Complementary diastereoselectivity in the intermolecular addition of titanium and magnesium naphtholates to asymmetric lactaldehydes

Article abstract of DOI:10.1039/a901456j

Addition of 7-benzyloxy-4,5-dimethoxy-1-naphthol 3 as its triisopropoxytitanium naphtholate to (2R, 1′R or S)-2-(1′-ethoxyethoxy)propanal 4 afforded solely (15, 2R, 1″R or S)-1-(7′-benzyloxy-4′,5′-dimethoxy-1′-hydroxy-2′- naphthyl)-2-(1″-ethoxyethoxy)propan-l-ol 5, being the erythro product arising from anti addition. Complementary reaction of the naphthol 3 as its bromomagnesium naphtholate with aldehyde 4 gave rise solely to the alternative (1R, 2R, 1″R or S) diastereomer 6. The naphthol 3 was prepared through the completely regioselective addition of 2-methoxyfuran 9 to 5-benzyloxy-3-methoxydehydrobenzene 8. This differentially protected bisalkoxybenzyne was conveniently prepared from vanillin. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a901456j

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Complementary diastereoselectivity in the intermolecular addition
of titanium and magnesium naphtholates to asymmetric
lactaldehydes
Robin G. F. Giles,*a Cynthia A. Joll,a Melvyn V. Sargentb and D. Matthew G. Tilbrookb
a Department of Chemistry, Murdoch University, Murdoch WA 6150, Australia
b Department of Chemistry, The University of Western Australia, Nedlands WA 6907, Australia
Received (in Cambridge, UK) 22nd February 1999, Accepted 3rd August 1999
Addition of 7-benzyloxy-4,5-dimethoxy-1-naphthol 3 as its triisopropoxytitanium naphtholate to (2R, 1ЈR or S)-
2-(1Ј-ethoxyethoxy)propanal 4 afforded solely (1S, 2R, 1ЉR or S)-1-(7Ј-benzyloxy-4Ј,5Ј-dimethoxy-1Ј-hydroxy-2Ј-
naphthyl)-2-(1Љ-ethoxyethoxy)propan-1-ol 5, being the erythro product arising from anti addition. Complementary
reaction of the naphthol 3 as its bromomagnesium naphtholate with aldehyde 4 gave rise solely to the alternative
(1R, 2R, 1ЉR or S) diastereomer 6 . The naphthol 3 was prepared through the completely regioselective addition
of 2-methoxyfuran 9 to 5-benzyloxy-3-methoxydehydrobenzene 8. This differentially protected bisalkoxybenzyne
was conveniently prepared from vanillin.
We have previously reported1 the synthesis in racemic form of
Alternative use of the titanium and magnesium naphtholates of
the aphid pigment derivatives, quinone A 1 and quinone AЈ 2.2
3 with the lactaldehyde derivative 4 would afford the products 5
and 6 of anti and syn addition respectively. Appropriate protec-
tion of the free hydroxy groups in 5 and 6, followed by a Lewis
acid-catalysed Mukaiyama reaction5 of the aryl ether and
acetal functions to achieve ring closure, should afford the
asymmetric naphthopyran system. This type of cyclisation is
related to methods used earlier for the formation of the race-
mates of the less highly substituted naphthopyranquinones
eleutherin and isoeleutherin.6 Standard manipulation of the
individual diastereomers would then afford the asymmetric
quinones 1 and 2. This paper describes syntheses of the naph-
thol 3 and the aldehyde 4 and the completely diastereoselective
reactions of this aldehyde with the titanium and magnesium
naphtholates of 3 to form the respective individual adducts 5
and 6.7 In model studies, the C-2 epimeric aldehyde 35 reacted
similarly with the respective naphtholates of the alternative
naphthol 10 to afford the adducts 37 and 39 with analogous
complete diastereoselectivity.7
Among naturally occurring naphthopyranquinones,3 these
compounds are unusual in that the substituents at C-3 and C-4
are trans in the former and cis in the latter. In considering routes
to asymmetric 1 and 2, we recognised the potential of the
discovery of Casiraghi and co-workers4 that complementary
highly diastereoselective C-arylations of asymmetric aldehydes
can be achieved with the use of either titanium or magnesium
phenolates. Since we have previously shown in the racemic
syntheses of 1 and 2 that benzyl and methyl are convenient
protecting groups for the phenolic oxygens at O-7 and O-9,
respectively, the syntheses shown in Scheme 1 were considered.
Results and discussion
We have previously shown that 3,5-dimethoxybenzyne 7 adds
to 2-methoxyfuran 9 to afford the two regioisomers, 4,5,7-
trimethoxy-1-naphthol 10 and 4,6,8-trimethoxy-1-naphthol 14,
in a high combined yield (77%).8 Importantly, the reaction was
highly regioselective, giving the products 10 and 14 in a ratio of
10:1. For the monobenzyl analogue 3 of 10, it was necessary
to generate the differently protected 5-benzyloxy-3-methoxy-
benzyne 8 for use in a related reaction with 2-methoxyfuran.
Synthesis of precursors to 5-benzyloxy-3-methoxybenzyne 8
The generation of benzyne 7 had been simplified by the ready
preparation of bromo tosylate 16 from the symmetrical tosylate
15.8 For unsymmetrical analogues, the related regioselective
bromination could not be achieved in the desired sense.9
Recognising the potential offered by the framework of the
commercially available starting material vanillin,
a five
step route to the bromo tosylate 20 was investigated (Scheme 2).
Vanillin was smoothly converted into 5-bromovanillin 17,10
from which the corresponding tosylate 18 was formed in high
yield. Attempts to carry out the Baeyer–Villiger oxidation on
Scheme 1
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This journal is © The Royal Society of Chemistry 1999
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The aryl triflate 33 was also investigated as a precursor to the
benzyne 8 on the basis of a report13 that aryl triflates react with
lithium diisopropylamide to form intermediate benzynes. Alde-
hyde 29 was regarded as an appropriate precursor to triflate 33,
and this was obtained through methylation of the known14 sali-
cylaldehyde 28. Baeyer–Villiger oxidation of the aldehyde 29
with meta-chloroperbenzoic acid gave the formate 30, the
product of aryl migration. The crude formate, which showed
Scheme 2
tosylate 18 gave the acid 21, characterised as its benzyl ester 22,
through migration of the hydride,11 and related reactions
occurred for the corresponding acetate and benzoate. Changing
to a more electron donating silyl protecting group provided the
tert-butyldimethylsilyl ether 23, Baeyer–Villiger oxidation of
which gave the desired formate 24. The structural assignment
was supported inter alia by the chemical shifts at δ 6.61 and 6.93
(J 2.6 Hz) of the two meta-coupled protons ortho to the formate
substituent in the 1H NMR spectrum, as well as the character-
istic singlet at δ 8.25 for the formate proton. The corresponding
aromatic resonances for the benzyl ester 22 were δ 7.56 and
7.87.
Since tert-butyldimethylsilyl ethers are stable to potassium
carbonate in methanol,12 the formate 24 was allowed to react
under these conditions with the subsequent addition of benzyl
bromide in a one pot reaction, affording the desired benzyl
ether 26 together with the intermediate phenol 25. The yields of
the products 26 and 25 were 64 and 26%, respectively, and thus
the desired benzyl ether 26 was obtained in a yield of 88% based
on consumed phenol 25. Furthermore, this phenol was recycled
to increase the quantity of the required 26.
Replacement of the silyl protecting group in 26 with tosyl
was also best achieved in a one pot reaction. The silyl ether 26
was treated with tetra-n-butylammonium fluoride in tetra-
hydrofuran, with subsequent addition of tosyl chloride and 1,8-
diazabicyclo[5.4.0]undec-7-ene. This procedure furnished the
required crystalline bromo tosylate 20 in a yield of 89%, which
is an improvement over the yield for a two step procedure
involving the isolation of intermediate phenol 27. Thus, the
bromo tosylate 20 was synthesised in four steps from the known
and readily available 5-bromovanillin 17 in an overall yield of
59%.
1
inter alia a characteristic resonance at δ 8.12 in its H NMR
spectrum for the formate proton, was hydrolysed to the corre-
sponding phenol 31 using methanolic potassium hydroxide.
The phenol 31 was prepared in a yield of 60% over the five steps
from 2,4-dihydroxybenzaldehyde, the starting material for sali-
cylaldehyde 28, which is a significant improvement on literature
methods15,16 from a commercially available starting material.
The monobromination of phenol 31 was investigated in the
hope that this might be achieved ortho to the phenolic substitu-
ent, as this would provide an alternative route, after tosylation,
to the previously prepared bromo tosylate 20. Methods17,18
for exclusive ortho bromination of phenols gave mixtures with
31. Bromination in glacial acetic acid containing sodium
acetate provided the meta-bromophenol 32 in a yield of 60%.
1
The structure 32 was assigned on the basis of the H NMR
spectrum, which showed the two para aromatic protons as two
singlets at δ 6.48 and 7.07, whereas for the isomeric ortho-
bromophenol 27 mentioned above, the two meta aromatic
protons appeared as two doublets (J 2.7 Hz) at δ 6.51 and 6.69.
The phenol 31 was then converted into the triflate 33 in high
yield. This triflate was therefore available in six simple steps
from commercially available 2,4-dihydroxybenzaldehyde in an
overall yield of 55%.
Regioselective Diels–Alder additions
Generation of the required 5-benzyloxy-3-methoxybenzyne 8 in
the presence of 2-methoxyfuran 9 was then investigated. Thus,
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a solution of the bromo tosylate 20 and 2-methoxyfuran 9 in dry
tetrahydrofuran at Ϫ78 ЊC was treated with n-butyllithium.
Acid-induced ring-opening of the derived adduct afforded the
naphthol 3 as a single regioisomer. Since this naphthol 3 was
unstable on standing, it was stored as the stable acetate 11,
isolated in a yield of 46%, or 56% based on consumed starting
material 20.
The triflate 33 was then examined as an alternative source of
the desired benzyne 8. A cooled (Ϫ78 ЊC) solution of lithium
diisopropylamide in tetrahydrofuran was added to a mixture of
the triflate 33 and 2-methoxyfuran 9 in the same solvent at the
same temperature. The derived naphthol 3 was converted into
its acetate 11, which was obtained in an optimised yield of 32%
over the two steps from triflate 33. The use of n-butyllithium in
place of lithium diisopropylamide reduced the overall yield of
11 to 11%.
Confirmation of the regiochemistry of the cycloaddition
reaction to form naphthol 3 was obtained through hydro-
genolysis of the benzyl ether 11 to form the naphthol 12, which
was in turn methylated to form the known trimethoxynaphthyl
acetate 13.19
The acetate 11 was reconverted into the naphthol 3 by reduc-
tion with lithium aluminium hydride immediately prior to its
use in diastereoselective additions.
The mass spectrum of compound 37 gave a molecular ion at
m/z 380 and a fragment ion 38 at m/z 290. In the H NMR
1
spectrum of 37, the major and minor diastereomers showed
vicinal coupling constants between the protons 1-H and 2-H of
4.3 and 4.0 Hz, respectively, and the corresponding 1-H chem-
ical shifts were δ 4.86 and 4.94. A comparison of these with the
related data for the two diastereomers of 39 (vide infra) showed
the compounds 37 to have smaller coupling constants and lower
field chemical shifts than those observed for compounds 39.4b,24
These values confirmed an anti arrangement of the two hetero
atoms at C-1 and C-2 in 37, i.e., compound 37 was the erythro
diastereomer.
Use of the alternative magnesium naphtholate4b of 10 with
the same aldehyde 35, once again under ultrasonication,
afforded the complementary threo product 39, i.e., the product
of solely syn addition. In this case, the yield was 73% and the
mixture of diastereomers at the acetal carbon was separable by
chromatography. The 1H NMR spectra showed vicinal coupling
between 1-H and 2-H for the major and minor diastereomers as
7.8 and 8.5 Hz, for which the 1-H chemical shifts were δ 4.57
and 4.56. These larger coupling constants and higher field
chemical shifts were diagnostic4b,24 of a C-1/C-2 threo arrange-
ment for the adduct.
In the complementary reactions of the titanium and mag-
nesium naphtholates of 10 with aldehyde 35, each process was
shown to be completely diastereoselective since neither 37 nor
Diastereoselective additions of asymmetric aldehydes to
naphthols
1
39 could be detected in the H NMR spectrum of the other
crude product.
In preliminary investigations into the proposed diastereo-
selective additions of the aldehyde 4 to the naphthol 3 to afford
the complementary adducts 5 or 6 (Scheme 1), use was made of
the C-2 epimeric aldehyde 35 and the more readily accessible
naphthol 10.8 The protected lactaldehyde 35 was obtained from
commercially available (S)-ethyl lactate, which is cheaper than
esters of the enantiomeric (R)-lactate.
Protection of the (S)-lactate with ethyl vinyl ether afforded
the ester 34 as a mixture of C-1Ј diastereomers.20 † Reduction
of this mixture with diisobutylaluminium hydride afforded
predominantly the aldehyde 3521 as a 55:45 mixture of C-1Ј
diastereomers, together with some of the diastereomeric alco-
hols 36, which did not interfere with the subsequent reactions.
With some modifications to the literature method,4b the alde-
hyde 35 was added to a toluene solution of the triisopropoxy-
titanium naphtholate of 10 with the application of ultrasonic
irradiation. The required product 37 was obtained with com-
The success of these model reactions encouraged the investi-
gation of the related diastereoselective reactions proposed in
Scheme 1 which would provide the correct absolute stereo-
chemistry for, and ultimately the total synthesis of, asymmetric
quinones A 1 and AЈ 2.
In a series of transformations related to the conversion of
(S)-ethyl lactate into the diastereomeric aldehydes 35 above, the
more expensive (R)-methyl lactate was similarly transformed,
via its ethoxyethyl derivative 40, into the aldehyde 4, contamin-
ated with some alcohol 41, both as mixtures of diastereomers at
the acetal carbon. Reaction of the triisopropoxytitanium naph-
tholate of 3 with the aldehyde 4 under ultrasonication led to the
isolation of the erythro product 5 in an unoptimised yield of
43%. Once again, it was not possible to separate the mixture of
diastereomeric acetals. Confirmation that arylation of the alde-
1
hyde had proceeded in the anti mode was provided by the H
NMR spectrum of adduct 5, in which the chemical shifts of
1-H for the major and minor diastereomers were δ 4.92 and
4.98, with respective 1-H–2-H coupling constants of 4.1 and 3.7
Hz. These chemical shifts were downfield of the corresponding
signals for the C-1 epimer 6 (vide infra) and the coupling con-
stants were smaller. Both these factors are once again diagnos-
tic4b,24 of anti diastereoselectivity for the product 5.
Alternative addition of the bromomagnesium naphtholate of
3 to the aldehyde 4 with ultrasonication afforded only the threo
adduct 6 in a yield of 78%. In this instance, the individual
diastereomers of 6 (~1:1) arising from the ethoxyethyl
protecting group were separated by chromatography. In the 1H
NMR spectra, the vicinal coupling constants (8.5 and 8.0 Hz)
were again larger and the chemical shifts (δ 4.57 and 4.58
respectively) were further upfield than for the corresponding
diastereomers of adduct 5. These data confirmed 6 as the
products of syn addition.
Once again, the use of the complementary titanium and
magnesium naphtholates of 3 with the aldehyde 4 was com-
pletely diastereoselective, leading to the anti and syn adducts,
5 and 6, respectively. The absence of the product 6 in the
titanium-mediated reaction and the alternative product 5 in
the magnesium-mediated reaction was confirmed by the lack
of the diagnostic 1-H signals of the alternative diastereomer in
the 1H NMR spectrum of each product.
plete diastereoselectivity at the newly formed asymmetric centre
C-1, in a yield of 63%. This product was an inseparable mixture
of diastereomers at the acetal carbon.
† Since the resolution achieved in our 1H and 13C NMR spectra was far
superior to that previously reported,21–23 the details of these spectra are
provided in the Experimental section.
The mechanistic aspects of this process of diastereoselective
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arylation of asymmetric α-alkoxy aldehydes by metal phenolates
have been discussed in some depth in the literature.4b,c,25–27 The
phenolates of certain coordinating metals are known to possess
the advantages of being Lewis acids and of providing an
activated nucleophilic aromatic ring with a reactive ortho-
carbon.4b,27 This allows the direct regioselective arylation of
carbonyl electrophiles, with the metal ion involved determining
the stereoselectivity with respect to the neighbouring chiral
centre.
When the metal ion is capable of bis-ligation with the alde-
hydic reactant, i.e., it is capable of chelation with both the alde-
hydic oxygen and the α-oxygen of the reactant, a double-chelate
“Cram cyclic” transition-state pertains.4c,25 This is the case with
the highly oxygenophilic MgBr ion in the magnesium naphtho-
late of 3 leading to a transition state 42 with the aldehyde 4,
Corresponding intramolecular diastereoselective control is
discussed in the accompanying paper.28
Experimental
Melting points were determined on a Reichert hot stage appar-
atus and are uncorrected. Optical rotations were measured
using an Optical Activity PolAAr 2001 polarimeter for chloro-
form solutions of c 1.0 at 20 ЊC unless otherwise stated and are
given in 10Ϫ1 deg cm2 gϪ1. The ultrasonication bath used was a
Branson B3200-E4, operating at a frequency of 44–50 kHz.
GC analyses employed a Hewlett Packard 5790A Series Gas
Chromatograph, with flame ionization detection. Electron
impact mass spectra were obtained on a Hewlett Packard 5986
spectrometer or on a Perkin-Elmer ITD Ion Trap Detector
spectrometer. High resolution mass spectra were measured on
an AEI MS 902 high resolution mass spectrometer. NMR
spectra were recorded using a Hitachi R-24B spectrometer (1H,
60 MHz), a Bruker AM-300 spectrometer (1H, 300 MHz; 13C,
75.5 MHz) or a Bruker ARX-500 spectrometer (1H, 500 MHz;
13C, 126 MHz). Unless otherwise stated, all spectra of purified
products were measured on the Bruker AM-300 spectrometer
in [2H]chloroform with tetramethylsilane as internal reference.
J Values are given in Hz. In the 13C NMR spectra, assignments
of signals with the same superscripts are interchangeable.
Normal work-up (A) refers to extraction with an organic sol-
vent, then washing of the organic extracts with aqueous hydro-
chloric acid (1 M), water, saturated aqueous sodium hydrogen
carbonate solution, water and brine. Normal work-up (B) refers
to addition of an organic solvent and water, removal of the
water layer and the organic layer was then washed with water
and brine. In each case, the organic phase was dried (MgSO4)
and the solvent evaporated under reduced pressure. Hexane
refers to the hydrocarbon fraction with bp 65–70 ЊC. Column
chromatography was performed on Merck silica gel 60 (70–230
mesh) and rapid filtration chromatography on Fluka silica gel
60 (230 mesh). Preadsorption was carried out on Merck silica
gel 60 (35–70 mesh). The adsorbent for radial chromatography
where the Si face of the aldehyde is shielded by the methyl group
and nucleophilic attack occurs solely from the Re face resulting
in the 1,2-syn product 6.
To achieve the alternative 1,2-anti selectivity, a metal ion
incapable of additional chelation to the α-oxygen, in this case
titanium, must be used, and reaction then occurs via a non-
cyclic “Felkin–Anh” transition state 43,4c,25 where steric and/or
electronic factors predominate. In this complex, the Re face is
shielded by the methyl substituent and arylation occurs solely
from the Si face, leading to the 1,2-anti product 5 of non-
chelation control.
was Merck silica gel 60 PF254
.
2-Bromo-4-formyl-6-methoxyphenyl toluene-p-sulfonate 18
A stirred solution of 5-bromovanillin 1710 (1.00 g, 4.33 mmol)
and triethylamine (0.90 cm3, 6.5 mmol) in dry tetrahydrofuran
(22 cm3) was treated portionwise at 0 ЊC with tosyl chloride
(0.91 g, 4.8 mmol). After 26 h at room temperature, water was
added and the mixture stirred (1 h). Extraction into ether was
followed by washing of the organic layers with aqueous sodium
hydroxide (1 M), water and brine, drying and evaporation
under reduced pressure to yield a yellow solid (1.58 g). This was
preadsorbed on silica gel and then subjected to rapid filtration
through a plug of silica gel (gradient elution: 20 and 50% ethyl
acetate–hexane) to provide the tosylate 18 as a yellow solid
(1.37 g, 82%). Recrystallisation from methylene chloride–
hexane gave needles, mp 118–9 ЊC (Found: C, 46.8; H, 3.1.
Conclusions
The bromo tosylate 20 was synthesised in four steps from the
known 5-bromovanillin 17 in an overall yield of 59%. The
naphthyl acetate 11 was derived from the bromo tosylate 20 in a
reasonable yield of 46% (approximately 56% based on con-
sumed 20). Preparation of the aryl triflate 33 required six steps
from commercially available 2,4-dihydroxybenzaldehyde and
proceeded in an overall yield of 55%. By contrast, the best yield
of the naphthyl acetate 11 produced from the aryl triflate 33
was 32%. Of the two methods investigated, the synthetic route
of choice for the preparation of the naphthyl acetate 11, from
aspects of both overall yield and number of synthetic steps, is
from vanillin via the bromo tosylate 20. Whereas the formation
of the naphthol 10 from the bromo tosylate 16 also produced
the regioisomer 14 in low yield,8 the naphthol 3 was the only
regioisomer isolated from either the bromo tosylate 20 or the
triflate 33.
Complete and complementary diastereoselectivity can be
achieved in the addition of naphthol 3 to aldehyde 4 through
the appropriate choice of metal as the naphtholate counterion.
Thus, the reactions of the titanium naphtholates of 3 and 10
with the aldehydes 4 and 35 separately afforded the anti 1,2-
addition products 5 and 37 as the sole adducts. Conversely,
the complementary magnesium naphtholates of 3 and 10 with
the same aldehydes respectively formed the corresponding
diastereomers 6 and 39 of syn 1,2-addition as the sole adducts.
C15H13BrO5S requires C, 46.8; H, 3.4%); νmax/cmϪ1 1701 (C᎐O),
᎐
1593, 1576 and 1470 (C᎐C); δ 2.49 (3H, s, CH3), 3.73 (3H, s,
᎐
H
OCH3), 7.38 (1H, d, J 1.8, 5-H), 7.38 and 7.89 (4H, AAЈBBЈ,
ArH), 7.67 (1H, d, J 1.8, 3-H) and 9.88 (1H, s, CHO); δC 21.7
(CH3), 56.2 (OCH3), 110.2 (C-5), 119.2 (C-2), 128.0 (C-3), 128.4
(C-2Ј and C-6Ј),a 129.5 (C-3Ј and C-5Ј),a 134.5 (C-4), 135.5
(C-4Ј),b 142.1 (C-1), 145.4 (C-1Ј),b 154.0 (C-6) and 189.54
(CHO); m/z 386 (Mϩ {81Br}, 4%), 384 (Mϩ {79Br}, 4), 231 (5),
229 (5), 155 (100), 91 (91) and 65 (17).
Benzyl 3-bromo-5-methoxy-4-(p-tolylsulfonyloxy)benzoate 22
A solution of the tosyl aldehyde 18 (250 mg, 0.65 mmol) and
m-chloroperbenzoic acid (231 mg of 85%, 1.14 mmol) in
methylene chloride (passed through basic alumina before use)
(5 cm3) was heated under reflux (4 h). During this time, a
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sample was removed and concentrated, the 1H NMR spectrum
(60 MHz) of which showed approximately 30% of starting
material remained (by integration of the aldehydic proton) with
signals for m-chloroperbenzoic acid and m-chlorobenzoic acid
obscuring some regions of the spectrum. The reaction mixture
was then concentrated and the residue dissolved in ethyl acetate.
The organic solution was washed a number of times with satur-
ated sodium hydrogen carbonate solution and then brine, and
dried and concentrated to a yellow solid (150 mg). The crude
product (142 mg) was dissolved in dry N,N-dimethylformamide
(4 cm3) and an excess of benzyl bromide (0.091 cm3, 0.76 mmol)
and anhydrous potassium carbonate (105 mg, 0.76 mmol)
added with stirring under nitrogen. After 17 h, thin layer
chromatography (TLC) indicated consumption of the lower Rf
component of the initial crude product, the continued presence
of the tosyl aldehyde 18 and a new, higher Rf product. The
reaction mixture was then quenched with water and normal
work-up (A) with ether yielded an orange oil (201 mg). This oil
was preadsorbed on silica gel and subjected to rapid filtration
through a plug of silica gel (20% ethyl acetate–hexane),
from which the higher Rf product 22 was obtained as an orange
oil (114 mg, 36%‡ over two steps). Further gradient elution
column chromatography of this oil with 10 and 20% ethyl
acetate–hexane as eluent gave an oil (Found: Mϩ, 490.0086.
C22H1979BrO6S requires M, 490.0086); νmax (film)/cmϪ1 1724
m-chloroperbenzoic acid (4.39 g, 20.4 mmol) in methylene
chloride (100 cm3) was heated under reflux (2 h) and then left
overnight at room temperature. The progress of the reaction at
this point was observed by 1H NMR spectroscopy (60 MHz) of
a concentrated sample which showed complete consumption of
the aldehydic starting material and a singlet at δ 8.15 indicative
of a formate proton. The reaction mixture was therefore
worked-up as described for the Baeyer–Villiger rearrangement
of 18 to give an orange oil (4.81 g, 96%) of the formate 24; νmax
(film)/cmϪ1 1744 (C᎐O), 1585 and 1491 (C᎐C); δ 0.21 (6H, s,
᎐
᎐
H
SiCH3), 1.03 (9H, s, CCH3), 3.78 (3H, s, OCH3), 6.61 (1H, d,
J 2.6, 6-H), 6.93 (1H, d, J 2.6, 2-H) and 8.25 (1H, s, OCHO);
δC Ϫ3.9 (SiCH3), 18.8 (CCH3), 25.9 (CCH3), 55.3 (OCH3),
104.5 (C-6), 114.7 (C-3), 117.0 (C-2), 143.2 (C-1), 147.2 (C-4),
151.0 (C-5) and 159.2 (OCHO); m/z 305 [(M Ϫ tBu) {81Br},
84%], 303 [(M Ϫ tBu) {79Br}, 79], 290 (45), 288 (46), 262
(100), 260 (99), 247 (21), 245 (22), 89 (18), 73 (45), 59 (15) and
57 (14).
5-Benzyloxy-1-bromo-2-(tert-butyldimethylsilyloxy)-3-
methoxybenzene 26
Potassium carbonate (1.28 g, 9.31 mmol) was added to a stirred
solution of the formate 24 (3.36 g, 9.31 mmol) in methanol (70
cm3) under nitrogen. After 10 min, the wine-red solution was
examined by TLC, which showed complete consumption of the
formate 24 and production of a lower Rf spot. Therefore, after
20 min, benzyl bromide (1.67 cm3, 14.0 mmol) was added. After
6 h, the reaction mixture was reduced in volume, water added
and the solution acidified with aqueous hydrochloric acid (1
M). It was extracted with ether and the ether extracts treated as
in normal work-up (B) to give a red oil (3.99 g). Gradient elu-
tion dry column chromatography with 2 to 80% ethyl acetate–
hexane as eluents gave the title compound 26 as an oil (2.53 g,
64% basic yield, 88% yield based on consumed phenol 25),
further purified by dry column chromatography with 5% ethyl
acetate–hexane and distillation to produce an oil, bp 160 ЊC/
0.025 mmHg (Kugelrohr) (Found: C, 57.1; H, 6.8. C20H27-
BrO3Si requires C, 56.7; H, 6.4%); νmax (film)/cmϪ1 1602, 1572,
(C᎐O), 1596, 1497 and 1463 (C᎐C); δ 2.47 (3H, s, CH3), 3.70
᎐
᎐
H
(3H, s, OCH3), 5.36 (2H, s, OCH2), 7.33–7.45 (5H, m, C6H5),
7.39 and 7.88 (4H, AAЈBBЈ, ArH), 7.56 (1H, d, J 1.9, 6-H)
and 7.87 (1H, d, J 1.9, 2-H); δC 21.7 (CH3), 56.3 (OCH3),
67.4 (OCH2), 112.8 (C-6), 118.4 (C-3), 126.5 (C-2), 128.4
(C-2Ј and C-6Ј),a 128.5 (C-3Ј and C-5Ј),a 128.5 (C-4Ј), 128.7
(C-2Љ and C-6Љ),a 129.5 (C-3Љ and C-5Љ),a 129.9 (C-1), 134.7
(C-1Ј), 135.5 (C-4Љ),b 141.0 (C-4), 145.3 (C-1Љ),b 153.5 (C-5)
and 164.5 (C᎐O); m/z 492 (Mϩ {81Br}, 1%), 490 (Mϩ {79Br}, 1),
᎐
337 (2), 335 (2), 230 (1), 228 (2), 203 (3), 201 (3), 155 (7) and
91 (100).
3-Bromo-4-(tert-butyldimethylsilyloxy)-5-methoxybenzaldehyde
23
1491 and 1468 (C᎐C); δ 0.21 (6H, s, SiCH3), 1.05 (9H, s,
᎐
H
Solid tert-butylchlorodimethylsilane (3.79 g, 25.2 mmol) was
added to a stirred solution of 5-bromovanillin 17 (4.00 g, 17.3
mmol) and imidazole (2.90 g, 42.5 mmol) in dry N,N-dimethyl-
formamide (100 cm3) under argon. After 4 h, the reaction
mixture was poured into water and extracted with ether. The
organic extracts were washed with water and brine, dried and
concentrated to an orange oil (6.57 g). Filtration through a pad
of silica gel with 20% ethyl acetate–hexane as eluent afforded
the silyl ether 23 as a yellow oil (5.33 g, 89%). A portion of this
was subjected to a further chromatographic separation with
10% ethyl acetate–hexane to give a yellow oil which crystallised
and was then recrystallised from methanol to furnish plates, mp
58–59.5 ЊC (Found: C, 48.3; H, 6.0. C14H21BrO3Si requires C,
CCH3), 3.76 (3H, s, OCH3), 4.97 (2H, s, OCH2), 6.50 (1H, d,
J 2.9, 4-H), 6.74 (1H, d, J 2.9, 6-H) and 7.31–7.46 (5H, m,
C6H5); δC Ϫ3.9 (SiCH3), 18.9 (CCH3), 26.0 (CCH3), 55.2
(OCH3), 70.7 (OCH2), 100.2 (C-4), 109.0 (C-6), 114.8 (C-1),
127.7 (C-2Ј and C-6Ј),a 128.1 (C-4Ј), 128.6 (C-3Ј and C-5Ј),a
136.6 (C-1Ј),b 137.2 (C-2),b 151.5 (C-5)c and 153.2 (C-3);c m/z
424 (Mϩ {81Br}, 0.3%), 422 (Mϩ {79Br}, 0.3), 367 (13), 365
(13), 352 (7), 350 (6), 271 (8), 91 (100) and 73 (50). This was
followed by 3-bromo-4-(tert-butyldimethylsilyloxy)-5-methoxy-
phenol 25 as a red oil (0.81 g, 26% yield from the formate 24),
further purified by column chromatography (10 and 20%
ethyl acetate–hexane) to provide a red oil, still containing
some trace impurities; νmax (film)/cmϪ1 3416 (OH), 1605, 1587
and 1493 (C᎐C); δ 0.16 (6H, s, SiCH3), 1.00 (9H, s, CCH3),
48.7; H, 6.1%); νmax/cmϪ1 1687 (C᎐O), 1586, 1567, 1489 and
᎐
᎐
H
1462 (C᎐C); δ 0.23 (6H, s, SiCH3), 1.02 (9H, s, CCH3), 3.85
3.73 (3H, s, OCH3), 4.81 (1H, br s, OH), 6.34 (1H, d, J 2.8,
6-H) and 6.56 (1H, d, J 2.8, 2-H); δC Ϫ3.9 (SiCH3), 18.9
(CCH3), 26.0 (CCH3), 55.2 (OCH3), 99.6 (C-6), 110.7 (C-2),
114.9 (C-3), 137.0 (C-4), 149.8 (C-5)a and 151.5 (C-1);a m/z
334 (Mϩ {81Br}, 1%), 332 (Mϩ {79Br}, 1), 319 (1), 317 (1), 304
(2), 302 (2), 277 (50), 275 (48), 262 (100), 260 (99), 182 (10),
73 (27) and 59 (12).
᎐
H
(3H, s, OCH3), 7.31 (1H, d, J 1.9, 6-H), 7.62 (1H, d, J 1.9, 2-H)
and 9.76 (1H, s, CHO); δC Ϫ3.8 (SiCH3), 18.9 (CCH3), 25.8
(CCH3), 55.3 (OCH3), 108.7 (C-6), 115.3 (C-3), 129.6 (C-2),
130.3 (C-1), 148.6 (C-4), 151.3 (C-5) and 189.7 (CHO); m/z
289 [(M Ϫ tBu) {81Br}, 97%], 287 [(M Ϫ tBu) {79Br}, 100], 274
(80), 273 (44), 272 (80), 271 (32), 245 (4), 243 (6), 73 (19) and 59
(14).
Recycling of 3-bromo-4-(tert-butyldimethylsilyloxy)-5-
methoxyphenol 25
3-Bromo-4-(tert-butyldimethylsilyloxy)-5-methoxyphenyl
formate 24
Potassium carbonate (46 mg, 0.33 mmol) was added to a
stirred solution of the phenol 25 (100 mg, 0.30 mmol) in
methanol (3 cm3) under argon. After 15 min, benzyl bromide
(0.072 cm3, 0.60 mmol) was added. After 3 days, work-up as
described for the preparation above produced an orange
oil (117 mg). Filtration through a pad of silica with 5 and
A solution of the silyl ether 23 (4.77 g, 13.8 mmol) and
‡ The low yield of the benzyl ester 22 arose from sodium hydrogen
carbonate washes to remove m-chlorobenzoic acid produced in the
Baeyer–Villiger reaction.
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038
3033

View Article Online
10% ethyl acetate–hexane as eluents yielded 5-benzyloxy-1-
bromo-2-(tert-butyldimethylsilyloxy)-3-methoxybenzene 26 as
a yellow oil (81 mg, approx. 80% pure, 51% yield), probably
contaminated by residual benzyl bromide.
Extraction with ether, washing of the organic layer with water,
aqueous sodium hydroxide (1 M), water and brine, drying and
concentrating gave the methoxy compound 29 (1.23 g, 100%)
as a cream crystalline solid. Recrystallisation from methanol
yielded cream plates, mp 92–94.5 ЊC [lit.,29 95 ЊC (ethanol–
water)]; νmax/cmϪ1 1664 (C᎐O), 1596, 1503 and 1475 (C᎐C);
᎐
᎐
4-Benzyloxy-2-bromo-6-methoxyphenol 27
δH 3.88 (3H, s, OCH3), 5.12 (2H, s, OCH2), 6.53 (1H, d, J 2.2,
3-H), 6.62 (1H, ddd, J 0.7, 2.2 and 8.7, 5-H), 7.32–7.51 (5H,
m, C6H5), 7.80 (1H, d, J 8.7, 6-H) and 10.29 (1H, d, J 0.7,
CHO); δC 55.6 (OCH3), 70.3 (OCH2), 98.8 (C-3), 106.4 (C-5),
119.2 (C-1), 127.5 (C-2Ј and C-6Ј),a 128.3 (C-4Ј), 128.7 (C-3Ј
and C-5Ј),a 130.7 (C-6), 135.9 (C-1Ј), 163.5 (C-2),b 165.2 (C-
4)b and 188.3 (CHO); m/z 242 (Mϩ, 37%), 92 (48), 91 (100)
and 65 (50).
A solution of the benzyl ether 26 (118 mg, 0.28 mmol) in tetra-
hydrofuran (4 cm3) was treated with tetra-n-butylammonium
fluoride trihydrate (220 mg, 0.70 mmol). After 3.5 h, water and
ether were added. The aqueous layer was acidified with aqueous
hydrochloric acid (1 M) and re-extracted with ether. The organic
extracts were then treated as in normal work-up (B) to give a
dark orange oil (87 mg). Filtration through a plug of silica
gel (20% ethyl acetate–hexane) produced a pale yellow oil (79
mg, 92%). This oil crystallised after trituration with hexane
while cooling in an acetone–dry ice bath. Recrystallisation
from methylene chloride–hexane afforded the phenol 27 as
spears, mp 55–6 ЊC (Found: C, 54.15; H, 3.9. C14H13BrO3
requires C, 54.4; H, 4.2%); νmax/cmϪ1 3507 (OH), 1607, 1588,
4-Benzyloxy-2-methoxyphenol 31
Following the method described above for the Baeyer–Villiger
rearrangement of silyl ether 23, the methoxy compound 29
(2.18 g, 9.01 mmol) was transformed into a mixture of 4-
benzyloxy-2-methoxyphenyl formate 30 and 4-benzyloxy-2-
methoxyphenol 31 as a red oil (2.22 g); νmax (film)/cmϪ1 3464
1498 and 1451 (C᎐C); δ 3.83 (3H, s, OCH3), 4.95 (2H, s,
᎐
H
OCH2), 5.51 (1H, br s, OH), 6.51 (1H, d, J 2.7, 5-H), 6.69
(1H, d, J 2.7, 3-H) and 7.28–7.42 (5H, m, C6H5); δC 56.3
(OCH3), 70.9 (OCH2), 100.1 (C-5), 107.6 (C-2), 109.0 (C-3),
127.6 (C-2Ј and C-6Ј),a 128.1 (C-4Ј), 128.6 (C-3Ј and C-5Ј),a
136.6 (C-1Ј),b 137.7 (C-1),b 147.6 (C-4)c and 152.5 (C-6);c
m/z 310 (Mϩ {81Br}, 2%), 308 (Mϩ {79Br}, 3), 92 (10), 91 (100),
65 (12) and 53 (6).
(OH), 1743 (C᎐O), 1613, 1508 and 1452 (C᎐C). The mixture of
᎐
᎐
predominantly formate 30 with some phenol 31 (2.22 g) was
dissolved in methanol (20 cm3) and a solution of potassium
hydroxide (1.45 g, 25.8 mmol) in water (20 cm3) added under
nitrogen. After 1.5 h, aqueous hydrochloric acid (1 M) (40 cm3)
was added, followed by extraction into ethyl acetate. The
organic layers were washed as in normal work-up (B) to give a
red oil (2.07 g). Column chromatography with 10 and 20% ethyl
acetate–hexane as eluents gave the phenol 31 as a red oil (1.58 g,
76% yield over two steps). Further column chromatography
with the same eluents gave an orange solid which was then
recrystallised from ether–hexane to furnish spears, mp 38–40 ЊC
4-Benzyloxy-2-bromo-6-methoxyphenyl toluene-p-sulfonate 20
Solid tetra-n-butylammonium fluoride trihydrate (4.97 g, 15.7
mmol) was added to a stirred solution of the benzyl ether 26
(5.55 g, 13.1 mmol) in tetrahydrofuran (100 cm3) under nitro-
gen. After 45 min, TLC showed consumption of the benzyl
ether 26 and production of the phenol 27. Therefore, after 1 h,
tosyl chloride (3.00 g, 15.7 mmol) was added. Since TLC after
4.5 h indicated the presence of a significant amount of tosyl
chloride, an aliquot of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (2.35 cm3, 15.7 mmol) was added, followed by a repeat
addition of tosyl chloride (3.00 g, 15.7 mmol) after 5 h. This
was necessary to ensure complete reaction of the phenol 27,
since this phenol and the bromo tosylate 20 have identical Rf’s
(30% ethyl acetate–hexane as eluent) and are very difficult to
separate chromatographically. After 7 h, work-up was by con-
centration of the suspension, addition of water and ethyl acet-
ate and then as described in the preparation of 27 above using
ethyl acetate. Two purifications of the red solid (9.82 g) by
gradient elution dry column chromatography (using 10 to
100% ethyl acetate–hexane) yielded the bromo tosylate 20 as a
light pink solid (5.42 g, 89%). Recrystallisation from methanol
furnished slightly hygroscopic, fine plates, mp 140.5–143 ЊC
(Found: C, 54.35; H, 3.9. C21H19BrO5S requires C, 54.4; H,
4.1%); νmax/cmϪ1 1594, 1484 and 1455 (C᎐C); δ 2.45 (3H, s,
(lit.,30 35–7 ЊC); νmax /cmϪ1 3446 (OH), 1512 and 1452 (C᎐C);
᎐
δH 3.85 (3H, s, OCH3), 5.00 (2H, s, OCH2), 5.24 (1H, s, OH),
6.46 (1H, dd, J 2.8 and 8.6, 5-H), 6.57 (1H, d, J 2.8, 3-H), 6.82
(1H, d, J 8.6, 6-H) and 7.31–7.45 (5H, m, C6H5); δC 55.9
(OCH3), 70.8 (OCH2), 100.4 (C-3), 105.5 (C-5), 114.0 (C-6),
127.6 (C-2Ј and C-6Ј),a 127.9 (C-4Ј), 128.6 (C-3Ј and C-5Ј),a
137.2 (C-1Ј), 140.0 (C-1), 147.0 (C-2) and 152.7 (C-4); m/z 230
(Mϩ, 88%), 153 (6), 139 (7), 111 (9), 92 (15), 91 (100) and 65
(17).
Examples of attempted bromination at C-6 of phenol 31
A. A solution (0.94 cm3) of bromine (23 mg, 0.14 mmol) in
glacial acetic acid was added dropwise to a stirred solution of
the phenol 31 (30 mg, 0.13 mmol) and sodium acetate (11 mg,
0.13 mmol) in glacial acetic acid (2 cm3). After 3 h, the reaction
mixture was poured into an excess of saturated aqueous sodium
hydrogen carbonate solution. Normal work-up (A) with ethyl
acetate (minus the acid wash) then gave a red oil (38 mg), the 1H
NMR spectrum (60 MHz) of which appeared to show the pres-
ence of one predominant product. Column chromatography
with 10 and 20% ethyl acetate–hexane gave 4-benzyloxy-5-
bromo-2-methoxyphenol 32 as a red oil (24 mg, 60%); δH (60
MHz) 3.70 (3H, s, OCH3), 4.95 (2H, s, OCH2), 5.15 (1H, br s,
OH), 6.48 (1H, s, 3-H), 7.07 (1H, s, 6-H) and 7.20–7.55 (5H, m,
C6H5); m/z 310 (Mϩ {81Br}, 4%), 308 (Mϩ {79Br}, 5), 229 (8),
91 (100) and 65 (24).
᎐
H
CH3), 3.55 (3H, s, OCH3), 4.98 (2H, s, OCH2), 6.47 (1H, d,
J 2.8, 5-H), 6.74 (1H, d, J 2.8, 3-H), 7.30–7.42 (5H, m, C6H5)
and 7.33 and 7.86 (4H, AAЈBBЈ, ArH); δC 21.6 (CH3), 55.8
(OCH3), 70.6 (OCH2), 100.3 (C-5), 109.4 (C-3), 118.3 (C-2),
127.6 (C-2Љ and C-6Љ),a 128.3 (C-4Љ), 128.4 (C-2Ј and C-6Ј),b
128.6 (C-3Љ and C-5Љ),a 129.3 (C-3Ј and C-5Ј),b 131.8 (C-1),
134.8 (C-4Ј),c 135.9 (C-1Љ),c 144.8 (C-1Ј),c 153.9 (C-4)d and
157.8 (C-6);d m/z 464 (Mϩ{81Br}, 0.1%), 462 (Mϩ {79Br}, 0.1),
309 (2), 307 (3), 155 (1), 92 (8), 91 (100) and 65 (2).
B. Using the original method for ortho-bromination
described by Pearson et al.,17 with quantities of reagents as
follows: tert-butylamine (0.055 cm3, 0.52 mmol) in dry toluene
(2 cm3) and bromine (42 mg, 0.26 mmol) in dry methylene
chloride (1.13 cm3), the phenol 31 (50 mg, 0.22 mmol) added in
dry methylene chloride (3 cm3) yielded a pink–red oil (52 mg).
4-Benzyloxy-2-methoxybenzaldehyde 29
The monobenzyl ether 2814 (1.16 g, 5.09 mmol) was dissolved in
dry N,N-dimethylformamide (35 cm3) and methyl iodide (0.64
cm3, 10.2 mmol), followed by anhydrous potassium carbonate
(0.84 g, 6.11 mmol), added with stirring. The suspension was
heated (4 h, 80 ЊC) and then cooled and poured into water.
1
Examination by TLC, GCMS and H NMR spectroscopy (60
MHz) indicated a complex mixture.
C. Following the adaptation of the original method for
ortho-bromination of phenols published by Sargent and co-
3034
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038

View Article Online
workers18 with bromine (0.22 mmol) in dry methylene chloride
(0.86 cm3) in the presence of isopropylamine (0.028 cm3, 0.33
mmol) in dry toluene (3 cm3), the phenol 31 (50 mg, 0.22 mmol)
in dry methylene chloride (2 cm3) was converted to a crude
red oil (57 mg). Analysis by TLC, GCMS and H NMR spec-
troscopy (60 MHz) indicated a mixture containing starting
material as the major component.
71.6; H, 5.7%); νmax /cmϪ1 1754 (C᎐O), 1625, 1612 and 1589
᎐
(C᎐C); δ 2.39 (3H, s, COCH3), 3.936 and 3.941 (each 3H, s,
᎐
H
OCH3), 5.15 (2H, s, OCH2), 6.62 and 6.73 (each 1H, d, J 2.3,
6- and 8-H), 6.67 (1H, d, J 8.5, 3-H), 7.10 (1H, d, J 8.5, 2-H)
and 7.32–7.50 (5H, m, C6H5); δC 21.0 (COCH3), 56.4 and 56.6
(OCH3), 70.1 (OCH2), 93.5 (C-6),a 99.6 (C-8),a 103.3 (C-3),a
114.1 (C-4a), 119.2 (C-2), 127.7 (C-2Ј and C-6Ј),b 128.2 (C-4Ј),
128.7 (C-3Ј and C-5Ј),b 130.7 (C-8a), 136.6 (C-1),c 139.2 (C-1Ј),c
155.4 (C-4),d 158.0 (C-7),d 158.8 (C-5)d and 169.7 (COCH3); m/z
352 (Mϩ, 19%), 310 (56), 281 (7), 219 (28), 191 (27), 91 (100)
and 65 (21).
1
(4-Benzyloxy-2-methoxy)phenyl trifluoromethanesulfonate 33
Following a literature procedure for the preparation of aryl
triflates,31 except that 2 equiv. (0.585 cm3, 3.48 mmol) of tri-
fluoromethanesulfonic (triflic) anhydride was used, the phenol
31 (400 mg, 1.74 mmol) was transformed into its triflate as a
crude orange oil (593 mg). Column chromatography with 10%
ethyl acetate–hexane as eluent gave the triflate 33 as a pale
yellow crystalline solid (570 mg, 91%). Recrystallisation of a
portion of this (170 mg) from methylene chloride–hexane
afforded needles (111 mg), mp 66–68 ЊC (Found: C, 50.0; H,
3.6. C15H13F3O5S requires C, 49.7; H, 3.6%); νmax/cmϪ1 1609 and
B. Dry diisopropylamine (0.187 cm3, 1.33 mmol) in dry tet-
rahydrofuran (4 cm3) was cooled to 0 ЊC under an atmosphere
of argon and a solution of n-butyllithium in hexane (0.61 cm3,
2.2 M, 1.34 mmol) was added. After stirring for 15 min, the
mixture was cooled to Ϫ78 ЊC. In a separate round-bottomed
flask, under argon, the aryl triflate 33 (100 mg, 0.28 mmol) was
dissolved in dry tetrahydrofuran (2 cm3) and an excess of 2-
methoxyfuran (0.30 cm3) added. This solution was also cooled
to Ϫ78 ЊC. The lithium diisopropylamide (LDA) solution was
then added dropwise via syringe to the aryl triflate solution over
10 min. After stirring for 1 h at Ϫ78 ЊC, the reaction mixture
was allowed to warm to room temperature over a further 2.5 h.
It was then acidified with concentrated hydrochloric acid,
stirred for 15 min and poured into water. Extraction with ethyl
acetate and washing of the organic phase as in normal work-up
(B) gave a red oil (254 mg). Radial chromatography (10 and
20% ethyl acetate–hexane) gave only one identifiable product:
7-benzyloxy-4,5-dimethoxy-1-naphthol 3, Rf 0.20 (30% ethyl
acetate–hexane), as a green oil (29 mg). This oil was dissolved in
dry pyridine (2 cm3) and acetic anhydride (0.3 cm3) added under
nitrogen. After 2 days, normal work-up (B) (ether), with an
additional dilute aqueous hydrochloric acid (1 M) wash, gave
the naphthalene 11 as an orange crystalline solid (31 mg, 32%
over two steps), Rf 0.27 (30% ethyl acetate–hexane). Recrystal-
lisation from methylene chloride–hexane produced pale orange,
fine needles of naphthalene 11 (24 mg, 25%), mp 107–9 ЊC.
C. Following the procedure described by Giles, Hughes and
Sargent for the preparation of 4,5-dimethoxy-1-naphthol,8
except that an aryl triflate was used instead of a bromo tosylate,
1.1 equiv. of n-butyllithium (0.19 cm3, 2.3 M, 0.46 mmol) and 10
equiv. of 2-methoxyfuran (0.38 cm3, 4.1 mmol) were used and
the addition was carried out at Ϫ78 ЊC followed by immediately
allowing the mixture to warm to room temperature, the aryl
triflate 33 (150 mg, 0.41 mmol) gave a brown oil (296 mg) as the
crude product. Column chromatography (10–30% ethyl
acetate–hexane) gave the naphthol 3 as a purple oil (38 mg).
This oil was dissolved in dry pyridine and acetic anhydride.
After 20 h, water and ether were added and stirring continued
for 3 h. Normal work-up (A) (ether) then gave a red oil (23 mg).
Column chromatography with 10 and 20% ethyl acetate–hexane
produced the naphthalene 11 as an orange solid (16 mg, 11%
over two steps).
1509 (C᎐C); δ 3.86 (3H, s, OCH3), 5.04 (2H, s, OCH2), 6.51
᎐
H
(1H, dd, J 2.8 and 8.9, 5-H), 6.64 (1H, d, J 2.8, 3-H), 7.12 (1H,
d, J 8.9, 6-H) and 7.32–7.44 (5H, m, C6H5); δC 56.1 (OCH3),
70.6 (OCH2), 101.3 (C-3), 105.0 (C-5), 118.7 (q, J 321, CF3),
122.8 (C-6), 127.5 (C-2Ј and C-6Ј),a 128.3 (C-4Ј), 128.7 (C-3Ј
and C-5Ј),a 132.8 (C-1), 136.1 (C-1Ј), 152.2 (C-2) and 159.2
(C-4); m/z 362 (Mϩ, 2%), 229 (5), 197 (7), 91 (100) and 65 (9).
1-Acetoxy-7-benzyloxy-4,5-dimethoxynaphthalene 11
A. Following the procedure described by Giles, Hughes and
Sargent for the preparation of 4,5-dimethoxy-1-naphthol,8
except that the temperature of the reaction was Ϫ80 ЊC, the
bromotosylate 20 (500 mg) gave a red oil (452 mg) as the crude
product.
The crude product was immediately dissolved in dry pyridine
(5 cm3) and acetic anhydride (0.20 cm3, 2.12 mmol) added with
stirring under argon. After 16 h, ether and water were added.
The water layer was removed and the organic layer was sub-
jected to a normal work-up (A) (ether) to give a red solid (393
mg). Dry column chromatography with 10 and 20% ethyl
acetate–hexane as eluents gave a green solid (218 mg) of pre-
dominantly Rf 0.27 (30% ethyl acetate–hexane) material, being
the required product 11 [purified further by radial chrom-
atography with the same eluents to give orange needles (176 mg,
46%)], and an orange oil (89 mg, approx. 18% recovery) of
1
predominantly Rf 0.34 material, identified by H NMR spec-
troscopy (60 MHz) as the starting material bromo tosylate
20 and a small amount of debrominated starting material.
In order to successfully purify the required product 11, the
green solid was dissolved in a mixture of dry ether and dry
tetrahydrofuran and the solution added to an excess of lithium
aluminium hydride in dry ether with stirring under nitrogen.
After 1.5 h, work-up was by the dropwise addition of saturated
ammonium chloride solution, the addition of anhydrous mag-
nesium sulfate and filtration of the resultant suspension
through Celite. Concentration of the filtrate was followed
by dry column chromatography (20 and 40% ethyl acetate–
hexane). The fractions containing 7-benzyloxy-4,5-dimethoxy-
1-naphthol 3, Rf 0.20 (30% ethyl acetate–hexane), were col-
lected to give a cream solid, δH (60 MHz) 3.80 and 3.90 (each
3H, s, OCH3), 5.10 (2H, s, OCH2), 6.54 and 6.75 (2H, AB, J 8,
3- and 2-H), 6.56 (1H, d, J 2, 6- or 8-H), 7.20–7.50 (6H, m,
C6H5 and 6- or 8-H) and 8.00 (1H, br s, OH).
This solid was dissolved in dry pyridine and an excess of
acetic anhydride added. Work-up as described directly above
for the same reaction gave a yellow solid. Dry column chrom-
atography (20 and 30% ethyl acetate–hexane) yielded a pale
green crystalline solid. Recrystallisation from methylene
chloride–hexane afforded fine needles of the naphthalene 11,
mp 109–109.5 ЊC (Found: C, 71.7; H, 5.8. C21H20O5 requires C,
Conversion of naphthalene 11 to 1-acetoxy-4,5,7-trimethoxy-
naphthalene 13
To a stirred solution of the naphthalene 11 (95 mg, 0.27 mmol)
in ethyl acetate (12 cm3) was added 10% palladium on carbon
catalyst (120 mg). The suspension was then subjected to an
atmosphere of hydrogen for 2.5 h. Filtration through a pad of
Celite and concentration of the filtrate gave 1-acetoxy-4,5-
dimethoxy-7-hydroxynaphthalene 12 as an orange solid (68 mg,
96%), Rf 0.06 (30% ethyl acetate–hexane), δH (60 MHz) 2.25
(3H, s, COCH3), 3.80 and 3.85 (each 3H, s, OCH3), 5.90 (1H, br
s, OH), 6.38 and 6.58 (each 1H, d, J 2, 6- and 8-H), 6.51 (1H, d,
J 8, 3-H) and 6.96 (1H, d, J 8, 2-H). Naphthol 12 (68 mg, 0.26
mmol) was dissolved in dry N,N-dimethylformamide (5 cm3)
and methyl iodide (0.041 cm3, 0.65 mmol), followed by
anhydrous potassium carbonate (43 mg, 0.31 mmol) were
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038
3035

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added with stirring. The suspension was heated (17 h, 60 ЊC)
and then cooled and poured into water. Extraction with ether,
washing of the organic layer with water and brine, drying and
concentrating gave the naphthalene 13 as an orange solid (65
mg, 91%). Recrystallisation from methylene chloride–hexane
furnished pale orange crystals (38 mg), mp 110.5–113 ЊC (lit.,19
110–2 ЊC; lit.,8 114–5 ЊC); δH 2.41 (3H, s, COCH3), 3.88 (3H, s,
OCH3), 3.92 (6H, s, OCH3), 6.52 and 6.63 (each 1H, d, J 2.3,
6- and 8-H), 6.65 (1H, d, J 8.4, 3-H) and 7.09 (1H, d, J 8.4, 2-H).
35; Major diastereomer) 1.19 (3H, t, J 7.1, 1Љ-CH3), 1.32 (3H, d,
J 7.0, 2-CH3), 1.38 (3H, d, J 5.4, 1Ј-CH3), 3.45–3.75 (2H,
m, OCH2), 4.15 (1H, dq, J 1.7 and 7.0, 2-H), 4.83 (1H, q, J 5.4,
1Ј-H) and 9.62 (1H, d, J 1.7, 1-H); δH (aldehyde 35; Minor
diastereomer) 1.17 (3H, t, J 7.1, 1Љ-CH3), 1.27 (3H, d, J 7.0,
2-CH3), 1.36 (3H, d, J 5.3, 1Ј-CH3), 3.45–3.75 (2H, m, OCH2),
3.94 (1H, dq, J 2.7 and 7.0, 2-H), 4.74 (1H, q, J 5.3, 1Ј-H) and
9.59 (1H, d, J 2.7, 1-H); m/z (aldehyde 35) 145 [(M Ϫ H), 0.4%],
131 (4), 117 (10), 101 (42), 73 (100), 57 (70) and 45 (100).
Conversion of naphthalene 11 to naphthol 3
(1R,2S,1ЉR or S)-2-(1Љ-Ethoxyethoxy)-1-(1Ј-hydroxy-4Ј,5Ј,7Ј-
trimethoxynaphthalene-2Ј-yl)propan-1-ol 37
The published method of Casiraghi et al.4b was modified as
follows:
The naphthalene 11 (370 mg, 1.05 mmol) was dissolved in dry
tetrahydrofuran (10 cm3) and the solution added dropwise to an
excess of lithium aluminium hydride (81 mg, 2.10 mmol) in dry
ether (8 cm3) with stirring. After 1 h, saturated ammonium
chloride solution was added dropwise, followed by anhydrous
magnesium sulfate and the resultant suspension was filtered
through Celite. Concentration of the filtrate gave the naphthol
3 as a yellow solid (326 mg, 100%).
Freshly prepared naphthol 108 (500 mg, 2.14 mmol) was dis-
solved in toluene (approx. 70 cm3, AR grade) in a 3-necked
round-bottomed flask. Water was then removed as its azeotrope
by distillation, using a gentle flame to heat the solution. The
system was then flushed with argon and fresh, neat titanium
tetraisopropoxide (0.748 cm3, 2.51 mmol) was added, pro-
ducing a red solution. The propan-2-ol–toluene azeotrope was
removed by distillation and then the distillation apparatus was
replaced by a septum. The solution was cooled in an ice bath
and the aldehyde 35 (1.03 g, approx. 4.23 mmol, 60% pure; pre-
pared the previous day) added via a syringe. After 40 min, the
flask was transferred to the ultrasonication bath for a further 10
h (bath temperature range: 10–40 ЊC). The reaction mixture was
then diluted with ether (200 cm3) and stirred vigorously over-
night with saturated sodium fluoride solution (200 cm3). Fil-
tration of the mixture through a pad of Celite was followed by
separation of the ether layer. The aqueous layer was re-extracted
with ether and the combined organic layers were washed
with brine, dried and concentrated to a low volume. Column
chromatography with 20–40% ethyl acetate–hexane gave:
1. Of Rf 0.30 (30% ethyl acetate–hexane), a bright yellow oil
(16 mg), a decomposition product of compound 37.
(2S, 1ЈR or S)-Ethyl 2-(1Ј-ethoxyethoxy)propanoate 34
Pyridinium toluene-p-sulfonate (PPTS; Aldrich) (1.26 g, 5.00
mmol) was added to a solution of (S)-ethyl lactate [Fluka
Chemie AG; measured [α]D Ϫ11.0 (neat)] (5.72 cm3, 50.0 mmol)
and ethyl vinyl ether (as supplied by Aldrich) (12.0 cm3, 125
mmol) in dry methylene chloride (170 cm3). After standing for
17 h, the solution was washed with water (three times), brine,
dried and concentrated to a yellow oil (10.52 g), [α]D Ϫ65.9.
Kugelrohr distillation gave, after the forerun was discarded,
compound 34 as a pale yellow liquid (6.54 g, 69%), bp 105–
130 ЊC/approx. 18 mmHg (Kugelrohr) (lit.,23 80 ЊC/20 mmHg;
lit.,22 74 ЊC/12 mmHg); [α]D Ϫ67.1 [lit.,23 Ϫ68.7 (c 5, CHCl3);
lit.,22 Ϫ78.9 (c 4.4, CHCl3)]; νmax (film)/cmϪ1 1751 (C᎐O);
᎐
δH (major diastereomer) 1.19 (3H, t, J 7.1, 1Љ-CH3), 1.29 (3H, t,
J 7.1, CO2CH2CH3), 1.37 (3H, d, J 5.4, 1Ј-CH3), 1.42 (3H, d,
J 7.0, 2-CH3), 3.49 and 3.62 (each 1H, dq, J 9.3 and 7.1,
1Ј-OCH2), 4.20 (2H, q, J 7.1, CO2CH2), 4.34 (1H, q, J 7.0, 2-H)
and 4.78 (1H, q, J 5.4, 1Ј-H); δH (minor diastereomer) 1.17 (3H,
t, J 7.1, 1Љ-CH3), 1.29 (3H, t, J 7.1, CO2CH2CH3), 1.32 (3H, d,
J 5.4, 1Ј-CH3), 1.39 (3H, d, J 7.0, 2-CH3), 3.53 and 3.70 (each
1H, dq, J 9.4 and 7.1, 1Ј-OCH2), 4.188 (1H, q, J 7.0, 2-H), 4.195
(2H, q, J 7.1, CO2CH2) and 4.79 (1H, q, J 5.4, 1Ј-H); δC (major
diastereomer) 14.2 (CH3CH2O2C), 15.3 (C-3), 18.9 (C-2Љ), 20.0
(C-2Ј), 60.2 (C-1Љ), 60.8 (CH2O2C), 69.9 (C-2), 99.3 (C-1Ј) and
173.4 (C-1); δC (minor diastereomer) 14.2 (CH3CH2O2C), 15.1
(C-3), 18.9 (C-2Љ), 19.7 (C-2Ј), 60.8 (CH2O2C), 61.1 (C-1Љ), 69.6
(C-2), 99.4 (C-1Ј) and 173.7 (C-1); m/z 145 [(M Ϫ OEt), 22%],
101 (10), 73 (99), 69 (29), 57 (14), 55 (15), 45 (100) and 43 (21).
2. Of Rf 0.12 (30% ethyl acetate–hexane), the required
product compound 37 as a mixture of diastereomers at C-1Љ, a
red oil (512 mg, 63%). This compound was reasonably stable,
but soon after chromatography always underwent a small
amount of decomposition to by-products at Rf 0.30 and base-
line material. Compound 37: (Found: Mϩ, 380.1834. C20H28O7
requires M, 380.1835); [α]D ϩ15.9 (c 0.9, CHCl3) (mixture of
diastereomers at C-1Љ); νmax (film)/cmϪ1 3349 (OH), 1612, 1516,
1471 and 1453 (C᎐C); δ (major diastereomer; 500 MHz) 1.19
᎐
H
(3H, t, J 7.1, CH3CH2), 1.20 (3H, d, J 6.4, 2-CH3), 1.30 (3H, d,
J 5.3, 1Љ-CH3), 3.50 and 3.63 (each 1H, dq, J 9.2 and 7.1, CH2),
3.70 (1H, s, 1-OH), 3.83, 3.91 and 3.92 (each 3H, s, OCH3), 4.07
(1H, dq, J 4.3 and 6.4, 2-H), 4.76 (1H, q, J 5.3, 1Љ-H), 4.86
(1H, d, J 4.3, 1-H), 6.24 (1H, s, 3Ј-H), 6.51 and 7.13 (each 1H,
d, J 2.3, 6Ј- and 8Ј-H) and 8.82 (1H, s, 1Ј-OH); δH (minor
diastereomer; 500 MHz) 1.14 (3H, d, J 6.6, 2-CH3), 1.15 (3H, t,
J 7.0, CH3CH2), 1.35 (3H, d, J 5.3, 1Љ-CH3), 3.43 and 3.56 (each
1H, dq, J 9.2 and 7.0, CH2), 3.70 (1H, s, 1-OH), 3.83, 3.91 and
3.92 (each 3H, s, OCH3), 4.11 (1H, dq, J 4.0 and 6.6, 2-H), 4.82
(1H, q, J 5.3, 1Љ-H), 4.94 (1H, d, J 4.0, 1-H), 6.26 (1H, s, 3Ј-H),
6.51 and 7.15 (each 1H, d, J 2.3, 6Ј- and 8Ј-H) and 8.81 (1H, s,
1Ј-OH); δC (major diastereomer; 126 MHz) 15.2 (C-3), 17.7
(CH3CH2), 20.3 (C-2Љ), 55.2, 56.1 and 57.5 (OCH3), 60.3 (CH2),
76.2 (C-2), 78.3 (C-1), 93.2 (C-1Љ), 99.4 (C-6Ј),a 99.6 (C-3Ј),a
105.3 (C-8Ј),a 113.5 (C-8Јa),b 117.1 (C-4Јa),b 129.6 (C-2Ј), 144.5
(C-1Ј), 149.9 (C-4Ј), 157.7 (C-7Ј)c and 157.9 (C-5Ј);c δC (minor
diastereomer; 126 MHz) 15.3 (C-3), 17.7 (CH3CH2), 20.5
(C-2Љ), 55.2, 56.2 and 57.5 (OCH3), 60.6 (CH2), 76.0 (C-2), 78.4
(C-1), 93.3 (C-1Љ), 98.9 (C-6Ј),a 99.4 (C-3Ј),a 105.5 (C-8Ј),a 113.5
(C-8Јa),b 117.1 (C-4Јa),b 129.6 (C-2Ј), 144.5 (C-1Ј), 149.9 (C-4Ј),
157.7 (C-7Ј)c and 157.9 (C-5Ј);c m/z 380 (Mϩ, 2%), 334 (4), 306
(5), 290 (64), 288 (19), 273 (14), 247 (29), 233 (16), 73 (65) and
45 (100).
(2S, 1ЈR or S)-2-(1Ј-Ethoxyethoxy)propanal 35
Neat diisobutylaluminium hydride (1.69 cm3, 9.5 mmol) was
added to dry hexane (6 cm3) in a pressure-equalising dropping
funnel. This solution was then added dropwise to a cooled
(Ϫ70 ЊC) solution of the ester 34 (1.50 g, 7.9 mmol) in dry ether
(12 cm3) under argon. After stirring for 1 h, saturated sodium
sulfate solution (3.2 cm3) was added dropwise. The mixture
was then allowed to warm to room temperature over 2 h, after
which time a gelatinous precipitate had formed. The mixture
was filtered through a pad of Celite and the residues washed
with ether. The filtrate was concentrated and the residue sub-
jected to Kugelrohr distillation to produce an oil (0.79 g), bp
100–115 ЊC/approx. 18 mmHg (Kugelrohr) [lit.,27 (pure alde-
hyde 35) 53–4 ЊC/17 mmHg], being a mixture of aldehyde 35
and alcohol 36 [(2S, 1ЈR or S)-2-(1Ј-ethoxyethoxy)propan-1-
ol], in an approximate ratio 7:3 (yields approx. 48 and 20%),
estimated by comparison of the integration of the aldehydic
proton signal with that of the multiplet for the acetal proton
(1Ј-H; δ 4.70) in the 1H NMR spectrum (60 MHz); δH (aldehyde
3036
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038

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(1S,2S,1ЉR)- and (1S,2S,1ЉS)-2-(1Љ-Ethoxyethoxy)-1-(1Ј-
hydroxy-4Ј,5Ј,7Ј-trimethoxynaphthalen-2Ј-yl)propan-1-ol 39
Using the method of Casiraghi et al.4b as follows:
converted into the diastereomeric esters 40 as a pale yellow oil
(12.50 g). Kugelrohr distillation gave the title compound as a
liquid (11.58 g, 100%), bp 110–130 ЊC/approx. 18 mmHg
(Kugelrohr) (Found: C, 54.1; H, 9.2. C8H16O4 requires C, 54.55;
H, 9.1%); [α]D ϩ77.8 (c 1.2, CHCl3); νmax (film)/cmϪ1 1756
A solution of the Grignard reagent ethylmagnesium bromide
in dry ether was prepared and an aliquot (1.16 cm3, containing
2.94 mmol) was transferred to a round-bottomed flask which
was then flushed with argon. A solution of the freshly prepared
naphthol 108 (550 mg, 2.35 mmol) in dry ether (25 cm3) was
added, leading to a heavy suspension. The ether was removed
under vacuum and dry methylene chloride (22 cm3) added to
the cream solid. The resulting suspension was cooled in an ice
bath and the aldehyde 35 (1.29 g, approx. 5.30 mmol, 60% pure;
prepared the previous day) added. After 20 min, the flask was
transferred to the ultrasonication bath for a further 7.5 h (bath
temperature range: 10–30 ЊC). The deep orange reaction mix-
ture was then poured into methylene chloride and saturated
ammonium chloride solution and stirred vigorously. After 1
day, the organic layer was separated and the aqueous layer re-
extracted with methylene chloride. The combined organic layers
were washed with water and brine, dried, filtered through Celite
and concentrated to a green oil (1.46 g). TLC (30% ethyl
acetate–hexane) showed minor spots at Rf 0.25 and on the base-
line, which were minor decomposition products seen repeatedly,
and two major spots at Rf 0.15 and 0.10 for the two diastereo-
mers (at C-1Љ) of 39. These two diastereomers were separable by
chromatography and column chromatography with 10–40%
ethyl acetate–hexane gave:
(C᎐O); δ (major diastereomer) 1.18 (3H, t, J 7.0, 1Љ-CH ), 1.35
᎐
H
3
(3H, d, J 5.3, 1Ј-CH3), 1.41 (3H, d, J 6.9, 2-CH3), 3.52 and 3.67
(each 1H, dq, J 9.4 and 7.0, 1Ј-OCH2), 3.74 (3H, s, CO2CH3),
4.35 (1H, q, J 6.9, 2-H) and 4.78 (1H, q, J 5.3, 1Ј-H); δH (minor
diastereomer) 1.16 (3H, t, J 7.0, 1Љ-CH3), 1.31 (3H, d, J 5.4,
1Ј-CH3), 1.39 (3H, d, J 6.8, 2-CH3), 3.49 and 3.61 (each 1H,
dq, J 9.3 and 7.0, 1Ј-OCH2), 3.74 (3H, s, CO2CH3), 4.20 (1H,
q, J 6.8, 2-H) and 4.77 (1H, q, J 5.3, 1Ј-H); δC (major diastereo-
mer) 15.3 (C-3), 19.0 (C-2Љ), 20.0 (C-2Ј), 51.9 (CH3O2C), 60.3
(C-1Љ), 69.8 (C-2), 99.4 (C-1Ј) and 173.9 (C-1); δC (minor dia-
stereomer) 15.1 (C-3), 18.9 (C-2Љ), 19.7 (C-2Ј), 51.9 (CH3O2C),
61.1 (C-1Љ), 69.9 (C-2), 99.6 (C-1Ј) and 174.1 (C-1); m/z 131
[(M Ϫ OEt), 3%], 101 (20), 88 (19), 73 (100) and 70 (34).
(2R,1ЈR or S)-2-(1Ј-Ethoxyethoxy)propanal 4
According to the procedure described above for the preparation
of aldehyde 35, (2R,1ЈR or S)-methyl 2-(1Ј-ethoxyethoxy)-
propanoate (1.40 g, 7.9 mmol) was reduced with diisobutylalu-
minium hydride (1.84 cm3, 10.3 mmol) to give an oil (1.55 g).
Kugelrohr distillation yielded an oil (0.90 g), bp 105–115 ЊC/
approx. 18 mmHg (Kugelrohr), being a mixture of aldehyde 4
and alcohol 41 [(2R,1ЈR or S)-2-(1Ј-ethoxyethoxy)propan-1-
ol], in an approximate ratio 7:3 (yields approx. 54 and 23%),
estimated by comparison of the integration of the aldehydic
proton signal with that of the multiplet for the acetal proton
1. Of Rf 0.15, one diastereomer of product 39, as a light green
solid (269 mg, 30%). Recrystallisation of a portion (100 mg)
from methylene chloride–hexane afforded small, light green
needles (87 mg), mp 124–127.5 ЊC (Found: Mϩ 380.1834.
1
(1Ј-H) in the H NMR spectrum (60 MHz); [α]D ϩ35.6 (c 1.5,
C20H28O7 requires M, 380.1835); [α]D ϩ57.0 (c 0.2, CHCl3); νmax
/
CHCl3) (aldehyde:alcohol, 6:4); νmax (film)/cmϪ1 (aldehyde 4)
cmϪ1 3431 and 3244 (OH), 1609, 1515, 1470 and 1450 (C᎐C);
1735 (C᎐O); the 1H NMR spectrum (300 MHz) was identical to
᎐
᎐
δH (500 MHz) 1.03 (3H, d, J 6.3, 2-CH3), 1.30 (3H, t, J 7.1,
CH3CH2), 1.39 (3H, d, J 5.2, 1Љ-CH3), 3.621 and 3.625 (each
1H, dq, J 7.0 and 7.1, CH2), 3.86, 3.92 and 3.94 (each 3H, s,
OCH3), 4.02 (1H, dq, J 8.5 and 6.3, 2-H), 4.56 (1H, d, J 8.5,
1-H), 4.72 (1H, q, J 5.2, 1Љ-H), 5.09 (1H, s, 1-OH), 6.34 (1H, s,
3Ј-H), 6.53 and 7.16 (each 1H, d, J 2.4, 6Ј- and 8Ј-H) and 8.87
(1H, s, 1Ј-OH); δC (126 MHz) 15.3 (C-3), 17.8 (CH3CH2), 20.7
(C-2Љ), 55.3, 56.1 and 57.5 (OCH3), 62.2 (CH2), 78.3 (C-2), 80.0
(C-1), 92.8 (C-1Љ), 99.3 (C-6Ј),a 100.6 (C-3Ј),a 106.5 (C-8Ј),a
113.7 (C-8Јa),b 116.7 (C-4Јa),b 129.3 (C-2Ј), 144.8 (C-1Ј), 149.9
(C-4Ј), 157.8 (C-7Ј)c and 158.0 (C-5Ј);c m/z 380 (Mϩ, 3%), 334
(7), 318 (11), 290 (100), 273 (26), 247 (50), 233 (11), 73 (8) and
57 (6).
that reported above for the pair of diastereomeric aldehydes 35,
since these are enantiomeric to the aldehyde pair 4.
(1S,2R,1ЉR or S)-1-(7Ј-Benzyloxy-1Ј-hydroxy-4Ј,5Ј-dimethoxy-
2Ј-naphthyl)-2-(1Љ-ethoxyethoxy)propan-1-ol 5
Following the procedure described above for the preparation
of 37, freshly prepared naphthol 3 (199 mg, 0.64 mmol) was
treated with titanium tetraisopropoxide (0.229 cm3, 0.77 mmol)
and the aldehyde 4 (375 mg, approx. 1.54 mmol, 60% pure) was
added. Column chromatography with 30–50% ethyl acetate–
hexane gave:
1. Of Rf 0.26 (30% ethyl acetate–hexane), a bright yellow
band containing a decomposition product.
2. Of Rf 0.10, after further chromatography, the other dia-
stereomer of product 39 as a deep green oil (contaminated with
some inseparable impurities) (520 mg, approx. 74% pure,
approx. 43% yield) (Found: Mϩ 380.1834. C20H28O7 requires M,
380.1835); [α]D ϩ12.4 (c 0.2, CHCl3; purity of sample: 74%);
2. Of Rf 0.08 (30% ethyl acetate–hexane), the required
product 5 as a mixture of diastereomers at C-1Љ, a deep red oil
(126 mg, 43%). This compound was reasonably stable, but soon
after chromatography always underwent a small amount of
decomposition to by-products at Rf 0.26 and baseline material.
Compound 5 (Found: Mϩ, 456.2131. C26H32O7 requires M,
456.2148); [α]D Ϫ8.6 (c 0.3, CHCl3) (mixture of diastereomers
at C-1Љ); νmax (film)/cmϪ1 3339 (OH), 1624, 1608, 1516, 1499 and
νmax (film)/cmϪ1 3333 (OH), 1610, 1516, 1471 and 1451 (C᎐C);
᎐
δH (500 MHz) 1.10 (3H, d, J 6.2, 2-CH3), 1.20 (3H, t, J 7.1,
CH3CH2), 1.38 (3H, d, J 5.3, 1Љ-CH3), 3.50 and 3.70 (each 1H,
dq, J 9.2 and 7.1, CH2), 3.83, 3.90 and 3.92 (each 3H, s, OCH3),
3.99 (1H, dq, J 7.8 and 6.2, 2-H), 4.28 (1H, s, 1-OH), 4.57 (1H,
d, J 7.8, 1-H), 4.79 (1H, q, J 5.3, 1Љ-H), 6.31 (1H, s, 3Ј-H), 6.51
and 7.13 (each 1H, d, J 2.1, 6Ј- and 8Ј-H) and 8.54 (1H, s,
1Ј-OH); δC (126 MHz) 15.1 (C-3), 17.7 (CH3CH2), 20.2 (C-2Љ),
55.2, 56.1 and 57.5 (OCH3), 61.7 (CH2), 75.4 (C-2), 79.6 (C-1),
92.9 (C-1Љ), 99.4 (C-6Ј),a 100.1 (C-3Ј),a 106.1 (C-8Ј),a 113.6
(C-8Јa),b 117.1 (C-4Јa),b 129.4 (C-2Ј), 144.5 (C-1Ј), 149.9 (C-4Ј),
157.8 (C-7Ј)c and 158.0 (C-5Ј);c m/z 380 (Mϩ, 15%), 362 (9), 334
(29), 318 (35), 291 (37), 290 (100), 273 (39), 261 (21), 247 (50),
233 (26), 73 (40) and 57 (7).
1454 (C᎐C); δ (major diastereomer; 500 MHz) 1.216 (3H, t,
᎐
H
J 7.1, CH3CH2), 1.217 (3H, d, J 6.5, 2-CH3), 1.34 (3H, d, J 5.3,
1Љ-CH3), 3.53 and 3.65 (each 1H, dq, J 9.2 and 7.1, CH2), 3.56
(1H, br s, 1-OH), 3.86 and 3.93 (each 3H, s, OCH3), 4.09 (1H,
dq, J 4.1 and 6.5, 2-H), 4.81 (1H, q, J 5.3, 1Љ-H), 4.92 (1H, d,
J 4.1, 1-H), 5.17 (2H, s, C6H5CH2), 6.29 (1H, s, 3Ј-H), 6.62 and
7.29 (each 1H, d, J 2.3, 6Ј- and 8Ј-H), 7.32–7.51 (5H, m, C6H5)
and 8.86 (1H, s, 1Ј-OH); δH (minor diastereomer; 500 MHz)
1.15 (3H, d, J 5.7, 2-CH3), 1.18 (3H, t, J 7.0, CH3CH2), 1.37
(3H, d, J 5.3, 1Љ-CH3), 3.47 and 3.59 (each 1H, dq, J 9.2 and 7.0,
CH2), 3.56 (1H, br s, 1-OH), 3.86 and 3.93 (each 3H, s, OCH3),
4.12 (1H, dq, J 3.7 and 5.7, 2-H), 4.84 (1H, q, J 5.3, 1Љ-H), 4.98
(1H, d, J 3.7, 1-H), 5.17 (2H, s, C6H5CH2), 6.31 (1H, s, 3Ј-H),
6.62 and 7.31 (each 1H, d, J 2.3, 6Ј- and 8Ј-H), 7.32–7.51 (5H,
m, C6H5) and 8.83 (1H, s, 1Ј-OH); δC (major diastereomer; 126
(2R, 1ЈR or S)-Methyl 2-(1Ј-ethoxyethoxy)propanoate 40
Following the method described above for the preparation of
compound 34, (R)-methyl lactate (6.20 cm3, 65.0 mmol) was
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038
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MHz) 15.1 (C-3), 15.2 (CH3CH2), 20.3 (C-2Љ), 56.2 and 57.5
(OCH3), 60.4 (CH3CH2), 70.0 (C6H5CH2), 76.3 (C-2), 78.3
(C-1), 94.2 (C-1Љ), 99.5 (C-6Ј),a 99.7 (C-3Ј),a 105.1 (C-8Ј),a
113.6 (C-8Јa),b 116.9 (C-4Јa),b 127.9 (C-2ٞ and C-6ٞ),c 128.0
(C-4ٞ), 128.6 (C-3ٞ and C-5ٞ),c 129.6 (C-2Ј), 136.8 (C-1ٞ),
144.5 (C-1Ј), 150.1 (C-4Ј), 157.2 (C-7Ј)d and 157.8 (C-5Ј);d
δC (minor diastereomer; 126 MHz) 14.4 (C-3), 15.2 (CH3CH2),
20.6 (C-2Љ), 56.2 and 57.6 (OCH3), 60.7 (CH3CH2), 70.0
(C6H5CH2), 76.1 (C-2), 78.4 (C-1), 94.3 (C-1Љ), 99.0 (C-6Ј),a
99.7 (C-3Ј),a 105.4 (C-8Ј),a 113.6 (C-8Јa),b 116.9 (C-4Јa),b 127.9
(C-2ٞ and C-6ٞ),c 128.0 (C-4ٞ), 128.6 (C-3ٞ and C-5ٞ),c 129.6
(C-2Ј), 136.8 (C-1ٞ), 144.5 (C-1Ј), 150.1 (C-4Ј), 157.2 (C-7Ј)d
and 157.8 (C-5Ј);d m/z 456 (Mϩ, 3%), 438 (4), 410 (5), 394 (18),
366 (52), 350 (18), 275 (15), 247 (38), 231 (23), 91 (100) and 73
(18).
456 (Mϩ, 1%), 438 (2), 410 (2), 394 (19), 366 (31), 349 (18), 275
(28), 247 (51), 229 (19), 91 (100) and 65 (12).
Acknowledgements
We gratefully acknowledge receipt of an Australian Postgradu-
ate Research Award (C. A. J.) and financial support from the
Senates of Murdoch University and The University of Western
Australia.
References
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(1R, 2R, 1ЉR)- and (1R, 2R, 1ЉS)-1-(7Ј-Benzyloxy-1Ј-hydroxy-
4Ј,5Ј-dimethoxy-2Ј-naphthyl)-2-(1Љ-ethoxyethoxy)propan-1-ol
6
Following the method described above for the preparation of
39, the freshly prepared naphthol 3 (326 mg, 1.05 mmol) in dry
ether (10 cm3) and dry tetrahydrofuran (4 cm3) was added to an
aliquot (0.43 cm3, containing 1.31 mmol) of ethylmagnesium
bromide in dry ether, resulting in a green solution, with further
treatment with the aldehyde 4 (0.63 g, approx. 3.02 mmol, 70%
pure). The crude product was obtained as a red oil (0.79 g).
TLC (30% ethyl acetate–hexane) showed minor spots at Rf 0.29
and on the baseline, which were minor decomposition products
seen repeatedly, and two major spots at Rf 0.14 and 0.09 for the
two diastereomers (at C-1Љ) of 6. These two diastereomers were
separable by chromatography and column chromatography
with 20–50% ethyl acetate–hexane gave:
1. Of Rf 0.14, one of the diastereomeric products 6, as a light
green solid (190 mg, 40%). Recrystallisation from methylene
chloride–hexane afforded deep cream needles (159 mg), mp 95–
96.5 ЊC (Found: C, 68.2; H, 7.7%; Mϩ 456.2169. C26H32O7
requires C, 68.4; H, 7.1%; M, 456.2148); [α]D Ϫ40.4 (c 0.3,
CHCl3); νmax/cmϪ1 3356 (OH), 1615, 1522, 1499, 1473 and 1456
4 (a) G. Casiraghi, M. Cornia, G. Casnati, G. G. Fava, M. F. Belicchi
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1121; (e) F. Bigi, G. Casnati, G. Sartori, C. Dalprato and R.
Bortolini, Tetrahedron: Asymmetry, 1990, 1, 861.
5 T. Mukaiyama, Org. React., 1982, 28, 203.
6 W. Eisenhuth and H. Schmid, Helv. Chim. Acta, 1958, 41, 2021.
7 A preliminary account of some of this work has been reported
previously: R. G. F. Giles, C. A. Joll, M. V. Sargent and D. M. G.
Tilbrook, Tetrahedron Lett., 1996, 37, 7851.
8 R. G. F. Giles, A. B. Hughes and M. V. Sargent, J. Chem. Soc.,
Perkin Trans. 1, 1991, 1581.
9 R. G. F. Giles and C. A. Joll, unpublished results.
10 H. W. Dorn, W. H. Warren and J. L. Bullock, J. Am. Chem. Soc.,
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11 J. March, Advanced Organic Chemistry: Reactions, Mechanisms and
Structure, McGraw-Hill, Japan, 4th edn., p. 1098, 1184.
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13 P. P. Wickham, K. H. Hazen, H. Guo, G. Jones, K. Hardee Reuter
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Smith, J. Chem. Soc., Perkin Trans. 1, 1974, 2435.
19 T. A. Chorn, R. G. F. Giles, I. R. Green, V. I. Hugo, P. R. K.
Mitchell and S. C. Yorke, J. Chem. Soc., Perkin Trans. 1, 1984, 1339.
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21 Y. Ito, Y. Kobayashi, T. Kawabata, M. Takase and S. Terashima,
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23 B. Seuring and D. Seebach, Helv. Chim. Acta, 1977, 60, 1175.
24 M. K. Meilahn, C. N. Statham, J. L. McManaman and M. E.
Munk, J. Org. Chem., 1975, 40, 3551.
25 M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1984, 23, 556.
26 K. Mead and T. L. Macdonald, J. Org. Chem., 1985, 50, 422.
27 G. Casiraghi, M. Cornia, G. Rassu, L. Zetta, G. G. Fava and
M. F. Belicchi, Carbohydr. Res., 1989, 191, 243 and references
therein.
28 R. G. F. Giles and C. A. Joll, J. Chem. Soc., Perkin Trans. 1, 1999,
3039.
29 A. Sonn and E. Patschke, Ber. Dtsch. Chem. Ges., 1925, 58, 1698.
30 J. Wu, J. L. Beal and R. W. Doskotch, J. Org. Chem., 1980, 45, 208.
31 L. R. Subramanian, M. Hanack, L. W. K. Chang, M. A. Imhoff,
P. v. R. Schleyer, F. Effenberger, W. Kurtz, P. J. Stang and T. E.
Dueber, J. Org. Chem., 1976, 41, 4099.
(C᎐C); δ (500 MHz) 1.04 (3H, d, J 6.4, 2-CH3), 1.30 (3H, t,
᎐
H
J 7.0, CH3CH2), 1.39 (3H, d, J 5.2, 1Љ-CH3), 3.62 and 3.64
(each 1H, dq, J 9.2 and 7.0, CH3CH2), 3.87 and 3.94 (each 3H,
s, OCH3), 4.03 (1H, dq, J 8.5 and 6.4, 2-H), 4.57 (1H, d, J 8.5,
1-H), 4.73 (1H, q, J 5.2, 1Љ-H), 5.10 (1H, s, 1-OH), 5.18 (2H, s,
C6H5CH2), 6.36 (1H, s, 3Ј-H), 6.62 and 7.29 (each 1H, d, J 2.4,
6Ј- and 8Ј-H), 7.32–7.52 (5H, m, C6H5) and 8.88 (1H, s, 1Ј-OH);
δC (126 MHz) 15.3 (C-3), 17.8 (CH3CH2), 20.8 (C-2Љ), 56.2 and
57.6 (OCH3), 62.2 (CH3CH2), 70.0 (C6H5CH2), 78.3 (C-2), 80.0
(C-1), 93.9 (C-1Љ), 99.7 (C-6Ј),a 100.6 (C-3Ј),a 106.6 (C-8Ј),a
113.9 (C-8Јa),b 116.7 (C-4Јa),b 127.9 (C-2ٞ and C-6ٞ),c 128.0
(C-4ٞ), 128.6 (C-3ٞ and C-5ٞ),c 129.3 (C-2Ј), 136.8 (C-1ٞ),
144.9 (C-1Ј), 149.9 (C-4Ј), 157.2 (C-7Ј)d and 157.9 (C-5Ј);d m/z
456 (Mϩ, 1%), 438 (1), 410 (2), 394 (11), 366 (24), 349 (10), 275
(20), 247 (34), 149 (12), 91 (100) and 65 (11).
2. Of Rf 0.09, one of the diastereomeric products 6, as an
unstable thick, red oil (183 mg, 38%); [α]D Ϫ8.4 (c 0.2, CHCl3);
νmax (film)/cmϪ1 3430 (OH), 1609, 1516, 1499 and 1454 (C᎐C);
᎐
δH (500 MHz) 1.12 (3H, d, J 6.2, 2-CH3), 1.23 (3H, t, J 7.1,
CH3CH2), 1.42 (3H, d, J 5.3, 1Љ-CH3), 3.53 and 3.74 (each 1H,
dq, J 9.2 and 7.1, CH3CH2), 3.86 and 3.94 (each 3H, s, OCH3),
4.01 (1H, dq, J 8.0 and 6.2, 2-H), 4.22 (1H, s, 1-OH), 4.58 (1H,
d, J 8.0, 1-H), 4.83 (1H, q, J 5.3, 1Љ-H), 5.17 (2H, s, C6H5CH2),
6.34 (1H, s, 3Ј-H), 6.62 and 7.28 (each 1H, d, J 2.3, 6Ј- and
8Ј-H), 7.32–7.51 (5H, m, C6H5) and 8.55 (1H, s, 1Ј-OH); δC (126
MHz) 15.2 (C-3), 17.7 (CH3CH2), 20.3 (C-2Љ), 56.2 and 57.5
(OCH3), 61.9 (CH3CH2), 70.0 (C6H5CH2), 75.3 (C-2), 79.8
(C-1), 94.0 (C-1Љ), 99.8 (C-6Ј),a 100.1 (C-3Ј),a 106.3 (C-8Ј),a
113.8 (C-8Јa),b 117.0 (C-4Јa),b 127.9 (C-2ٞ and C-6ٞ),c 128.1
(C-4ٞ), 128.6 (C-3ٞ and C-5ٞ),c 129.4 (C-2Ј), 136.8 (C-1ٞ),
144.7 (C-1Ј), 150.0 (C-4Ј), 157.3 (C-7Ј)d and 157.9 (C-5Ј);d m/z
Paper 9/01456J
3038
J. Chem. Soc., Perkin Trans. 1, 1999, 3029–3038