromatography (10% ethyl acetate–hexane)
to afford 2,4-diisopropoxybenzaldehyde as an orange oil (18.1 g,
96%) (Found: Mϩ, 222.1256. C13H18O3 requires M, 222.1253);
᎐
3
1691s (C᎐O), 1594 (ArC᎐C), 1250s (C–O–C), 1003m and 913m
᎐
᎐
(᎐CH); δ (200 MHz; CDCl3; Me4Si) 7.48–7.32 (5H, m, Ph),
᎐
H
6.43 (1H, s, 5-H), 5.95–5.75 (1H, m, 2Ј-H), 4.98–4.87 (2H, m,
3Ј-H2), 4.90 (2H, s, OCH2), 3.89 and 3.81 (each 3H, s, OCH3),
3.42 (2H, br dt, J 6.2 and 1.6, 1Ј-H2) and 2.45 (3H, s, COCH3);
δC (50.32 MHz; CDCl3) 204.6 (CO), 154.0, 153.3, 140.0
(3 × ArC–O), 137.7 (ArC–C), 136.9 (2Ј-C), 131.8 (ArC–C),
128.3, 127.9, 127.8 (3 × PhC), 124.0 (ArC–C), 115.5 (3Ј-C),
95.1 (5-C), 74.9 (OCH2), 55.9 and 55.8 (2 × OCH3), 32.6
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
803

View Article Online
νmax(film)/cmϪ1 1682s (C᎐O), 1602s and 1573m (ArC᎐C),
until no further effervescence was observed. The mixture was
᎐
᎐
1386m and 1375m [CH3, CH(CH3)2] and 1261s (C–O–C);
δH (400 MHz; CDCl3; Me4Si) 10.31 (1H, s, CHO), 7.78 (1H, d,
J 8.7, 6-H), 6.47 (1H, dd, J 8.7 and 2.2, 5-H), 6.43 (1H, d, J 2.2,
3-H), 4.66–4.59 [2H, m, 2 × CH(CH3)2], 1.39 [6H, d, J 6.0,
CH(CH3)2] and 1.36 [6H, d, J 6.1, CH(CH3)2]; δC (100.63 MHz;
CDCl3) 188.2 (CHO), 164.4 and 162.2 (2 × ArC–O), 129.9
(6-C), 119.3 (1-C), 106.9 (5-C), 101.0 (3-C), 70.8 and 70.1
[2 × CH(CH3)2] and 21.7 [2 × CH(CH3)2]; m/z (EI) 222 (Mϩ,
29%), 180 (12), 138 (100), 109 (4) and 43 (14).
extracted with dichloromethane (6 × 50 cm3) and this extract
was dried (MgSO4) and the solvent was removed in vacuo.
The resultant residue was purified by column chromatography
(5–10% ethyl acetate–hexane) to afford the ketone 20 as a dark
oil (1.30 g, 94%) (Found: Mϩ, 292.1971. C17H24O4 requires M,
292.1675); νmax(film)/cmϪ1 1762s (C᎐O), 1655 (ArC᎐C), 1409m
᎐
᎐
(CH3, CH3CO), 1384m and 1373m (–CH3), 1021m (C–O–C)
and 999m and 916m (᎐CH); δH (200 MHz; CDCl3; Me4Si) 7.44
᎐
(1H, s, 6-H), 6.50 (1H, s, 3-H), 6.13–5.96 (1H, m, 2Ј-H), 5.46–
5.20 (2H, m, 3Ј-H2), 4.65–4.53 [4H, m, 2 × CH(CH3)2 and
1Ј-H2], 2.60 (3H, s, COCH3) and 1.39 [12H, d, J 6.1, 4 ×
2,4-Diisopropoxybenzaldehyde (16.9 g, 75.8 mmol) was dis-
solved in distilled methanol (100 cm3) and the solution was
cooled in an ice-bath. Magnesium monoperoxyphthalic acid
hexahydrate (MMPP) (56.3 g, 0.11 mol) was added gradually to
the stirred solution over a period of 20 min. The solution was
left to stir for 60 h at room temperature under nitrogen. The
solution, which changed from pale yellow to pink, was filtered
and then solvent was removed in vacuo. The resultant red oil
was purified by column chromatography (10% ethyl acetate–
hexane). The phenol 18 was isolated as a yellow oil (10.07 g,
63%) (Found: Mϩ, 210.1242. C12H18O3 requires M, 210.1256);
CH(CH ) ]; δ (50.32 MHz; CDCl ) 197.5 (C᎐O), 153.6, 152.8
᎐
3
2
C
3
and 143.0 (3 × ArC–O), 133.4 (2Ј-C), 120.9 (1-C), 117.1 (3Ј-C),
116.2 (6-C), 102.6 (3-C), 71.8 and 71.2 [2 × CH(CH3)2], 70.4
(1Ј-C), 32.2 (COCH3) and 22.0 and 21.9 [2 × CH(CH3)2]; m/z
(EI) 292 (Mϩ, 17%), 277 (4), 250 (3), 235 (2), 209 (7), 167 (100),
149 (77) and 41 (60).
2-Allyl-3-benzyloxy-4,6-diisopropoxyacetophenone 22
Ketone 20 (1.00 g, 3.42 mmol) was heated in an oil-bath at
160 ЊC for 24 h under an argon atmosphere until NMR spec-
troscopy showed that the Claisen rearrangement was complete.
Acetone (50 cm3), benzyl bromide (2.9 g, 17.0 mmol) and
anhydrous potassium carbonate (2.4 g, 17.0 mmol) were added
and the reaction mixture was heated at reflux, under an argon
atmosphere, for 17 h. After cooling, the solution was filtered
and the solvent was removed in vacuo. The resulting brown oil
was purified by column chromatography (hexane, and then
5% ethyl acetate–hexane) to afford the ketone 22 as a clear yel-
low oil (1.03 g, 79%) (Found: Mϩ, 382.2139. C24H30O4 requires
M, 382.2144); νmax(film)/cmϪ1 1692s (C᎐O), 1591vs (ArC᎐C),
νmax (film)/cmϪ1 4000br (OH), 1594s, (ArC᎐C), 1385m and
᎐
1373m [C–CH3, CH(CH3)2], 1284s (C–O–C) and 1001s and
987s (C–O, C–OH); δH (200 MHz; CDCl3; Me4Si) 6.80 (1H, d,
J 8.7, 6-H), 6.49 (1H, d, J 2.7, 3-H), 6.37 (1H, dd, J 8.7 and
2.7, 5-H), 5.70 (1H, br s, OH), 4.46 and 4.36 [each 1H, sept,
J 6.1, 2 × CH(CH3)2] and 1.27 and 1.26 [each 6H, d, J 6.1,
CH(CH3)2]; δC (50.32 MHz; CDCl3) 151.0, 144.8 and 140.7
(3 × ArC–O), 114.1 (6-C), 107.7 (3-C), 104.0 (5-C), 71.1 and
70.5 [2 × CH(CH3)2] and 21.7 and 21.6 [2 × CH(CH3)2]; m/z
(EI) 210 (Mϩ, 77%), 168 (27) and 126 (100).
᎐
᎐
1-Allyloxy-2,4-diisopropoxybenzene 14
1421m (–CH3, CH3CO), 1373m (–CH3), 1218s (C–O–C),
2,4-Diisopropoxyphenol 18 (10.0 g, 47.8 mmol) was dissolved
in acetone (400 cm3). Anhydrous potassium carbonate (16.5 g,
0.12 mmol) and allyl bromide (10.3 cm3, 14.4 g, 0.12 mol) were
added and the stirred solution was heated at reflux under a
nitrogen atmosphere for 24 h. Excess of anhydrous potassium
carbonate (16.5 g, 0.12 mol) and allyl bromide (10.3 cm3, 14.4 g,
0.12 mol) were added and the solution was heated at reflux
under a nitrogen atmosphere for a further 24 h. The solution
was then filtered and the solvent removed in vacuo. The result-
ant yellow oil was purified by column chromatography (5%
ethyl acetate–hexane). The triether 14 was isolated as a yellow
oil (11.17 g, 94%) (Found: Mϩ, 250.1556. C15H22O3 requires M,
1172m and 1160m (–CH ) and 999m and 912m (᎐CH); δH (400
᎐
3
MHz; CDCl3; Me4Si) 7.47–7.30 (5H, m, Ph), 6.42 (1H, s, 5-H),
5.90–5.80 (1H, m, 2Ј-H), 4.96–4.90 (2H, m, 3Ј-H2), 4.91 (2H, s,
OCH2), 4.58 [1H, sept, J 6.1, CH(CH3)2], 4.46 [1H, sept, J 6.1,
CH(CH3)2], 3.42 (2H, br dt, J 6.2 and 1.5, 1Ј-H), 2.46 (3H, s,
COCH3), 1.37 [6H, d, J 6.1, CH(CH3)2] and 1.31 [6H, d, J 6.1,
CH(CH3)2]; δC (100.63 MHz; CDCl3) 204.9 (CO), 151.9, 151.2
and 141.4 (3 × ArC–O), 137.9 (ArC–C), 137.0 (2Ј-C), 131.9
(ArC–C), 128.2, 127.9 and 127.7 (3 × PhC), 125.8 (ArC–C),
115.3 (3Ј-C), 100.9 (5-C), 74.7 (CH2), 71.3 and 71.1 [2 ×
CH(CH3)2], 32.6 (COCH3), 30.6 (1Ј-C) and 22.0 and 22.0
[2 × CH(CH3)2]; m/z (EI) 382 (Mϩ, 52%), 291 (28), 249 (15), 207
(100), 165 (7), 91 (59) and 41 (13).
250.1569); νmax(film)/cmϪ1 1612m and 1584m (ArC᎐C), 1382m
᎐
and 1372m (–CH3), 1241s (C–O–C), 1167m (–CH3) and 1000s
and 929m (᎐CH); δ (200 MHz; CDCl3; Me4Si) 6.81 (1H, d,
1-(2-Allyl-3-benzyloxy-4,6-diisopropoxyphenyl)ethanol 24
᎐
H
J 8.8, 6-H), 6.52 (1H, d, J 2.9, 3-H), 6.40 (1H, dd, J 8.8 and 2.9,
5-H), 6.04 (1H, ddt, J 17.2, 10.5 and 5.2, 2Ј-H), 5.37 (1H, dd,
J 17.2 and 1.6, 3Ј-H), 5.22 (1H, dd, J 10.5 and 1.6, 3Ј-H), 4.52–
4.38 [4H, m, 1Ј-H2 and 2 × CH(CH3)2], 1.34 [6H, d, J 6.1,
CH(CH3)2] and 1.29 [6H, d, J 6.0, CH(CH3)2]; δC (100.63 MHz;
CDCl3) 152.8, 149.0 and 143.7 (3 × ArC–O), 134.1 (2Ј-C), 116.8
(3Ј-Ca), 116.7 (6-Ca), 107.4 (3-Cb), 106.8 (5-Cb), 71.6 and 71.1
[2 × CH(CH3)2], 70.4 (1Ј-C) and 22.1 and 22.0 [2 × CH(CH3)2];
m/z (EI) 250 (Mϩ, 11%), 209 (3), 194 (11), 179 (2), 167 (14), 125
(100) and 110 (70).
Lithium aluminium hydride (0.20 g, 5.2 mmol) was added over
a period of 10 min to a solution of ketone 22 (1.00 g, 2.61
mmol) in diethyl ether (100 cm3). The reaction mixture was then
stirred under an argon atmosphere for 2 h. Methanol (10 cm3)
was added carefully, followed by water (20 cm3). The mixture
was then extracted with diethyl ether (3 × 50 cm3), which was
dried (MgSO4) and the solvent was removed in vacuo. The
resultant yellow oil was purified by column chromatography
(10% ethyl acetate–hexane) to afford the alcohol 24 as a clear
yellow oil (0.93 g, 93%) (Found: Mϩ, 384.2303. C24H32O4
requires M, 384.2301); νmax(film)/cmϪ1 3547br (OH), 2867m
5-Allyloxy-2,4-diisopropoxyacetophenone 20
(OCH ), 1594s, (ArC᎐C), 1385s and 1371s [–CH , CH(CH ) ],
᎐
2
3
3 2
Acetic trifluoroacetic anhydride was pre-formed by adding
glacial acetic acid (0.33 cm3, 0.35 g, 5.8 mmol) to stirred TFAA
(0.81 cm3, 1.0 g, 4.8 mmol) and the mixture was then added to a
solution of 1-allyloxy-2,4-diisopropoxybenzene 14 (1.2 g, 4.8
mmol) in dichloromethane (20 cm3) under argon. The solution
was stirred for 72 h and gradually darkened to a purple-blue
colour. Water (20 cm3) and dichloromethane (50 cm3) were
added to the solution, and the excess acid was neutralised by
careful addition of solid sodium hydrogen carbonate during 2 h
1271s (C–O–C, ArC–O–C) and 993s and 909m (᎐CH); δH (400
᎐
MHz; CDCl3; Me4Si) 7.48–7.30 (5H, m, Ph), 6.48 (1H, s,
5-H), 6.00–5.88 (1H, m, 2Ј-H), 5.04–4.88 (4H, m, 3Ј-H2 and
OCH2Ph), 4.61 [1H, sept, J 6.1, CH(CH3)2], 4.53 [1H, sept,
J 6.1, CH(CH3)2], 4.02 (1H, br s, OH), 3.73 (1H, q, J 6.4,
CHCH3), 3.51–3.30 (2H, m, 1Ј-H2), 1.53 (3H, d, J 6.6, CHCH3)
and 1.42–1.32 [12H, m, 2 × CH(CH3)2]; δC (100.63 MHz;
CDCl3) 151.6, 149.6 and 141.3 (3 × ArC–O), 138.0 (ArC–C),
136.9 (2Ј-C), 131.6 (ArC–C), 128.2, 127.9 and 127.7 (3 × PhC),
804
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811

View Article Online
125.1 (ArC–C), 115.4 (3Ј-C), 101.3 (5-C), 74.8 (OCH2), 71.5
and 71.0 [2 × CH(CH3)2], 67.2 (CHOH), 30.5 (1Ј-C), 23.7
(CHCH3) and 22.3, 22.2, 22.1 and 21.9 [2 × CH(CH3)2]; m/z
(EI) 384 (Mϩ, 14%), 293 (58), 251 (13), 209 (36), 191 (100), 163
(15), 91 (58) and 43 (14).
and 22.1 [CH(CH3)2]; m/z (EI) 358, 356 (Mϩ, 9%), 277 (20), 235
(100), 191 (18) and 43 (16).
The intermediate acid 27 (0.670 g, 1.88 mmol) and anhydrous
sodium acetate (0.027 g, 3.29 mmol) were dissolved in acetic
anhydride (15 cm3) and were heated at reflux for 6 h. The reac-
tion mixture was allowed to cool and diluted with water (20
cm3) and diethyl ether (20 cm3). Saturated aq. sodium hydrogen
carbonate was then added with stirring until effervescence had
ceased. The aqueous layer was extracted with diethyl ether
(3 × 50 cm3). The combined organic layers were then dried
(MgSO4), and removed in vacuo. The naphthoate 28 (0.53 g,
74%) was obtained as a yellow crystalline material, mp 108–
109 ЊC (from hexane–ethyl acetate), after purification by
column chromatography (5% ethyl acetate–hexane) (Found:
Mϩ, 380.0255. C19H17BrO5 requires M, 380.0259); νmax(film)/
cmϪ1 1716s (C᎐O), 1600m (ArC᎐C), 1267s (C–O–C), 1213s
5-Benzyloxy-6,8-diisopropoxy-trans-1,3-dimethylisochromane 26
Sublimed potassium tert-butoxide (1.52 g, 13.5 mmol) was
added to a solution of the alcohol 24 (1.30 g, 3.38 mmol) in
DMF (20 cm3). The reaction mixture was stirred under argon at
75 ЊC for 10 min. Water (50 cm3) and ice (10 cm3) were added
and the mixture was extracted with diethyl ether (3 × 50 cm3).
The organic phases were combined, dried (MgSO4), and evap-
orated under vacuum. Subsequent column chromatography
(5% ethyl acetate–hexane) afforded the isochromane 26 (1.11 g,
85%) as a clear oil (Found: Mϩ, 384.2307. C24H32O4 requires M,
᎐
᎐
(C–O) and 693m (C–Br); δH (200 MHz; CDCl3; Me4Si) 8.86
(1H, d, J 1.7, 1-H), 7.71 (1H, d, J 8.6, 7-H), 7.68 (1H, d, J 1.7,
3-H), 6.83 (1H, dd, J 8.6 and 0.4, 6-H), 4.68 [1H, sept, J 6.0,
CH(CH3)2], 3.98 (3H, s, CO2CH3), 2.38 (3H, s, COCH3)
and 1.40 [6H, d, J 6.0, CH(CH3)2]; δC (50.32 MHz; CDCl3)
169.5 (OAca), 165.9 (CO2Mea), 153.4 (5-Cb), 147.2 (4-Cb), 134.1
(8a-C), 131.1 (7-Cc), 128.7 (2-C), 128.4 (1-Cc), 123.5 (4a-C),
119.7 (3-C), 114.3 (8-C), 110.6 (6-C), 70.8 [CH(CH3)2], 52.4
(CO2CH3), 21.7 [CH(CH3)2] and 21.3 (COCH3); m/z (EI) 382,
380 (Mϩ, 60%), 340, 338 (38), 298, 296 (100), 267, 265 (38), 240,
238 (56), 217 (31) and 158 (35).
384.2301); νmax(film)/cmϪ1 1600m (ArC᎐C), 1373m and 1360m
᎐
[–CH3, CH(CH3)2], 1217m (C–O–C) and 1122s, 1066m and
813m (C–O–C); δH (400 MHz; CDCl3; Me4Si) 7.47–7.30 (5H,
m, Ph), 6.37 (1H, s, 7-H), 5.01 (1H, q, J 6.6, 1-H), 4.93 (2H, s,
OCH2), 4.55–4.44 [2H, m, 2 × CH(CH3)2], 3.98–3.93 (1H, m,
3-H), 2.76 (1H, dd, J 17.0 and 3.3, 4-H pseudo-equatorial),
2.30 (1H, dd, J 17.0 and 10.8, 4-H pseudo-axial), 1.48 (3H, d,
J 6.6, 1-CH3), 1.35 (3H, d, J 6.0, 3-CH3), 1.34 [6H, d, J 6.1,
CH(CH3)2], 1.29 [3H, d, J 6.9, CH(CH3)CH3] and 1.27 [3H,
d, J 7.1, CH(CH3)CH3]; δC (100.63 MHz; CDCl3) 149.6,
148.9 and 140.3 (3 × ArC–O), 138.2 and 128.8 (2 × ArC–C),
128.3, 128.1 and 127.8 (3 × PhC), 122.1 (ArC–C), 101.1
(7-C), 74.2 (OCH2), 71.8 and 69.9 [2 × CH(CH3)2], 68.3 (1-C),
62.4 (3-C), 31.0 (4-C), 22.4, 22.3, 22.2 and 22.1
Methyl 8-bromo-5-isopropoxy-4-methoxy-2-naphthoate 30
Potassium hydroxide (0.28 g, 5.0 mmol) in methanol (10 cm3)
was added to a solution of ester 28 (1.59 g, 4.17 mmol) in
methanol (100 cm3) and the reaction mixture was stirred for 1 h
under argon. The methanol was removed in vacuo and the
organic material dissolved in toluene (50 cm3). The organic
phase was washed with water (3 × 100 cm3) and then with
hydrochloric acid (1 M; 100 cm3). The organic phase was then
evaporated in vacuo to afford the intermediate naphthol 29
(1.34 g, 95%) as a yellow solid, mp 103–109 ЊC, which was
not purified further (Found: Mϩ, 338.0151. C15H15BrO4
requires M, 338.0153); νmax(film)/cmϪ1 3360br (OH), 1720s
a
a
(2 × CH(CH3)2 ), 21.9 (1-CH3 ) and 19.8 (3-CH3); m/z (EI)
384 (Mϩ, 18%), 293 (54), 251 (37), 209 (100), 167 (57), 91
(56) and 43 (32).
Methyl 4-acetoxy-8-bromo-5-isopropoxy-2-naphthoate 28
A solution of 2-bromo-5-isopropoxybenzaldehyde18 (2.97 g,
0.12 mmol) and dimethyl succinate (2.14 g, 0.15 mmol) in dry
tert-butyl alcohol (10 cm3) was added to a boiling solution of
freshly sublimed potassium tert-butoxide (1.51 g, 13.4 mmol) in
dry tert-butyl alcohol (40 cm3) over a period of 15 min. The reac-
tion mixture was heated under reflux for a further 45 min, then
allowed to cool, diluted with water (50 cm3) and acidified with
conc. hydrochloric acid. The organic material was extracted
into toluene (3 × 100 cm3) and the solvent removed by evapor-
ation under reduced pressure. Diethyl ether (100 cm3) and sat-
urated aq. sodium hydrogen carbonate (20 cm3) were added to
the resultant oil. The organic phase was separated and the
aqueous phase washed a further two times with diethyl ether
(2 × 100 cm3). The aqueous phase was then made acidic with
conc. hydrochloric acid and the resulting mixture extracted
with diethyl ether (3 × 100 cm3), which was then dried
(MgSO4), and removed under vacuum. The residue was purified
by column chromatography (20% ethyl acetate–hexane) to
afford the intermediate acid 27 as a mixture of geometrical
isomers (60:40). The product 27 was a pale yellow oil which
hardened into an opaque yellow semi-solid (2.88 g, 66%)
(Found: Mϩ, 356.0268. C17H17BrO5 requires M, 356.0259);
νmax(film)/cmϪ1 3200–3100br (COO–H), 1701m (CO2Me), 1659s
(C᎐O), 1600m and 1567 (ArC᎐C), 1280s (C–O–C), 1227s (C–O,
᎐
᎐
ArC–OH) and 1100s (C–O); δH (200 MHz; CDCl3; Me4Si) 9.86
(1H, s, OH), 8.37 (1H, d, J 1.6, 1-H), 7.61 (1H, d, J 8.4, 7-H),
7.45 (1H, d, J 1.6, 3-H), 6.71 (1H, d, J 8.4, 6-H), 4.81 [1H, sept,
J 6.1, CH(CH3)2], 3.97 (3H, s, CO2CH3) and 1.50 [6H, d, J 6.1,
CH(CH3)2]; δC (50.32 MHz; CDCl3) 166.7 (CO2CH3), 155.5
(4-Ca), 153.8 (5-Ca), 134.0 (8a-C), 130.3 (7- and 2-Cb), 120.8
(1-Cb), 118.9 (4a-C), 115.9 (8-C), 110.7 (3-Cc), 108.8 (6-Cc), 73.5
[CH(CH3)2], 52.3 (CO2CH3) and 21.9 [CH(CH3)2]; m/z (EI) 340,
338 (Mϩ, 65%), 298, 296 (100) and 217 (14).
Dimethyl sulfate (1.0 cm3, 1.3 g, 0.11 mol) and potassium
carbonate (1.5 g, 0.11 mol) were added sequentially to a solu-
tion of the foregoing naphthol 29 (0.77 g, 2.3 mmol) in acetone
(100 cm3). The reaction mixture was heated at reflux under an
argon atmosphere for 18 h. The acetone was removed in vacuo
after which water (100 cm3) and diethyl ether (100 cm3) were
added. The organic phase was washed successively with aq.
ammonia (10%; 3 × 100 cm3), water (100 cm3), hydrochloric
acid (10% v/v; 100 cm3) and water (100 cm3). The organic
solvent was dried (MgSO4), and evaporated in vacuo to yield a
crude material, which was purified by column chromatography
(5% ethyl acetate–hexane) to give the ether 30 (0.79 g, 99%) as
thin white crystals, mp 102–103 ЊC (from CH2Cl2–hexane)
(Found: Mϩ, 352.0300. C16H17BrO4 requires M, 352.0310);
νmax(film)/cmϪ1 1728vs (OCO), 1589m (ArC᎐C), 1368s [CH ,
(CO H), 1601 (ArC᎐C), 1368m [CH , CH(CH ) ], 1241s (C–O)
᎐
2
3
3 2
and 706m (C–Br); δH [200 MHz; CO(CD3)2] (assignments in
brackets are for the minor geometrical isomer) 7.80 (7.72) (1H,
s, CH᎐C) 7.55 (7.29) (1H, d, J 8.8, 3-H), 7.04 (6.83) (1H, d,
᎐
J 3.0, 6-H), 6.90 (6.75) (1H, dd, J 8.8 and 3.0, 4-H), 4.58 (4.47)
[1H, sept, J 6.0, CH(CH3)2], 3.82 (3H, s, CO2CH3), (3.63) 3.44
(2H, s and d, J 0.6, CH2) and 1.29 [6H, d, J 6.0, CH(CH3)2];
᎐
3
δC [50.32 MHz; CO(CD ) ] 172.3, 168.0 (168.0) (2 × C᎐O),
CH(CH3)2], 1282vs and 1256s (C–O) and 1163m [CH3,
CH(CH3)2]; δH (200 MHz; CDCl3; Me4Si) 8.56 (1H, d, J 1.4,
1-H), 7.70 (1H, d, J 8.4, 7-H), 7.45 (1H, d, J 1.4, 3-H), 6.87 (1H,
d, J 8.4, 6-H), 4.53 [1H, sept, J 6.0, CH(CH3)2], 4.00 and 3.99
᎐
3
2
158.3 (157.9) (ArC–O), (141.5) 141.1 (3-C), 136.9 (1-Ca), 134.4
(133.9) (6-C), 129.1 (HC᎐Ca), (119.6) 119.4 (4-Cb), 117.7 (117.3)
᎐
(HC᎐Cb), 71.0 (70.9) [CH(CH ) ], 52.6 (CO CH ), 34.0 (CH )
᎐
3
2
2
3
2
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
805

View Article Online
(each 3H, s, CO2CH3 and OCH3) and 1.40 [6H, d, J 6.1,
CH(CH3)2]; δC (50.32 MHz; CDCl3) 166.9 (CO2CH3), 157.7
(5-Ca), 155.0 (4-Ca), 134.4 (8a-C), 131.1 (7-Cb), 128.8 (2-C),
122.8 (1-Cb), 122.6 (4a-C), 115.5 (8-C), 114.8 (6-C), 105.8 (3-C),
73.3 [CH(CH3)2], 56.4 (OCH3), 52.4 (CO2CH3) and 21.9
[CH(CH3)2]; m/z (EI) 354, 352 (Mϩ, 27%), 312, 310 (100), 297,
295 (24), 253, 251 (9) and 172 (9).
6,8-Dimethoxy-trans-1,3-dimethylisochroman-5-ol 33
Method A. 10% Palladium on carbon (0.07 g, 10% by mass)
was added to a solution of isochromane 25 (0.656 g, 2.00 mmol)
in dry methanol (40 cm3) and the mixture was stirred at room
temperature under a hydrogen pressure of one atmosphere.
After 4 h the mixture was filtered through a small Celite plug
and the solvent was removed in vacuo to afford the isochromanol
33 as a dark oil (0.48 g, 100%) (Found: Mϩ, 238.1193. C13H18O4
requires M, 238.1205); νmax(film)/cmϪ1 3300br (OH), 1626s
(8-Bromo-5-isopropoxy-4-methoxy-2-naphthyl)methanol 31
(ArC᎐C), 1260s and 1087s (C–O–C); δ (200 MHz; CDCl3;
᎐
Lithium aluminium hydride (0.020 g, 0.56 mmol) was added to
a solution of compound 30 (0.200 g, 0.56 mmol) in dry diethyl
ether (5 cm3) and the mixture was stirred under an argon
atmosphere for 1 h. The mixture was filtered through a short
Celite column and the solvent was removed in vacuo to yield the
alcohol 31 (0.18 g, 98%) as a clear oil, with identical spectro-
scopic properties to those reported in the literature3e (Found:
Mϩ, 324.0364. C15H17BrO3 requires M, 324.0361); νmax(film)/
cmϪ1 3600m (OH, free), 3347br (OH, hydrogen bonded), 2833m
H
Me4Si) 6.39 (1H, s, 7-H), 5.07 (1H, q, J 6.5, 1-H), 4.55 (1H, br s,
OH), 4.15–3.95 (1H, m, 3-H), 3.86 and 3.77 (each 3H, s, OCH3),
2.81 (1H, dd, J 17.0 and 3.4, 4-H pseudo-equatorial), 2.36
(1H, dd, J 17.0 and 10.8, 4-H pseudo-axial), 1.48 (3H, d, J 6.5,
1-CH3) and 1.33 (3H, d, J 6.1, 3-CH3); δC (50.32 MHz; CDCl3)
148.5, 144.3 and 136.4 (3 × ArC–O), 120.9 and 120.5 (2 ×
ArC–C), 93.8 (7-C), 68.1 (1-C), 62.2 (3-C), 56.2 and 55.8
(2 × OCH3), 30.1 (4-C), 21.9 (1-CH3) and 19.7 (3-CH3); m/z
(EI) 238 (Mϩ, 24%), 223 (100), 208 (14) and 193 (7).
(C–H, OCH ), 1587s and 1573s (ArC᎐C) and 1266s (C–O–C);
᎐
3
δH (400 MHz; CDCl3; Me4Si) 7.64 (1H, d, J 0.8, 8-H), 7.61 (1H,
d, J 8.3, 2-H), 6.83 (1H, d, J 0.8, 6-H), 6.74 (1H, d, J 8.3, 3-H),
4.76 (2H, br s, CH2OH), 4.49 [1H, sept, J 6.1, CH(CH3)2], 3.90
(3H, s, OCH3), 2.42 (1H, br s, OH) and 1.39 [6H, d, J 6.1,
CH(CH3)2]; δC (100.625 MHz; CDCl3) 157.4 (4-Ca), 154.8
(5-Ca), 140.4 (7-C), 134.8 (8a-C), 130.6 (2-C), 119.9 (4a-C),
117.4 (8-C), 114.4 (1-C), 113.0 (6-C), 105.9 (3-C), 73.3
[CH(CH3)2], 65.3 (CH2OH), 56.3 (OCH3) and 21.9 [CH(CH3)2];
m/z (EI) 326, 324 (Mϩ, 31%), 284, 282 (100), 269, 267 (19), 203
(6) and 115 (20).
Method B. A small scoop of palladium black (≈ 0.050 g) in
water was washed with methanol (2 × 20 cm3) followed by dry
methanol (2 × 2 cm3). (CAUTION: dry palladium black is very
pyrophoric and the catalyst must stay wet with solvent.) A
formic acid–methanol mixture (10%; 2 cm3) was added and the
reaction mixture was stirred vigorously for 10 min. The benzyl-
protected compound 25 (0.088 g, 0.27 mmol) was added to the
catalyst in a formic acid–methanol mixture (10%; 2 cm3) and
the reaction mixture was stirred for 45 min at ambient temper-
ature under an argon atmosphere. The palladium black was
removed by filtration and the catalyst was washed with meth-
anol (2 × 20 cm3). The solvent was removed in vacuo to afford
the isochromanol 33 as a dark oil (0.064 g, 100%). Spectral data
for this product were identical to those obtained in method A.
5-Bromo-3-bromomethyl-8-isopropoxy-1-methoxynaphthalene
32
1,2-Dibromotetrachloroethane (0.48 g, 1.47 mmol) was added
to a solution of alcohol 31 (0.478 g, 1.47 mmol) and triphenyl-
phosphine (0.39 g, 1.47 mmol) in dichloromethane (10 cm3).
The reaction mixture was stirred under argon at room tempera-
ture for 30 min, after which the solvent was removed in vacuo.
Column chromatography (5% ethyl acetate–hexane) afforded
the product 32 (0.49 g, 86%) as a white solid, with identical
spectroscopic properties to those reported in the literature.3e
Mp 124–126 ЊC (from acetone) (lit.,3e 126 ЊC, from acetone);
δH (200 MHz; CDCl3; Me4Si) 7.80 (1H, d, J 1.6, 4-H), 7.65 (1H,
d, J 8.4, 6-H), 6.89 (1H, d, J 1.6, 2-H), 6.79 (1H, d, J 8.4, 7-H),
4.63 (2H, s, CH2Br), 4.51 [1H, sept, J 6.1, CH(CH3)2], 3.97 (3H,
s, OCH3) and 1.39 [6H, d, J 6.1, CH(CH3)2]; δC (50.32 MHz;
CDCl3) 158.0 (8-Ca), 155.1 (1-Ca), 136.9 (3-C), 134.8 (4a-C),
131.0 (6-C), 120.4 (8a-C), 120.0 (4-C), 114.3 (5-C), 113.7 (2-C),
107.5 (7-C), 73.3 [CH(CH3)2], 56.4 (OCH3), 34.0 (CH2Br) and
22.0 [CH(CH3)2].
6,8-Dimethoxy-trans-1,3-dimethylisochroman-5-yl trifluoro-
methanesulfonate 35
Dry pyridine (0.27 cm3, 0.26 g, 3.3 mmol) was added to a
solution of isochromanol 33 (0.71 g, 3.00 mmol) in dry chloro-
form (20 cm3) under an argon atmosphere in a Schlenk tube.
This mixture was added through a cannula to a Schlenk tube
containing trifluoromethanesulfonic anhydride (0.95 g, 3.30
mmol), forming a purple-red reaction mixture. The reaction
mixture was then stirred for 18 h under argon. Ice–water (10
cm3) were added and the water layer was extracted with chloro-
form (3 × 10 cm3), which was separated, dried (MgSO4), and
removed in vacuo. Column chromatography (dichloromethane)
yielded the triflate 35 as a white semi-solid (0.98 g, 88%)
(Found: Mϩ, 370.0699. C14H17F3O6S requires M, 370.0698);
νmax(KBr pellet)/cmϪ1 1618m and 1589m (ArC᎐C), 1207vs and
᎐
1135vs (R–SO2–OR), 1086s (C–O–C) and 763m (C–F, CF3);
δH (200 MHz; CDCl3; Me4Si) 6.46 (1H, s, 7-H), 5.03 (1H, q,
J 6.6, 1-H), 4.11–3.96 (1H, m, 3-H), 3.87 and 3.83 (each 3H, s,
OCH3), 2.77 (1H, dd, J 16.8 and 3.3, 4-H pseudo-equatorial),
2.44 (1H, dd, J 16.8 and J 10.6, 4-H pseudo-axial), 1.47 (3H, d,
J 6.6, 1-CH3) and 1.33 (3H, d, J 6.1, 3-CH3); δC (50.32 MHz;
CDCl3) 155.0 and 150.1 (2 × ArC–O), 128.8 (5-C), 121.8 and
120.7 (2 × ArC–C), 118.6 (q, J 320.2, CF3), 94.1 (7-C), 67.8
(1-C), 61.9 (3-C), 56.0 and 55.5 (2 × OCH3), 30.5 (4-C), 21.6
(1-CH3) and 19.4 (3-CH3); m/z (EI) 370 (Mϩ, 22%), 355 (100),
237 (72), 222 (22), 207 (22) and 193 (95).
5-Bromo-8-isopropoxy-1-methoxy-3-methylnaphthalene 4
-Selectride (1 M in tetrahydrofuran; 0.26 cm3, 0.26 mmol) was
added dropwise to a stirred solution of dibromide 32 (0.100 g,
0.26 mmol) in dry dichloromethane (5 cm3) under an argon
atmosphere at 0 ЊC. The reaction mixture was stirred for a
further 2 h, after which the solvent was removed in vacuo. Puri-
fication by column chromatography afforded the naphthalene 4
(0.08 g, 100%) as a white solid, with identical spectroscopic
properties to those reported in the literature.3e Mp 74–76 ЊC
(from propan-2-ol) (lit.,3e 78 ЊC); δH (200 MHz; CDCl3; Me4Si)
7.62–7.58 (1H, m, 4-H), 7.60 (1H, d, J 8.3, 6-H), 6.72–6.68
(1H, m, 2-H), 6.70 (1H, d, J 8.3, 7-H), 4.49 [1H, sept, J 6.1,
CH(CH3)2], 3.92 (3H, s, OCH3), 2.49 (3H, d, J 0.5, ArCH3)
and 1.37 [6H, d, J 6.1, CH(CH3)2]; δC (50.32 MHz; CDCl3)
157.1 (8-Ca), 154.9 (1-Ca), 137.6 (3-C), 135.0 (4a-C), 130.3
(6-C), 119.4 (4-C), 118.9 (8a-C), 113.8 (5-C), 112.2 (2-Cb), 109.4
(7-Cb), 73.1 [CH(CH3)2], 56.4 (OCH3), 22.1 (ArCH3) and 22.0
[CH(CH3)2].
6,8-Dimethoxy-trans-1,3-dimethylisochroman-5-yl diethyl
phosphate 36
Isochromanol 33 (0.18 g, 0.76 mmol) was added to a suspension
of sodium hydride (50% in oil; 0.044 g, 0.91 mmol) in THF (5
cm3) and the mixture was stirred for 20 min under an argon
atmosphere. Diethyl phosphorochloridate (0.12 cm3, 0.91
806
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811

View Article Online
mmol) was added dropwise by syringe and the mixture was
stirred under argon for 20 h. Diethyl ether (50 cm3) was added
and the organic phase was washed with aq. sodium hydroxide
(10% m/v; 3 × 20 cm3). The organic solvent was dried (MgSO4),
and removed in vacuo to give a light yellow residue. This com-
pound was subjected to column chromatography (50% ethyl
acetate–hexane to 10% methanol–hexane) to give the phosphate
ester 36 (0.28 g, 100%) as a light pink solid, mp 74.5–75.5 ЊC
(from chloroform) (Found: C, 54.28; H, 7.32; Mϩ, 374.1483.
C17H27O7P requires C, 54.54; H, 7.32%; M, 374.1494); νmax(KBr
pellet)/cmϪ1 1618 (ArC᎐C), 1280s (P᎐O), 1225m (C–O–C, ArC–
O–C), 1050s (P–O–CAr) and 1032vs and 825w (P–O–C);
δH (200 MHz; CDCl3; Me4Si) 6.38 (1H, s, 7-H), 5.04 (1H, q,
J 6.5, 1-H), 4.29–4.20 (2H, m, CH2CH3), 4.18–3.98 (3H, m,
CH2CH3 and 3-H), 3.87 and 3.80 (each 3H, s, OCH3), 2.89 (1H,
dd, J 17.0 and 3.2, 4-H pseudo-equatorial), 2.46 (1H, dd, J 17.0
and 10.9, 4-H pseudo-axial) and 1.48–1.29 (12H, m, 1- and
3-CH3 and 2 × OCH2CH3); δC (50.32 MHz; CDCl3) (values in
brackets refer to minor diastereomer) 152.6 (152.5) (149.4),
149.4, 131.3 and (131.1) (3 × ArC–O), 127.5, (127.5), 120.1 and
(120.0) (2 × ArC–C), (94.3), 94.3 (7-C), 67.7 (1-C), 64.2, (64.0),
(63.1) and 63.0 (2 × OCH2), 61.9 (3-C), 55.9 and 55.2
(2 × OCH3), 30.7 (4-C), 21.6 (1-CH3), 19.4 (3-CH3), 16.0 (15.9),
15.8 and (15.7) (2 × OCH2CH3); m/z (EI) 374 (Mϩ, 13%), 359
(100) and 205 (32).
δC (50.32 MHz; CDCl3) 155.2 and 154.9 (2 × ArC–O), 134.7
and 122.3 (2 × ArC–C), 104.4 (5-C), 94.2 (7-C), 67.9 (1-C), 62.6
(3-C), 56.3 and 55.3 (2 × OCH3), 36.9 (4-C), 21.7 (1-CH3) and
19.5 (3-CH3); m/z (EI) 302, 300 (Mϩ, 11%), 287, 285 (100), 221
(4) and 206 (7).
5-Iodo-6,8-dimethoxy-trans-1,3-dimethylisochromane 10
Sublimed iodine (0.23 g, 0.89 mmol) and silver() sulfate (0.28 g,
0.89 mmol) in absolute ethanol (10 cm3) were added dropwise
to a stirred solution of 38 (0.17 g, 1.08 mmol) in absolute
ethanol (10 cm3). Additional absolute ethanol (10 cm3) was
used to wash residues from the dropping funnel into the reac-
tion mixture. The mixture was stirred under argon at room
temperature for 3 h, during which time the mixture colour
changed from an orange to a bright yellow. The precipitate was
filtered off, and washed with ethanol (20 cm3). The organic
solvent was then removed under vacuum and replaced with
dichloromethane (10 cm3) to give a bright yellow solution. This
solution was washed successively with aq. sodium hydroxide
(10% m/v; 20 cm3) and water (20 cm3). The organic phase was
separated, dried (MgSO4), and then evaporated in vacuo. Purifi-
cation by flash chromatography afforded the iodide 10 as a
white solid (0.25 g, 94%), mp 111–112 ЊC (from ethanol; sub-
limes above 85 ЊC and goes green with time) (Found: Mϩ,
348.0221. C13H17IO3 requires M, 348.0222); νmax(KBr pellet)/
cmϪ1 2850w (OCH ), 1600m and 1566 (ArC᎐C) and 1215s,
᎐
᎐
᎐
3
6,8-Dimethoxy-trans-1,3-dimethylisochroman 38
1171m, 1069s and 816m (C–O–C); δH (400 MHz; CDCl3;
Me4Si) 6.34 (1H, s, 7-H), 5.02 (1H, q, J 6.6, 1-H), 4.08–4.03
(1H, m, 3-H), 3.87 and 3.83 (each 3H, s, OCH3), 2.74 (1H, dd,
J 17.0 and 3.5, 4-H pseudo-equatorial), 2.35 (1H, dd, J 17.0 and
10.8, 4-H pseudo-axial), 1.46 (3H, d, J 6.6, 1-CH3) and 1.35
(3H, d, J 6.1, 3-CH3); δC (100.63 MHz; CDCl3) 157.1 and 156.5
(2 × ArC–O), 137.5 and 122.9 (2 × ArC–C), 93.5 (7-C), 82.2
(5-C), 68.0 (1-C), 63.1 (3-C), 56.4 and 55.3 (2 × OCH3), 42.3
(4-C), 21.7 (1-CH3) and 19.5 (3-CH3); m/z (EI) 348 (Mϩ, 16%)
and 333 (100).
Phosphate 38 (0.28 g, 0.75 mmol) was dissolved in diethyl ether
(5 cm3) and added to a stirred solution of liquid ammonia (50
cm3) at Ϫ78 ЊC. Potassium metal was added in small pieces until
a dark blue colour persisted for 15 min. Excess of ammonium
chloride was then added and propan-2-ol (50 cm3) was added to
destroy excess of potassium metal. The ammonia was allowed
to evaporate overnight and water (20 cm3) was added to the
mixture. The aqueous layer was extracted with diethyl ether
(5 × 20 cm3), which was dried (MgSO4), and concentrated
in vacuo. Column chromatography gave the isochromane 38 as
a clear oil (0.17 g, 100%) (Found: Mϩ, 222.1268. C13H18O3
requires M, 222.1256); νmax(film)/cmϪ1 2850m (OCH3), 1608m
6,8-Diisopropoxy-trans-1,3-dimethylisochroman-5-ol 34
10% Palladium on carbon (0.11 g; 10% by mass) was added to a
solution of isochromane 26 (1.09 g, 2.83 mmol) in dry methanol
(50 cm3) and the mixture was stirred at room temperature in an
autoclave at a hydrogen pressure of one atmosphere. After 2 h
the mixture was filtered through a small Celite plug and the
solvent was removed in vacuo to afford the isochromanol 34
(0.82 g, 100%) as a brown oily, low melting solid (Found: Mϩ,
294.1844. C17H26O4 requires M, 294.1831); νmax(film)/cmϪ1
and 1600 (ArC᎐C) and 1212s and 1090s (C–O–C); δ (200
᎐
H
MHz; CDCl3; Me4Si) 6.29 (1H, d, J 2.3, 5-H), 6.21 (1H, d, J 2.3,
7-H), 5.03 (1H, q, J 6.5, 1-H), 4.16–4.00 (1H, m, 3-H), 3.78 (6H,
s, 2 × OCH3), 2.68–2.49 (2H, m, 4-H2), 1.48 (3H, d, J 6.5,
1-CH3) and 1.30 (3H, d, J 6.1, 3-CH3); δC (50.32 MHz; CDCl3)
158.9 and 156.5 (2 × ArC–O), 135.1 and 120.6 (2 × ArC–C),
104.0 (5-C), 96.3 (7-C), 68.3 (1-C), 62.6 (3-C), 55.2 and 55.1
(2 × OCH3), 36.4 (4-C), 21.8 (1-CH3) and 19.8 (3-CH3); m/z (EI)
222 (Mϩ, 18%), 207 (100), 192 (6) and 177 (6).
3547br (OH), 1617s (ArC᎐C), 1383m and 1373m [CH , CH-
᎐
3
(CH3)2], 1244m (C–O–C), 1121vs (C–OH) and 1100m, 1064m
and 814m (C–O–C); δH (400 MHz; CDCl3; Me4Si) 6.35 (1H, s,
7-H), 5.36 (1H, s, OH), 5.03 (1H, q, J 6.6, 1-H), 4.47 [1H, sept,
J 6.1, CH(CH3)2], 4.39 [1H, sept, J 6.0, CH(CH3)2], 4.07–4.02
(1H, m, 3-H), 2.79 (1H, dd, J 17.0 and 3.4, 4-H pseudo-
equatorial), 2.36 (1H, dd, J 17.0 and 10.9, 4-H pseudo-axial),
1.49 (3H, d, J 6.6, 1-CH3), 1.36–1.32 [12H, m, 2 × CH(CH3)2]
and 1.26 (3H, d, J 6.0, 3-CH3); δC (100.63 MHz; CDCl3) 146.3,
142.0 and 137.7 (3 × ArC–O), 122.3 and 120.8 (2 × ArC–C),
99.1 (7-C), 72.2 and 70.5 [2 × CH(CH3)2], 68.4 (1-C), 62.2
5-Bromo-6,8-dimethoxy-trans-1,3-dimethylisochromane 12
Isochromane 38 (0.155 g, 0.70 mmol) was dissolved in a mixture
of chloroform (5 cm3) and acetic acid (5 cm3) and the solution
was cooled to 0 ЊC under an atmosphere of argon. Bromine
(0.036 cm3, 0.11 g, 0.70 mmol) was dissolved in acetic acid (2.5
cm3) and added slowly by syringe to the stirred solution. After
105 min, water (10 cm3) was added and the mixture was
extracted with chloroform (3 × 20 cm3). The organic layer was
washed successively with water (2 × 10 cm3), saturated aq.
sodium bicarbonate (10 cm3) and brine (10 cm3). After drying
of the organic phase (MgSO4), the solvent was removed in
vacuo and the product 12 was obtained after column chrom-
atography as a clear oil (0.19 g, 93%) (Found: Mϩ, 300.0353.
C13H1779BrO3 requires M, 300.0361); νmax(film)/cmϪ1 2850m
a
(3-C), 30.3 (4-C), 22.3, 22.3, 22.1 and 22.0 [2 × CH(CH3)2 ],
a
22.0 (1-CH3 ) and 19.8 (3-CH3); m/z (EI) 294 (Mϩ, 34%), 279
(57), 237 (56), 195 (100) and 167 (10).
6,8-Diisopropoxy-trans-1,3-dimethylisochroman-5-yl diethyl
phosphate 37
(OCH ), 1598m and 1575m (ArC᎐C) and 1212vs and 1078m
᎐
3
(C–O–C); δH (200 MHz; CDCl3; Me4Si) 6.38 (1H, s, 7-H), 5.04
(1H, q, J 6.6, 1-H), 4.14–3.92 (1H, m, 3-H), 3.89 and 3.82 (each
3H, s, OCH3), 2.83 (1H, dd, J 17.3 and 3.5, 4-H pseudo-
equatorial), 2.37 (1H, dd, J 17.3 and 10.9, 4-H pseudo-axial),
1.47 (3H, d, J 6.6, 1-CH3) and 1.34 (3H, d, J 6.1, 3-CH3);
Sodium hydride (60% in oil; 0.13 g, 3.24 mmol) was added to a
solution of isochromanol 34 (0.79 g, 2.7 mmol) in THF (50
cm3) and the mixture was stirred for 20 min under an argon
atmosphere. Diethyl phosphorochloridate (0.43 cm3, 0.51 g, 3.0
mmol) was added dropwise by syringe and the mixture was
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
807

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stirred at room temperature for 20 h. Diethyl ether (50 cm3) was
added and the organic phase was washed successively with aq.
sodium hydroxide (10% m/v; 3 × 20 cm3) and water (50 cm3).
The organic layer was dried (MgSO4), and removed in vacuo to
give a light yellow residue. This was purified by column chrom-
atography (50% ethyl acetate–hexane to 10% methanol–hexane)
to give the phosphate ester 37 as a clear oil (0.93 g, 81%)
(Found: Mϩ, 430.2111. C21H35O7 requires M, 430.2120); νmax
CH(CH3)2], 68.3 (1-C), 63.2 (3-C), 42.7 (4-C), 22.2, 22.2, 22.0
a a
and 21.9 [2 × CH(CH3)2 ], 21.8 (1-CH3 ) and 19.6 (3-CH3); m/z
(EI) 404 (Mϩ, 36%), 389 (100), 347 (70), 305 (92) and 178 (7).
6,7-Dimethoxy-trans-1,3-dimethyl-5-(1-naphthyl)isochromane
43
Method 1. Bromide 12 (0.090 g, 0.30 mmol), 1-naphthyl-
boronic acid 40 (0.10 g, 0.60 mmol) and tetrakis(triphenyl-
phosphine)palladium(0) (0.035 g, 0.03 mmol, 10 mol%) were
added under a stream of argon to a Pyrex culture tube.
Degassed toluene (1.5 cm3) and saturated aq. sodium bicarbon-
ate (1.5 cm3) were added and the tube was sealed. The tube was
then heated at 110 ЊC for 20 h, and then allowed to cool to
ambient temperature. Brine (10 cm3) was added and the mixture
was extracted with ethyl acetate (3 × 5 cm3). The organic
extracts were combined, dried (MgSO4), and then the solvent
was removed in vacuo. Purification of the residue by preparative
thin-layer chromatography (PLC) (5% ethyl acetate–hexane)
afforded the biaryl compound 43 as a brown oil (0.029 g, 28%)
(diastereomeric ratio 66:34), naphthalene (0.020 g, 26%) and
unreacted bromoisochromane 12 (0.033 g, 37%) (Found: Mϩ,
348.1717. C23H24O3 requires M, 348.1725); νmax(film)/cmϪ1
(film)/cmϪ1 2860w (OCH ), 1610m (ArC᎐C), 1367m (CH ),
᎐
2
3
1295m (P᎐O), 1124s (C–O–C) and 1035s (P–O–C); δ (400
᎐
H
MHz; CDCl3; Me4Si) 6.36 (1H, s, 7-H), 5.00 (1H, q, J 6.5, 1-H),
4.54–4.44 [2H, m, 2 × CH(CH3)2], 4.28–4.21 (4H, m, 2 ×
CH2CH3), 4.05–4.00 (1H, m, 3-H), 2.90 (1H, dd, J 16.9 and 3.1,
4-H pseudo-equatorial), 2.46 (1H, dd, J 16.9 and 10.9, 4-H
pseudo-axial), 1.47 (3H, d, J 6.6, 1-CH3), 1.37–1.33 (15H, m,
5 × CH3), 1.31 (3H, d, J 6.1, CH3) and 1.29 (3H, d, J 6.0,
3-CH3); δC (100.63 MHz; CDCl3) (values in parentheses refer to
the minor stereoisomer) 150.5 (150.4), 147.4 (147.4) (132.3) and
132.2, (3 × ArC–O), 127.8 (127.8) and 121.3 (2 × ArC–C), 99.0
(7-C), 71.1 and 69.8 [2 × CH(CH3)], 67.9 (1-C), (64.0), 63.9,
63.9 and (63.9) (2 × OCH2CH3), 62.0 (3-C), 30.9 (4-C), 21.9
a
a
(1-CH3 ), 21.9, 21.8, 21.8 and 21.7 [2 × CH(CH3)2 ], 19.4
a
(3-CH3 ) and 15.9 and 15.9 (2 × OCH2CH3); m/z (EI) 430 (Mϩ,
3055w (ArC–H), 2837w (C–H, OCH ), 1597s (ArC᎐C), 1485m
᎐
3
31%), 415 (62), 373 (100), 331 (33) and 43 (20).
(ArC–C) and 1210s, 1087s and 1070m (C–O–C); δH (400 MHz;
CDCl3) (assignments in brackets are for the minor diastereo-
isomer) 7.90–7.84 (2H, m, 2 × ArH), 7.55–7.24 (5H, m,
5 × ArH), 6.49 (1H, s, 7-H), 5.18–5.14 (1H, m, 1-H), 3.90–3.80
(1H, m overlapping with OCH3, 3-H) (3.92), 3.91 (3H, s, OCH3)
(3.61), 3.60 (3H, s, OCH3), 2.25–2.17 (1H, m, 4-H pseudo-
equatorial), 1.93–1.87 (1H, m, 4-H pseudo-axial), 1.56 (1.55)
(3H, d, J 6.5, 1-CH3) and 1.07 (1.04) (3H, d, J 6.1, 3-CH3);
δC (100.63 MHz; CDCl3) (156.8), 156.7, 155.8 (3 × ArC–O),
135.1, 134.6 (134.5), 133.7 (133.7), 132.7 (4a-, 1Ј-, 4aЈ-, 8aЈ-C),
128.2 (128.2), 128.0 (127.6), 127.3 (125.9) (125.8), 125.8, 125.7
(125.6), 125.6, 125.6 and (125.5) (7 × ArC–H), 120.4 (120.3)
120.2 and 120.1 (8a- and 5-C), 93.3 (93.3) (7-C), 68.4 (68.3)
(1-C), 62.8 (62.7) (3-C) (56.1), 56.0 and 55.3 (2 × OCH3), 34.7
(33.8) (4-C), 21.8 (21.7) (1-CH3) and 20.0 (19.9) (3-CH3); m/z
(EI) 348 (Mϩ, 75%), 334 (100) and 166 (45).
6,8-Diisopropoxy-trans-1,3-dimethylisochromane 39
Liquid ammonia (50 cm3) was distilled into a solution of iso-
chromane 37 (0.53 g, 1.23 mmol) in diethyl ether (5 cm3) at
Ϫ78 ЊC. Potassium metal was added in small pieces until a dark
blue colour persisted for 15 min. Excess of ammonium chloride
was then added and propan-2-ol (50 cm3) was added to destroy
excess of potassium metal. The ammonia was allowed to
evaporate overnight and water (50 cm3) was added to the mix-
ture. The aqueous layer was extracted with diethyl ether (3 × 50
cm3), which was dried (MgSO4), and concentrated in vacuo.
Column chromatography gave the isochromane 39 as a clear oil
(0.31 g, 91%) (Found: Mϩ, 278.1875. C17H26O3 requires M,
278.1882); νmax(film)/cmϪ1 1610s and 1591 (ArC᎐C), 1383m and
᎐
1372m [CH3, CH(CH3)2] and 1204m, 1069s and 829m (C–O–
C); δH (400 MHz; CDCl3; Me4Si) 6.25 (1H, d, J 2.1, 5-H), 6.18
(1H, d, J 2.1, 7-H), 5.00 (1H, q, J 6.6, 1-H), 4.53–4.45 [2H, m,
2 × CH(CH3)2], 4.09–4.04 (1H, m, 3-H), 2.62–2.51 (2H, m,
4-H2), 1.48 (3H, d, J 6.6, 1-CH3), 1.34–1.31 [9H, m, CH(CH3)-
CH3, CH(CH3)2], 1.30 [3H, d, J 6.0, CH(CH3)CH3] and 1.28
(3H, d, J 6.1, 3-CH3); δC (100.63 MHz; CDCl3) 157.0 and 154.6
(2 × ArC–O), 135.1 and 121.1 (2 × ArC–C), 106.0 (5-C), 99.5
(7-C), 69.8 and 69.5 [2 × CH(CH3)2], 68.5 (1-C), 62.6 (3-C),
Method 2. Isochromane 12 (0.050 g, 0.17 mmol) and
1-naphthylboronic acid pinacol ester 41 (0.063 g, 0.25 mmol)
were dissolved in DMF (3 cm3) in a Schlenk tube under an
argon atmosphere. The reaction mixture was degassed with
argon for a further 30 min. Dichloro-[1,1Ј-bis(diphenyl-
phosphino)ferrocene]palladium() [PdCl2(dppf)]30 (0.006 g,
0.0083 mmol, 5 mol%) and degassed aq. sodium carbonate
(2 M; 0.42 cm3, 0.083 mol) were added, forming a white precipi-
tate which dissolved when heated at 80 ЊC for 18 h. Water (10
cm3) was added and the reaction mixture was extracted with
diethyl ether (3 × 10 cm3). The organic phase was separated and
washed sequentially with water (10 cm3), brine (10 cm3) and
water (10 cm3), before being dried (MgSO4) and the solvent
removed in vacuo. Purification by PLC (5% ethyl acetate–
hexane) afforded the desired naphthylisochromane 43 (8.0 mg,
14% based on bromoisochromane 12) (diastereomeric ratio
58:42), racemic 1,1Ј-binaphthyl (21.0 mg, 66% based on
boronic ester 41) and debrominated pyran 38 (17.0 mg, 46%
based on bromoisochromane 12). The product 43 was identical
to that synthesized by Method 1.
a
36.5 (4-C), 22.2, 22.1, 22.1 and 21.8 [2 × CH(CH3)2 ], 21.8
a
(1-CH3 ) and 19.8 (3-CH3); m/z (EI) 278 (Mϩ, 18%), 263 (100),
221 (40), 179 (89) and 43 (17).
5-Iodo-6,8-diisopropoxy-trans-1,3-dimethylisochromane 11
Sublimed iodine (0.30 g, 1.19 mmol) and silver() sulfate (0.37 g,
1.19 mmol) in absolute ethanol (15 cm3) were added dropwise
to a stirred solution of 39 (0.30 g, 1.08 mmol) in absolute
ethanol (25 cm3). After 3 h the reaction mixture was treated in
the same manner as for 10 to afford, after purification by flash
chromatography (10% ethyl acetate–hexane), the iodide 11 as a
colourless oil (0.41 g, 94%) (Found: Mϩ, 404.0851. C17H25IO3
requires M, 404.0848); νmax(film)/cmϪ1 1586s and 1560s
(ArC᎐C), 1380s and 1373s [CH , CH(CH ) ], 1212s, 1105s and
᎐
3
3 2
5-(4-Isopropoxy-5-methoxy-7-methyl-1-naphthyl)-6,8-
dimethoxy-trans-1,3-dimethoxyisochromane 7
1071 (C–O–C) and 614m (C–I); δH (200 MHz; CDCl3; Me4Si)
6.34 (1H, s, 7-H), 4.99 (1H, q, J 6.6, 1-H), 4.58–4.43 [2H, m,
2 × CH(CH3)2], 4.11–4.01 (1H, m, 3-H), 2.73 (1H, dd, J 17.0
and 3.6, 4-H pseudo-equatorial), 2.35 (1H, dd, J 17.0 and 10.9,
4-H pseudo-axial), 1.48 (3H, d, J 6.6, 1-CH3), 1.40–1.33 [12H,
m, 2 × CH(CH3)2] and 1.30 (3H, d, J 6.0, 3-CH3); δC (100.63
MHz; CDCl3) 155.7 and 154.4 (2 × ArC–O), 137.8 and 124.4
(2 × ArC–C), 99.2 (7-C), 85.2 (5-C), 72.6 and 69.8 [2 ×
The bromonaphthalene 4 (0.10 g, 0.32 mmol) was dissolved in
dry THF (5 cm3) and the solution was cooled to Ϫ78 ЊC under
an argon atmosphere. n-Butyllithium (1.4 M; 0.27 cm3, 0.38
mmol) was added by syringe over a period of 10 min and the
solution became yellow. After stirring of the mixture for a
further 7 min, triisopropyl borate (0.22 cm3, 0.95 mmol) was
808
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811

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added by syringe and the mixture was stirred at Ϫ78 ЊC for
a further 5 min. The reaction mixture was then warmed to
room temperature over a period of 18 h. Saturated aq.
ammonium chloride (10 cm3) and ice (10 cm3) were added
and the reaction mixture was stirred for a further 10 min before
being extracted successively with diethyl ether (2 × 10 cm3) and
dichloromethane (2 × 10 cm3). The organic phases were com-
bined, dried (MgSO4), and the solvent removed under vacuum
to afford a residue of 4-isopropoxy-5-methoxy-7-methyl-1-
naphthylboronic acid 9 which was used without further purifi-
cation and without delay.
The boronic acid 9 (assume 0.31 mmol) was transferred to a
small round-bottomed flask with DMF (1 cm3) and oxygen was
excluded by three freeze–thaw cycles. The flask was sealed and
transferred to an argon tent. Iodide 10 (0.054 g, 0.15 mmol),
tribasic potassium phosphate (K3PO4) (0.10 g, 0.48 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.031 mmol,
20 mol% based on iodide 10) were added sequentially under
flowing argon. The flask was sealed, and then heated, with
stirring, under an argon atmosphere at 100 ЊC for 65 h. The
mixture was then cooled and brine (10 cm3) was added. The
reaction mixture was extracted with diethyl ether (4 × 10 cm3),
which was dried (MgSO4), and removed in vacuo. Purification
by column chromatography (5–20% ethyl acetate–hexane)
afforded the biaryl compound 7 as a dark oil (0.069 g,
96%) (diastereoisomeric ratio 60:40) (Found: Mϩ, 450.2411.
C28H34O5 requires M, 450.2406); νmax(film)/cmϪ1 2837w (CH,
mixture was cooled to ambient temperature, diluted with brine
(10 cm3) and extracted with diethyl ether (4 × 10 cm3). The
organic layers were then combined, dried (MgSO4), and the
solvent removed in vacuo. Column chromatography (5–20%
ethyl acetate–hexane) and subsequent PLC (5% ethyl acetate–
hexane) afforded the biaryl compound 8 as a yellow oil (0.026 g,
15% based on iodide 11, diastereomeric ratio 62:38) (Found:
Mϩ, 506.3020. C32H42O5 requires M, 506.3032); νmax(film)/cmϪ1
2860m (C–H, OCH ), 1584s (ArC᎐C) and 1274m (C–O–C); δ
᎐
2
H
(400 MHz; CDCl3; Me4Si) (assignments in brackets are for the
minor diastereoisomer) 7.09 (7.05) (1H, d, J 7.9, 2Ј-H), 6.90
(6.85) (1H, d, J 7.9, 3Ј-H), 6.78 (6.69) (1H, br s, 8Ј-Ha), 6.64
(6.63) (1H, d, J 1.3, 6Ј-Ha), 6.56 (1H, s, 7-H), 5.13 (5.12) (1H, d,
J 6.6, 1-H), 4.65–4.53 [2H, m, 2 × CH(CH3)2], 4.03 [1H, sept,
J 6.0, CH(CH3)2], 4.00–3.95 (1H, m, 3-H), 3.95 (3H, s, OCH3),
(2.32) 2.31 (3H, 2 × s, 7Ј-CH3), 2.23 (1H, dd, J 17.1 and 3.1,
4-H pseudo-equatorial), (2.19–2.14) (1H, m, 4-H, pseudo-
equatorial), 2.00–1.93 (1H, m, 4-H pseudo-axial), (1.57) 1.55
(3H, d, J 6.6, 1-CH3) and 1.44–0.87 [21H, m, 3 × CH(CH3)2
and 3-CH3]; δC (100.63 MHz; CDCl3) (156.8), 156.8, 155.3
(155.2) (153.9), 153.9 (153.4) and 153.3 (4 × ArC–O), 136.8
(136.6), 135.4 (135.2), 134.9 and (134.8) (3 × ArC–C), (128.7)
128.4 (2Ј-C), 127.9 (127.8), 123.6 (123.4) (122.0) and 121.8
(3 × ArC–C), 118.1 (118.0) (8Ј-Ca), 117.8 (ArC–C), 112.2
(112.1) (3Ј-C), (108.4) 108.4 (6Ј-Ca), 100.4 (100.3) (7-C), 72.9
(72.8), 72.3 (72.2) (69.6) and 69.4 [3 × CH(CH3)2], (68.6) 68.5
(1-C), 62.8 (3-C) (56.3), 56.2 (OCH3), (34.9) 34.5 (4-C), 22.3–
21.7 [3 × CH(CH3)2, ArCH3, 1-CH3] and (20.0) 20.0 (3-CH3);
m/z (EI) 506 (Mϩ, 100%), 491 (52), 449 (64), 407 (33), 365 (27)
and 183 (31).
OCH ), 1583vs (ArC᎐C), 1372s [–CH , CH(CH ) ], 1277s
᎐
3
3
3 2
(C–O–C), 1175s [–CH3, CH(CH3)2] and 1110s and 812m
(C–O–C); δH (400 MHz; CDCl3; Me4Si) (assignments in
brackets are for the minor diastereoisomer) 6.99 (6.97) (1H, d,
J 7.9, 2Ј-H) (6.83), 6.82 (1H, d, J 7.9, 3Ј-H), 6.68–6.66 and 6.60–
6.55 (2H, m, 6Ј-H and 8Ј-H), 6.40 (1H, s, 7-H), 5.09 (5.07) (1H,
q, J 6.5, 1-H), (4.51) 4.51 [1H, sept, J 6.1, CH(CH3)2], (3.86)
3.86 (3H, s, OCH3), 3.86–3.83 (1H, m overlapping with OCH3,
3-H), 3.84 (3.83) (3H, s, OCH3), 3.55 (3.54) (3H, s, OCH3),
(2.25) 2.23 (3H, s, ArCH3), 2.12 (1H, dd, J 17.1 and 3.3, 4-H
pseudo-equatorial), (2.06) (1H, d, J 17.1, 4-H pseudo-equa-
torial), (1.85) (1H, dd, J 17.1 and 7.3, 4-H pseudo-axial), 1.83
(1H, d, J 17.1, 4-H pseudo-axial), (1.48) 1.47 (3H, d, J 6.5,
1-CH3), (1.36) 1.35 [6H, d, J 6.1, CH(CH3)2] and (1.00) 0.98
(3H, d, J 6.1, 3-CH3); δC (100.63 MHz; CDCl3) 157.1 (157.1),
156.9 (156.8), 155.5, 154.3 and (154.3) (4 × ArC–O), 136.6
(136.5), 135.8 (135.6), 135.0 (134.9) and 128.5 (4 × ArC–C),
128.1 (2Ј-C), 127.1 (127.2), 121.3 (121.2) (120.3) and 120.0 (3 ×
ArC–C), (117.9), 117.8 (8Ј-Ca), 111.5 (111.4) (3Ј-Ca), 108.9
(108.9) (6Ј-Ca), 93.5 (93.5) (2 × 7-C), 72.6 (72.6) [2 ×
CH(CH3)2], 68.3 (68.3) (1-C), 62.8 (3-C), (56.5) 56.4, 56.2 (56.2)
4-(6,8-Dimethoxy-trans-1,3-dimethylisochroman-5-yl)-8-
methoxy-6-methyl-1-naphthol 44
Isopropyl-protected naphthol 7 (0.050 g, 0.11 mmol) was dis-
solved in dry dichloromethane (5 cm3) and the solution was
cooled to Ϫ78 ЊC under an argon atmosphere. Boron tri-
chloride (1 M; 0.33 cm3, 0.33 mmol) was added dropwise over a
period of 5 min. The reaction mixture was stirred for 30 min,
during which time it assumed a dark red colour. The mixture
was then warmed to room temperature and methanol (2 cm3)
was added. The solvent was removed under vacuum and the
residue was purified by column chromatography (5–20% ethyl
acetate–hexane) to afford the phenol 44 as a brown oil (0.023 g,
51%) (diastereoisomeric ratio 66:34) (Found: Mϩ, 408.1944.
C25H28O5 requires M, 408.1937); νmax(film)/cmϪ1 3407br (OH),
1616s and 1589s (ArC᎐C) and 1257s, 1092m, 1079s, 1049m and
᎐
834m (C–O–C); δH (200 MHz; CDCl3; Me4Si) (assignments in
brackets are for the minor diastereoisomer) 9.40 (9.39) (1H, s,
OH), 7.11 (7.06) (1H, d, J 7.9, 3-H), 6.87 (6.86) (1H, d, J 7.9,
2-H), 6.69–6.67 (1H, m, 5-Ha), 6.63–6.59 (1H, m, 7-Ha), 6.48
(1H, s, 7Ј-H), 5.17 (5.14) (1H, q, J 6.6, 1-H), 4.06 (3H, s, OCH3),
4.05–3.80 (1H, m, overlapping with OCH3, 3Ј-H), 3.92 (3H, s,
OCH3), 3.63 (3.62) (3H, s, OCH3), (2.33) 2.32 (3H, d, J 0.7,
ArCH3), 2.24 (1H, dd, J 17.0 and 3.3, 4Ј-H pseudo-equatorial),
(2.20) (1H, dd, J 17.0, 4Ј-H pseudo-equatorial), 1.98–1.84 (1H,
m, 4Ј-H pseudo-axial), (1.56) 1.55 (3H, d, J 6.6, 1-CH3)
and (1.09) 1.07 (3H, d, J 6.1, 3-CH3); δC (50.32 MHz; CDCl3)
156.2, 153.8 and 146.0 (3 × ArC–O), 136.0, 135.5, 135.0 and
130.0 (4 × ArC–C), 129.6 (3-C), 124.8, 120.0 and 118.5
(3 × ArC–C), 118.6 (5-Ca), (109.6), 109.4 (2-Ca), 106.3 (7-Ca),
93.4 (7Ј-C), 68.3 (1Ј-C), 62.8 (3Ј-C) (56.2), 56.2, 56.0 and 55.2
(3 × OCH3), (34.6) 33.7 (4Ј-C), 22.2 (ArCH3), 21.7 (1Ј-CH3)
and 19.9 (3Ј-CH3); m/z (EI) 408 (Mϩ, 54%), 393 (100) and 349
(7).
b
and 55.2 (3 × OCH3), (34.6) 33.6 (4-C), 22.3 (22.2) (ArCH3 ),
b
22.0 [CH(CH3)2 ], 21.7 (21.7) (1-CH3) and 20.0 (20.0) (3-CH3);
m/z (EI) 450 (Mϩ, 74%), 435 (18), 408 (13), 393 (100) and 196
(32).
When this experiment was conducted with bromoiso-
chromane 12 rather than the iodide 10, a lower yield of biaryl 7
was obtained (24%) (diastereomeric ratio 60:40).
6,8-Diisopropoxy-5-(4-isopropoxy-5-methoxy-7-methyl-1-
naphthyl)-trans-1,3-dimethylisochromane 8
2,6-Di-tert-butyl-4-methylphenol (0.054 g, 0.25 mmol), tribasic
potassium phosphate (0.22 g, 0.11 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (0.081 g, 0.07 mmol, 20
mol%) were placed in a two-necked flask. The vessel was purged
with argon and iodide 11 (0.142 g, 0.35 mmol) and boronic
acid 9 (0.192 g, 0.70 mmol) were added sequentially in degassed
DMF (2 × 1 cm3). The dropping funnel was washed with
degassed DMF (0.5 cm3) and the reaction mixture was stirred
and heated at 100–105 ЊC under argon for 94 h. During this
time the reaction mixture colour changed from a dark green to
a bright blue and finally became a dark purple. The reaction
4Ј,4Љ-Bis(6,8-dimethoxy-1,3-trans-dimethylisochroman-5-yl)-
8Ј,8Љ-dimethoxy-6Ј,6Љ-dimethyl-2Ј,2Љ-bi-(1Ј-naphthol) 6
(a) Dimerisation. Phenol 44 (0.015 g, 0.037 mmol) was dis-
solved in freshly dried chloroform (3 cm3) containing triethyl-
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
809

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amine (0.2%). Silver() oxide (0.15 g, 10 mass equiv.) was added
and the mixture was stirred under air for 9 days in the dark until
all the starting material had been consumed with an extra
portion of silver() oxide (0.10 g) added after 2 days. During
this time the reaction mixture assumed a dark purple colour.
The mixture was filtered through a short Celite plug and the
solvent was removed in vacuo. The residue was purified by
column chromatography (5% methanol–dichloromethane) to
afford the intermediate ene-dione 45 (0.016 g, 100%) as a dark,
purple semi-solid (Found: Mϩ, 812.3551. C50H52O10 requires M,
812.3561); m/z (EI) 812 (Mϩ, 100%) and 391 (17).
W. A. L. v. O. would like to thank AECI for additional financial
support. We thank Ms C. F. Broli for preparing some of
the starting materials. Mrs S. Heiss of this University and
Dr P. Boshoff (Cape Technikon) are thanked for recording
NMR spectra and mass spectra, respectively.
References and notes
1 Reviews: (a) G. Bringmann and F. Pokorny, in The Alkaloids.
Chemistry and Pharmacology, ed. G. A. Cordell, Academic Press,
San Diego, 1995, Vol. 46, ch. 4, pp. 127–271; (b) G. Bringmann,
R. Walter and R. Weirich, in Houben-Weyl: Methods of Organic
Chemistry, ed. G. Helmchen, R. W. Hoffmann, J. Mulzer and
E. Schaumann, Georg Thieme Verlag, Stuttgart and New York,
1995, Vol. E21a, pp. 567–586.
2 (a) J. B. McMahon, M. J. Currens, R. J. Gulakowski, R. W.
Buckheit, Jr., C. Lackman-Smith, Y. F. Hallock and M. R. Boyd,
Antimicrob. Agents Chemother., 1995, 39, 484; (b) J. G. Supko and
L. Malspeis, Antimicrob. Agents Chemother., 1995, 39, 9; (c) M.
Boyd, Y. F. Hallock, J. H. Cardellina II, K. P. Manfredi, J. W. Blunt,
J. B. McMahon, R. W. Buckheit, Jr., G. Bringmann, M. Schäffer,
G. M. Cragg, D. W. Thomas and J. G. Jato, J. Med. Chem., 1994, 37,
1740; (d) K. P. Manfredi, J. W. Blunt, J. H. Cardellina II, J. B.
McMahon, L. L. Pannell, G. M. Cragg and M. R. Boyd, J. Med.
Chem., 1991, 34, 3402.
3 Some recent syntheses: (a) T. R. Hoye, M. Chen, B. Hoang, L. Mi
and O. P. Priest, J. Org. Chem., 1999, 64, 7184; (b) T. Watanabe and
M. Uemura, Chem. Commun., 1998, 871; (c) G. Bringmann, R.
Götz, P. A. Keller, R. Walter, M. R. Boyd, F. Lang, A. Garcia,
J. J. Walsh, I. Tellitu, K. V. Bhaskar and T. R. Kelly, J. Org. Chem.,
1998, 63, 1090; (d) P. D. Hobbs, V. Upender and M. I. Dawson,
Synlett, 1997, 965; (e) G. Bringmann, R. Götz, S. Harmsen,
J. Holenz and R. Walter, Liebigs Ann., 1996, 2045; ( f ) T. R. Hoye
and M. Chen, J. Org. Chem., 1996, 61, 7940; (g) P. Chau, I. R.
Czuba, M. A. Rizzacasa, G. Bringmann, K.-P. Gulden and
M. Schäffer, J. Org. Chem., 1996, 61, 7101; (h) V. Upender, D. J.
Pollart, J. Liu, P. D. Hobbs, C. Olsen, W.-R. Chao, B. Bowden,
J. L. Crase, D. W. Thomas, A. Pandey, J. A. Lawson and M. I.
Dawson, J. Heterocycl. Chem., 1996, 33, 1371; (i) T. R. Hoye and
L. Mi, Tetrahedron Lett., 1996, 37, 3097; (j) P. D. Hobbs, V.
Upender, J. Liu, D. J. Pollart, D. W. Thomas and M. I. Dawson,
Chem. Commun., 1996, 923; (k) A. V. R. Rao, M. K. Gurjar, D. V.
Ramana and A. K. Chheda, Heterocycles, 1996, 43, 1; (l) T.
Watanabe, K. Kamikawa and M. Uemura, Tetrahedron Lett., 1995,
36, 6695; (m) B. N. Leighton and M. A. Rizzacasa, J. Org. Chem.,
1995, 60, 5702 and references therein; (n) G. Bringmann,
S. Harmsen, J. Holenz, T. Geuder, R. Götz, P. A. Keller, R. Walter,
Y. F. Hallock, J. H. Cardellina II and M. R. Boyd, Tetrahedron,
1994, 50, 9643; (o) T. R. Kelly, A. Garcia, F. Lang, J. J. Walsh,
K. V. Bhaskar, M. R. Boyd, R. Götz, P. A. Keller, R. Walter and
G. Bringmann, Tetrahedron Lett., 1994, 35, 7621; (p) G. Bringmann,
R. Götz, P. A. Keller, R. Walter, P. Henschel, M. Schäffer,
M. Stäblein, T. R. Kelly and M. R. Boyd, Heterocycles, 1994, 39,
503; (q) T. R. Hoye, M. Chen, L. Mi and O. P. Priest, Tetrahedron
Lett., 1994, 35, 8747; (r) G. Bringmann, R. Weirich, H. Reuscher,
J. R. Jansen, L. Kinzinger and T. Ortmann, Liebigs Ann. Chem.,
1993, 877.
(b) Reduction. Method 1.—10% Palladium on carbon (0.016
g, 1 mass equiv.) was added to a solution of the foregoing ene-
dione 45 (0.016 g) in a dichloromethane (2.5 cm3)–methanol
(2.5 cm3) mixture. The mixture was stirred at ambient temper-
ature under hydrogen (1 atm) for 120 min. The catalyst was
removed by filtration through a short Celite column in a
Pasteur pipette. An additional amount of the dichloromethane–
methanol mixture (50:50; 10 cm3) was used to wash the Celite.
The fractions were combined and the solvent removed in vacuo
to afford a yellow, semi-solid compound (0.014 g) that went oily
after a short period of time. The compound was further puri-
fied on C18 reversed-phase silica (methanol) to yield the product
6 as a semi-solid (0.012 g, 75% over two steps). Over a period of
time the solid darkened to a deep purple colour (Found: Mϩ,
814.3717. C50H54O10 requires M, 814.3717); νmax(film)/cmϪ1
3372br (OH), 2830w (C–H, OCH3) and 1240s and 1081s (C–O–
C); δH (400 MHz; CDCl3; Me4Si) (assignments in brackets are
for the minor diastereoisomer) (unprimed and triply primed
locants refer to the isochromane ring carbons) 9.83–9.73 (2H, m,
1Ј-OH and 1Љ-OH), 7.35–7.30 (2H, m, 3Ј-H and 3Љ-H), 6.91–
6.69 (2H, m, 7Ј-H and 7Љ-Ha), 6.65–6.60 (2H, m, 5Ј- and 5Љ-H),
6.47 (2H, s, 7- and 7ٞ-Ha), 5.17–5.14 (2H, m, 1- and 1ٞ-H), 4.03
b
(4.03) (6H, s, 6- and 6ٞ-OCH3 ), 3.97–3.86 (2H, m overlapping
b
with OCH3s, 3- and 3ٞ-H), 3.90 (6H, s, 8- and 8ٞ-OCH3 ), 3.63
(6H, s, 8Ј- and 8Љ-OCH3), 2.45–2.30 (2H, m, 4- pseudo-
equatorial and 4ٞ-H pseudo-equatorial), 2.35, (2.34), (2.33), 2.32
(6H, 4 × s, 6Ј- and 6Љ-ArCH3), 2.04–1.90 (2H, m, 4- pseudo-axial
and 4ٞ-H pseudo-axial), 1.57–1.52 (6H, m, 1- and 1ٞ-CH3) and
1.12–1.08 (6H, m, 3- and 3ٞ-CH3); δC (100.63 MHz; CDCl3)
157.0 (157.0) (8Ј- and 8Љ-C), 156.5, 156.5 (6-C and 6ٞ-C), 155.4
(155.4) (8- and 8ٞ-C), 150.6 (150.6) (1Ј- and 1Љ-C), 135.2 (6Ј-
and 6Љ-Cc), 135.1 (4aЈ- and 4aЉ-Cc), (135.0) 134.9 (3Ј- and 3Љ-C),
132.8 (132.7) (4a- and 4aٞ-C), (124.1) 124.0 (4Ј- and 4Љ-C),
(120.3) 120.2 (5- and 5ٞ-Cd), 120.0 (120.0) (5Ј- and 5Љ-Cd),
118.6 (2Ј- and 2Љ-Cd), 118.4 (8aЈ- and 8aЉ-C), (113.6) 113.5 (8a-
and 8aٞ-C), 106.3 (7Ј- and 7Љ-C), (93.6) 93.4 (7- and 7ٞ-C), 68.3
(68.3) (1- and 1ٞ-C), (62.9) 62.8 (3- and 3ٞ-C), 56.2 (56.2) (6-
e
e
and 6ٞ-OCH3 ), 56.1 (56.0) (8- and 8ٞ-OCH3 ), 55.2 (8Ј- and 8Љ-
OCH3), 33.7 (4- and 4ٞ-C), 22.1 (6Ј and 6Љ-CH3), 21.7 (3- and
3ٞ-CH3) and 20.0 (1- and 1ٞ-CH3); m/z (EI) 816.3782 (18%)
(M ϩ 2H)ϩ, 815.3748 (57) (M ϩ H)ϩ, 814 (Mϩ, 100) and 392
(22); m/z (ES) 853.3 (50%) (M ϩ K)ϩ, 837.5 (100) (M ϩ Na)ϩ,
815.5 (76) (M ϩ H)ϩ, 771.5 (48) and 407.3 (20).
4 (a) T. Kametani, in The Total Synthesis of Natural Products,
ed. J. ApSimon, John Wiley & Sons, Inc., New York, 1977,
Vol. 3, pp. 1–272; (b) M. D. Rozwadowska, Heterocycles, 1994, 39,
903.
5 T. R. Hoye and L. Mi, J. Org. Chem., 1997, 62, 8586.
6 (a) General reviews: (i) S. P. Stanforth, Tetrahedron, 1998, 54, 263;
(ii) G. Bringmann, R. Walter and R. Weirich, Angew. Chem., Int. Ed.
Engl., 1990, 29, 977; (b) Suzuki coupling reviews: (i) A. Suzuki, Acc.
Chem. Res., 1982, 15, 178; (ii) N. Miyaura and A. Suzuki, Chem.
Rev., 1995, 95, 2457; (iii) A. Suzuki, in Metal-Catalyzed Cross-
Coupling Reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH,
Weinheim, 1998, pp. 49–97; (iv) A. Suzuki, J. Organomet. Chem.,
1999, 576, 147.
Method 2. The foregoing ene-dione 45 (16 mg, 0.019 mmol)
was dissolved in methanol (25 cm3) and irradiated (GEC
Alsthom 1500 W 230 V Visible Light) for 4 min with stirring of
the solution during which time the reaction mixture’s colour
changed from a dark purple to a clear yellow. The solvent
was removed in vacuo and the residue was purified by column
chromatography (5–30% ethyl acetate–hexane) to afford the
product 6 as a yellow oil (0.007 g, 46%). The product 6 had the
same spectroscopic properties as the product obtained from
Method 1.
7 Y. F. Hallock, K. P. Manfredi, J. W. Blunt, J. H. Cardellina II,
M. Schäffer, K.-P. Gulden, G. Bringmann, A. Y. Lee, J. Clardy,
G. François and M. R. Boyd, J. Org. Chem., 1994, 59, 6349.
8 Announcement in J. Nat. Prod., 1992, 55, 1018.
9 (a) G. Bringmann, M. Wenzel, T. R. Kelly, M. R. Boyd, R. J.
Gulakowski and R. Kaminsky, Tetrahedron, 1999, 55, 1731 and
references therein; (b) H. Zhang, D. E. Zembower and Z. Chen,
Bioorg. Med. Chem. Lett., 1997, 7, 2687; (c) ref. 3h.
Acknowledgements
This work was supported by the Foundation for Research
Development (FRD) and the University of the Witwatersrand.
10 C. B. de Koning, J. P. Michael and W. A. L. van Otterlo, Tetrahedron
Lett., 1999, 40, 3037.
810
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24 The results of the single X-ray crystal study confirmed the structure.
Empirical formula C17H27O7P; monoclinic; C2/c; a = 19.798,
b = 11.232, c = 19.333 Å. These results will be reported in full
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Paper a908367g
J. Chem. Soc., Perkin Trans. 1, 2000, 799–811
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