The synthesis of oxygenated naphthyl stannanes possessing ortho-methoxy substituents for use in stille coupling reactions

Article abstract of DOI:10.1071/C98106

The preparation of oxygenated naphthyl stannanes bearing an ortho-methoxy substituent is described, including stannanes (23) and (25) which are key intermediates for the synthesis of dimeric pyranonaphthoquinone antibiotics. Stannanes (17), (19) and (21)-(23) were obtained by metalhalogen exchange of the corresponding bromonaphthalenes. In an alternative approach to effect stannylation, a palladium(0)-mediated coupling reaction using hexaalkylditin reagents was examined. The Stille coupling reaction between naphthyl stannanes (23) and (25) and the corresponding bromonaphthalenes (11) and (24) failed to effect coupling to the desired binaphthyls.

Full text of DOI:10.1071/C98106

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 19–29
.
The Synthesis of Oxygenated Naphthyl Stannanes
Possessing ortho-Methoxy Substituents
for Use in Stille Coupling Reactions
Margaret A. Brimble A,B and Letecia J. Duncalf A
A
School of Chemistry, F11, University of Sydney, Camperdown, N.S.W. 2006.
Author to whom correspondence should be addressed.
B
The preparation of oxygenated naphthyl stannanes bearing an ortho-methoxy substituent is described,
including stannanes (23) and (25) which are key intermediates for the synthesis of dimeric
pyranonaphthoquinone antibiotics. Stannanes (17), (19) and (21)–(23) were obtained by metal–
halogen exchange of the corresponding bromonaphthalenes. In an alternative approach to e ect
stannylation, a palladium(0)-mediated coupling reaction using hexaalkylditin reagents was examined.
The Stille coupling reaction between naphthyl stannanes (23) and (25) and the corresponding
bromonaphthalenes (11) and (24) failed to e ect coupling to the desired binaphthyls.
Introduction
The red pigment actinorhodin (1) was rst isolated1
3
from the mycelia of Streptomyces coelicolor and dis-
played litmus-type properties, bright blue in alkali and
red in acid. The structure of this pigment was deter-
mined by mass spectrometric studies4 and extensive
chemical degradation5,6 and the point of dimeriza-
tion has subsequently been unequivocally determined
from biosynthetic studies.7 Several other pigments
related to actinorhodin (1) have also been isolated8
from the cultures of Streptomyces coelicolor including
the dilactone -actinorhodin (2); these all possess
an oxygen atom ortho to the linkage site. Apart
from the reported activity of actinorhodin (1) against
Staphylococcus aureus2 the biological activity of these
dimeric pyranonaphthoquinones has been relatively
unexplored, although kalafungin (3) and nanaomycin
A (4) which are closely related to the monomeric units
of these dimeric structures have been proposed to act
as bioreductive alkylating agents.9
Recent work developed by this research group has
established an e cient synthesis of several monomeric
members of the pyranonaphthoquinone antibiotics,
namely kalafungin (3),10 nanaomycin A (4), frenolicin
B (5)11 and arizonin C1 (6),12 in which the key step
involved furofuran annulation of a naphthoquinone to
a furo[3,2-b]naphtho[2,1-d]furan followed by oxidative
rearrangement to a furo[3,2-b]naphtho[2,3-d]pyran.
In order to apply this methodology to the synthesis
of dimeric pyranonaphthoquinones, at some point in the
synthesis formation of a new C–C bond between each
Manuscript received 18 June 1998
᭧ CSIRO 1999
0004-9425/99/010019$ 05.00
10.1071/CH98106

20
M. A. Brimble and L. J. Duncalf
half of the molecule was required. Our rst approach
towards the synthesis of the actinorhodins hinged on
construction of the monomeric unit with a view to
e ecting oxidative coupling in the nal step. Towards
this end, the synthesis13 of the monomeric unit of
actinorhodin (1) was completed; however, attempts to
e ect oxidative coupling to the dimer by using various
oxidizing agents proved unsuccessful.
Given these disappointing results, an alternative
synthetic strategy was proposed wherein the biaryl
linkage could be introduced at an earlier stage in
the synthesis by using a palladium(0)-catalysed cross-
coupling reaction between an organotin reagent and a
bromonaphthalene (Stille coupling).14
Results and Discussion
An e cient synthesis of dimeric pyranonaphtho-
quinone antibiotics bearing a methoxy substituent
ortho to the linkage site could be envisaged by e ect-
ing a double furofuran annulation of bisnaphthoquinone
(7) with 2-trimethylsilyloxyfuran (8) to a ord the bis-
naphthofuran adduct (9). This adduct would then
undergo oxidative rearrangement upon treatment with
ceric ammonium nitrate to the pyranonaphthoquinone
skeleton present in the natural product (Scheme 1).
Bisnaphthoquinone (7), in turn, is derived from the
dimeric naphthalene (10) after e ecting deprotection
and a double Fries rearrangement. The key step for this
approach requires construction of the binaphthyl linkage
through a Stille coupling reaction14 between a protected
bromonaphthalene (11) and the corresponding organo-
stannane (12). Towards this end, we herein report
syntheses of a range of naphthyl stannanes bearing
ortho-methoxy substituents and subsequent attempts
to e ect a Stille coupling reaction to construct the
biaryl linkage.
We have previously reported15 an e cient synthesis
of the bromonaphthol (13) using an ortho-speci c
bromination strategy. With the bromonaphthol (13) in
hand, it was envisaged that a metal–halogen exchange
could be employed to synthesize the organostannane
required for the Stille coupling reaction. Thus, use of
this methodology would require protection of naphthol
(13) as a benzyl ether. Towards this end, an excess of
sodium hydride was added to a solution of naphthol
(13) in dimethylformamide at 0 C, followed by the
addition of 1 equiv. of benzyl bromide to a ord the
benzylated bromide (11) in 88% yield (Scheme 2).
The product analysed correctly for C19H17BrO3, with
a molecular ion at m/z 374/372 in the mass spectrum
supporting this as the molecular formula. The infrared
spectrum indicated the absence of the hydroxy group
1
and an absorbance at 1054 cm
was assigned to the
C–O stretch. The 1H n.m.r. spectrum displayed a
singlet at 5 11 assigned to the benzylic protons,
protons of the benzyl protecting group. The doublets
at 6 71 and 6 89 with coupling constant J3,2 8 4 Hz
were assigned to H 3 and H 2 respectively, and two
doublets at 7 59 and 7 92 with coupling constant
whilst two multiplets in the aromatic region resonating
at 7 35–7 43 and 7 54–7 57, integrating for three and
two protons respectively, were due to the aromatic

Naphthyl Stannanes in Stille Coupling Reactions
21
J7,8 9 0 Hz were assigned to H 7 and H 8 respectively.
The 13C n.m.r. spectrum was also consistent with the
proposed structure, exhibiting a methylene carbon at
72 7 and a quaternary carbon signal at 137 3 assigned
to C 10.
Given the apparent reluctance of (11) to undergo stan-
nylation, its behaviour was then compared to two other
highly oxygenated bromonaphthalene intermediates,
namely 3-bromo-1,4,5-trimethoxynaphthalene16 (15)
and 8-benzyloxy-2-bromo-1,4-dimethoxynaphthalene17
(16). Reaction of the trimethoxybromide (15) with
1 5 equiv. of butyllithium at
100 C followed by
immediate quenching of the resultant aryllithium with
tributyltin chloride furnished the desired stannane (17)
albeit in poor yield (7%), together with signi cant
quantities of the protonated naphthalene (18) (58%)
(Scheme 3). High-resolution mass spectrometry estab-
lished the molecular formula C25H40O3Sn, with the
base peak in the mass spectrum corresponding to loss
of a butyl group from the parent ion. The 1H n.m.r.
spectrum featured a multiplet at 0 87–1 38 integrat-
ing for 27 protons assigned to the butyl protons. Two
aromatic doublets at 6 91 and 7 86 with coupling
constant Jortho 8 4 Hz were assigned to H 6 and H 8
respectively. The triplet at
7 36 was assigned to
H 7, whilst the remaining aromatic singlet at 6 80 was
assigned to H 2. The benzyloxy stannane analogue
(19) together with the protonated naphthalene (20)
were prepared in a similar manner to that described
above for (17) in 10 and 61% yields respectively.
Scheme 2. Reagents and conditions: (i) NaH, PhCH2Br,
dimethylformamide, 0 C, 88%; (ii) BuLi (2 equiv.), tetrahy-
drofuran, N2, 100 C, then either (a) 90 s, Bu3SnCl (2 equiv.),
N2, 100 C [to give (14) (77%)], or (b) immediate addition
of Me3SnCl (1 equiv.), tetrahydrofuran, N2, 100 C [to give
(23) (26%) and (14) (68%)].
With the desired bromonaphthalene (11) in hand,
our attention then focused on its transformation to
stannane (12). Thus, bromonaphthalene (11) was
treated with butyllithium at 100 C in tetrahydro-
furan. Addition of tributyltin chloride after 90 s,
however, failed to give the desired stannane (12);
rather the protonated naphthalene (14) was obtained
exclusively in 77% yield (Scheme 2). High-resolution
mass spectrometry con rmed the molecular formula
C19H18O3. A six-proton singlet at 3 95 in the 1H
n.m.r. spectrum was assigned to the coincident methoxy
groups, whilst a two-proton singlet at 5 13 was assigned
to the benzylic protons. Two doublets at 6 72 and
6 89 were assigned to H 3 and H 2 respectively, whilst
H 7 appeared as a multiplet resonating at 7 58–7 62.
A double doublet at 6 93 with coupling constants
Jortho 9 6 and Jmeta 1 0 Hz was assigned to H 6,
whilst the more down eld double doublet was assigned
to H 8, the proton peri to the methoxy substituent.
The 13C n.m.r. spectrum featured a methylene carbon
at 73 1 and a quaternary carbon at 138 0 assigned
to C 10.
It therefore appeared that in order to e ect stanny-
lation of (11) a shorter reaction time between formation
of the aryllithium intermediate and quenching with
the tin electrophile was required. With this in mind, a
series of experiments were conducted whereby the time
between the addition of butyllithium and the addition
of tributyltin chloride was incrementally reduced; how-
ever, in all cases the naphthalene (14) was the only
product isolated from the reaction mixture.
Scheme 3. Reagents and conditions: (i) BuLi (1 5 equiv.),
tetrahydrofuran, N2, 100 C, then Bu3SnCl (1 5 equiv.), N2,
100 C to room temp.; (ii) BuLi (1 5 equiv.), tetrahydrofuran,
N2, 78 C, then Me3SnCl (1 5 equiv.), N2, 78 C to room
temp.
The substantial formation of naphthalenes (14), (18)
and (20) from the attempted stannylation of bromides
(11), (15) and (16), respectively, suggested that the
combined electron-donating e ects of the oxygenated
substituents results in a marked increase in the basic
character of the naphthyl anions. Jung et al.18 reported
similar observations in their attempts to alkylate highly
oxygenated bromides and their subsequent studies with
D2O provided evidence that protonation was occurring
from the tetrahydrofuran solvent itself.

22
M. A. Brimble and L. J. Duncalf
The presence of an ortho-methoxy group may also
Whereas no stannylation of bromide (11) had been
achieved by using tributyltin chloride as the electrophile,
a 26% yield of stannane (23) when using trimethyltin
chloride represented a substantial improvement. These
observations appear to indicate that steric hindrance
of the ortho-methoxy group and the steric bulk of the
attacking electrophile are important factors contribut-
ing to low yields of the stannanes obtained. Extensive
variations to the reaction conditions were examined
including reversing the addition sequence of reagents;
however, no improvement in the overall yield of (23)
was observed. A variety of other solvents were also
evaluated. Unchanged starting material (11) was recov-
ered from the reaction mixture when ether was used
as solvent. Similarly, combinations of ether–hexane
suppressed formation of the aryllithium intermediate,
resulting in recovered bromide (11) even after prolonged
stirring before addition of the tin reagent. The use of
less polar solvents often results in formation of an ion
pair that decreases the basicity of the aryllithium; in
particular, toluene has been employed with considerable
success.19,20 In a somewhat unexpected result, use of
toluene as solvent a orded an enhanced yield of the
protonated naphthalene (14) (80%) at the expense of
the desired stannane (23) (11%).
contribute to the low yield of stannanes observed.
Undesirable steric crowding around the reaction site
potentially reduces the accessibility of the naphthyl
anion to the electrophile. In the event the attacking
electrophile is a bulky reagent such as tributyltin
chloride, so it is not surprising that high yields of
protonated compounds are obtained. Presumably pro-
tonation of the extremely basic naphthyl anion occurs
before reaction with the tin reagent can proceed.
The presence of a bulky benzyloxy group peri to the
methoxy group in the bromonaphthalenes (11) and (16)
may well increase steric crowding, forcing the methoxy
group to occupy a position shielding the lithiated site.
In an e ort to minimize detrimental steric e ects, the
use of a less bulky tin reagent, namely trimethyltin
chloride, was therefore investigated.
Stannylation of the trimethoxy bromide (15) was
undertaken by using similar conditions described pre-
viously; however, trimethyltin chloride was substituted
for tributyltin chloride (Scheme 3). In this case, the
desired stannane (21) was obtained in 29% yield in
addition to the protonated naphthalene (18) (60%).
In a similar result, quenching of the naphthyllithium
species generated from the benzyloxybromide (16) with
trimethyltin chloride resulted in formation of the desired
stannane (22) in 35% yield.
In light of the di culties experienced with the
lithiation reaction an alternative approach was sought
whereby the organostannane was prepared from a
For the synthesis of stannanes (21) and (22) by
metal–halogen exchange of the corresponding bromides
(15) and (16), trimethyltin chloride gave superior results
to tributyltin chloride, as the latter reagent is too
sterically hindered. In a similar fashion, trimethyltin
chloride was also shown to be the reagent of choice
to e ect stannylation of the bromonaphthalene (11),
the precursor to the actinorhodins. Bromonaphthalene
(11) was metallated with butyllithium (1 equiv.) in
tetrahydrofuran at 100 C, generating the naphthyl-
lithium species which was immediately trapped with
trimethyltin chloride to a ord stannane (23) in 26% yield
(Scheme 2). As expected, protonated naphthalene (14)
was the major product (68% yield). High-resolution
mass spectrometry of the stannane (23) established the
molecular formula C22H26O3Sn. 1H and 13C n.m.r.
spectroscopy further con rmed the proposed structure.
palladium(0)-catalysed cross-coupling reaction with a
25
hexaalkylditin reagent.21
This route could also
e ect dimerization of the in-situ generated stan-
nane to the desired binaphthyl in a single operation.
Initial work was therefore focused on the use of
(Bu3Sn)2 to e ect palladium(0)-mediated stannylation
of bromonaphthalenes (11), (15) and (16). Use of
tetrakis(triphenylphosphine)palladium(0) and dichloro-
bis(triphenylphosphine)palladium(II) in toluene failed
to e ect any coupling despite the use of up to 8 equiv. of
the (Bu3Sn)2 reagent, although considerable quantities
of protonated naphthalenes (14), (18) and (20) were
isolated from the reaction mixture. The coupling reac-
tion proved to be more successful when (Me3Sn)2 was
used, presumably due to its more sterically accessible
tin–tin bond, a ording the desired stannanes (23),
(17) and (19) in 22, 15 and 20% yields respectively
(Scheme 4). Complete conversion of starting material
into the products required the addition of 8 equiv. of
the ditin reagent. It therefore appeared that steric
e ects due to the presence of the ortho-methoxy
group suppress the stannylation reaction and hence
the subsequent in situ coupling.
1
The H n.m.r. spectrum displayed two sets of aromatic
doublets at 6 69 and 6 87 with coupling constant
J3,2 8 4 Hz assigned to H 3 and H 2 respectively, and
two doublets at 7 50 and 8 02 with coupling constant
J7,8 8 2 Hz assigned to H 7 and H 8. Since H 8 is peri
to the methoxy group at C 1, the resonance for H 8 is
deshielded as expected. The three-proton singlet at
3 71 was assigned to the methoxy group ortho to the
stannyl substituent (5-OMe), whilst 1-OMe resonated
at 3 95. The quaternary carbon at 132 9 in the 13C
n.m.r. spectrum was assigned to the carbon bearing
the stannyl group (C 6), and a down eld shift of the
resonance assigned to C 5 from 150 1 in the parent
bromide (11) to 161 0 in stannane (23) was observed.
With the desired actinorhodin stannane (23) in
hand, attention was then focused on the subse-
quent Stille coupling with the bromonaphthalene (11)
to construct the critical binaphthyl (10). Use of
tetrakis(triphenylphosphine)palladium(0) and dichloro-
bis(triphenylphosphine)palladium(II) in toluene failed
to e ect coupling after prolonged heating under re ux

Naphthyl Stannanes in Stille Coupling Reactions
23
(Scheme 5). Despite the addition of fresh catalyst no
dimerization was observed with only the naphthalene
(14), originating from aryl stannane (23), and the
starting bromide (11) being recovered in 71 and 63%
yields respectively. The use of other solvents, namely
dimethylformamide, tetrahydrofuran and dioxan, was
equally unsuccessful.
and the bromide (11) which are both presumably too
hindered to enter into the coupling event. Unsuccessful
coupling reactions of severely hindered aryl stannanes
have been reported in the literature.32,33 There is
also considerable literature precedent which indicates
that methoxy groups ortho to the stannane exert a
detrimental e ect on the e ciency of the coupling
35
reaction.32
Experimental evidence has also estab-
lished that electron-rich aryl bromides generally provide
lower yields of coupled products than aryl bromides
with electron-withdrawing substituents32,34,36 due to
a slow rate of oxidative addition to palladium(0). As
expected, owing to the presence of three electron-
donating groups including an ortho-methoxy group,
coupling of bromide (11) with stannane (23) proved
to be particularly problematic.
The disadvantage of using a metal–halogen exchange
to synthesize organotin reagents is that it does not allow
a wide variety of functional groups to be present in the
naphthyl stannane, hence it was necessary to use the
protected bromide (11) in these reactions. In contrast,
mild palladium(0)-catalysed coupling of hexaalkylditin
reagents with aryl bromides tolerates a wide range
of functionality on the naphthyl bromide.14 Hence, it
was envisaged that the binaphthyl linkage could be
constructed at a later step in the synthesis by e ecting
a Stille coupling14 between the bromonaphthol (24)
and the stannane (25) which already had an acetyl
group at C 2 in place as required for the ensuing
furofuran annulation with 2-trimethylsilyloxyfuran (8)
(Scheme 6).
Scheme 4. Reagents and conditions: (i) 10% PdCl2(PPh3)2,
(Me3Sn)2 (8 equiv.), toluene, argon, re ux, 72 h.
Towards this end, acetylation of the bromonaph-
thol (13) with acetic anhydride, triethylamine and
4-dimethylaminopyridine in dichloromethane a orded
acetate15 (26) in 98% yield. Attempts to e ect
palladium(0)-mediated stannylation of acetate (26)
by employing similar conditions to those previously
described were unsuccessful. Rather than the proto-
nated naphthalene being recovered, the bromonaphthol
(13) was obtained in 42% yield presumably due to
deacetylation of the starting material. Fries rearrange-
ment of acetate (26) was then accomplished upon
treatment with boron tri uoride etherate to a ord the
desired acetylnaphthol15 (24) in 71% yield.
With toluene as solvent, the palladium(0)-catalysed
coupling of the acetylnaphthol (24) with (Me3Sn)2 was
then undertaken (Scheme 6). After heating the reaction
mixture under re ux for 40 h, careful puri cation by
ash chromatography a orded three products of similar
polarity, the desired stannane (25), unreacted bromide
(24) and the naphthalene (27) in 28, 16 and 17% yields
respectively. The addition of fresh catalyst and excess
ditin reagent failed to promote complete conversion of
the starting material into products. The structure of
stannane (25) was con rmed upon spectroscopic anal-
ysis. High-resolution mass spectrometry established
the molecular formula C17H22O4Sn. The base peak
at m/z 395 in the mass spectrum corresponds to loss
Scheme 5. Reagents and conditions: (i) 10% PdCl2(PPh3)2,
toluene, argon, re ux, 72 h.
Several modi cations to the catalytic system were
then examined. The use of a so-called ‘ligandless’
catalyst,26,27 namely tris(dibenzylideneacetone)dipalla-
dium(0)28 and triphenylarsine, which has resulted in
signi cant rate enhancements over the previous more
traditional catalysts, was also disappointing under a
range of di erent conditions. Similarly, the inclusion
31
of copper(I) iodide29
as a cocatalyst that has been
shown to give improved rates and yields in Stille
couplings a orded no coupled product.
The major obstacle to dimerization would seem
to be the use of an ortho-substituted stannane (23)

24
M. A. Brimble and L. J. Duncalf
Scheme 6. Reagents and conditions: (i) Ac2O, Et3N, 4-dimethylaminopyridine, CH2Cl2, room temp.; (ii) (Me3Sn)2
(8 equiv.), 10% PdCl2(PPh3)2, toluene, N2, re ux, 72 h; (iii) BF3.OEt2, 120 C; (iv) (Me3Sn)2 (8 equiv.), 10%
PdCl2(PPh3)2, toluene, argon, re ux, 40 h.
of a methyl fragment from the molecular ion. The
infrared spectrum displayed a stretch at 1621 cm
Baeyer–Villiger oxidation–hydrolysis sequence proved
unsuccessful. Treatment of aldehyde (29) with meta-
chloroperoxybenzoic acid in dichloromethane e ected
oxidation of the formyl group to the carboxylic acid,
which then undergoes lactonization with the peri-
hydroxy substituent to a ord lactone (31) in 13%
yield. Accurate mass determination was consistent
with the molecular formula C12H7BrO3 and the infrared
1
attributed to the carbonyl group, while a broad band
1
at 3333 cm
was indicative of a hydroxyl stretch.
The resonance at
0 36 in the 1H n.m.r. spectrum
integrating for nine protons was assigned to the methyl
protons of the Me3Sn group, whilst two singlets at
3 87 and 3 98 were assigned to the two methoxy
groups. The aromatic resonances were consistent with
the expected substitution pattern. The 13C n.m.r.
spectrum showed a down eld shift in the resonances of
both C 7 at 134 3 and C 8 at 164 1 relative to the
bromide (24) where they resonated at 116 7 and 155 5
1
spectrum exhibited a strong absorption at 1790 cm
indicative of an ester carbonyl group. The 1H n.m.r.
spectrum displayed all the features consistent with
the proposed lactone structure, namely a singlet at
4 12 assigned to the methoxy group and the absence
of signals at 9 61 and 13 10 due to the formyl and
hydroxy groups of the starting material. Two aromatic
doublets at 7 55 and 7 68 were assigned to H 6 and
H 5 respectively, whilst doublets at 7 07 and 8 10 were
assigned to H 3 and H 2 respectively. The 13C n.m.r.
spectrum exhibited a signal for a carbonyl carbon
respectively. A methyl carbon signal at
8 3 was
assigned to the methyl groups of the tin substituent.
With stannane (25) in hand, a Stille coupling with
bromide (24) was then examined with a view to
constructing the dimeric linkage. Use of dichloro-
bis(triphenylphoshine)palladium(II) in toluene failed to
a ord any coupled product and considerable amounts
of both starting materials remained in addition to the
formation of the protonated naphthalene (27).
Given that the ortho-methoxy group in naphthyl
stannanes (23) and (25) may have a ected their abil-
ity to participate in a Stille coupling, an alternative
protecting group for the ortho-hydroxy substituent
was sought that would exert no serious steric hin-
drance. Towards this end, the bromo acetonide (28)
was proposed as a suitable synthetic equivalent to the
bromonaphthalene (11) (Scheme 7). It was envisaged
that the isopropylidene group would reduce steric hin-
drance around the reaction centre, thereby facilitating
access of the tin electrophile to the naphthyl anion.
Bromo aldehyde15 (29) was readily available as an
intermediate from the earlier synthesis of bromonaph-
thalene (11). Initial attempts to directly transform
the bromo aldehyde (29) to the diol (30) by a
at
164 9, whilst a signal at 161 5 was assigned
to C 4, the carbon bearing the methoxy group. The
rather low mass recovery for the oxidation can be
attributed to the coordination of the free hydroxy
group in aldehyde (29) to meta-chloroperoxybenzoic
acid, thereby rendering puri cation di cult.
It became apparent that protection of hydroxy alde-
hyde (29) as a benzyl ether was required. Towards
this end, benzylation of (29) was e ected in 87%
yield by using an excess of sodium hydride and ben-
zyl bromide in dimethylformamide. Benzyl ether (32)
analysed correctly for C19H15BrO3. A carbonyl stretch
1
at 1662 cm
in the infrared spectrum supported the
presence of an aldehyde. A singlet in the 1H n.m.r.
spectrum at 4 94 integrating for two protons was
assigned to the benzylic protons, whilst a ve-proton
aromatic multiplet at 7 36–7 57 established the pres-
ence of a benzyl ether. Two aromatic doublets at

Naphthyl Stannanes in Stille Coupling Reactions
25
acid followed by hydrolysis of the resultant formate
with p-toluenesulfonic acid in aqueous tetrahydrofuran
a orded the naphthol (33) in 65% overall yield. The
product correctly analysed for C18H15BrO3 with a
molecular ion at m/z 358/360 in the mass spectrum
supporting this structure. The absence of a carbonyl
1
stretch at 1662 cm
band at 3389 cm
and the presence of a broad
characteristic of a hydroxy group
1
were evident in the infrared spectrum. A three-proton
singlet at
3 93 in the 1H n.m.r. spectrum was
assigned to the methoxy group, whilst a singlet at
8 86 due to the hydroxy group further con rmed
the proposed structure. The 13C n.m.r. spectrum
displayed a methyl carbon at
55 5 assigned to
the methoxy carbon on C 4 and quaternary carbons
at 119 0 and 134 5 were assigned to C 7 and C 10
respectively.
Subsequent hydrogenation of (33) e ected quanti-
tative deprotection of the benzyl ether to the naph-
thalenediol (30) which was not puri ed, but taken
directly to the following step. By using methodology
reported by Yoshii et al.,37 the naphthalenediol (30) was
treated with 2,2-dimethoxypropane and acetone in the
presence of 70% perchloric acid to give the acetonide
(28) in 60% yield. High-resolution mass spectrometry
con rmed the molecular formula C14H13BrO3. The
1H n.m.r. spectrum displayed two doublets at 6 73
and 6 81 with coupling constant J3,2 8 2 Hz assigned
to H 3 and H 2 respectively, whilst two doublets at
7 53 and 7 65 with coupling constant J7,8 8 9 Hz
were assigned to H 7 and H 8. An aliphatic six-proton
singlet at 1 41 was assigned to the coincident methyl
protons of the isopropylidene, whilst the singlet at
3 95 was assigned to the methoxy group. The 13C
n.m.r. spectrum was also consistent with the proposed
structure, exhibiting a methyl carbon signal at 25 9
and a quaternary signal at 103 2 assigned to C 10 of
the isopropylidene group.
With the required acetonide (28) in hand, attention
was then focused on conversion into the corresponding
stannane (34) by means of a lithium–halogen exchange
under similar conditions to those described earlier for
the synthesis of the naphthyl stannanes (17), (19) and
(23). Thus, the bromo acetonide (28) was treated with
butyllithium at 78 C in tetrahydrofuran to generate
the aryllithium species followed by immediate trapping
with trimethyltin chloride (Scheme 7). Puri cation
by ash chromatography a orded an inseparable mix-
ture of the desired stannane (34) and the protonated
naphthalene (35) in a 1 : 4 ratio as determined by
Scheme 7. Reagentsand conditions: (i) m-chloroperoxybenzoic
acid, CH2Cl2, re ux, KF, 13%; (ii) NaH, PhCH2Br, dimethylfor-
mamide, 0 C, 87%; (iii) m-chloroperoxybenzoic acid, CH2Cl2,
KF, room temp., then p-TsOH, tetrahydrofuran/H2O (9 : 1),
N2, re ux, 65% over two steps; (iv) H2, Pd/C, EtOAc, room
temp.; (v) 2,2-dimethoxypropane, acetone, perchloric acid
(70%), room temp., 60% over two steps; (vi) BuLi (2 equiv.),
tetrahydrofuran, N2, 78 C, then Me3SnCl (2 equiv.), N2,
78 C to room temp.
6 91 and 8 10 with coupling constant J3,2 8 3 Hz
were assigned to H 3 and H 2 respectively, and two
doublets at 7 70 and 8 05 with coupling constant J6,5
9 0 Hz were assigned to H 6 and H 5. The 13C n.m.r.
spectrum exhibited a methylene carbon at 75 7 and
a carbonyl carbon at 193 6.
Conversion of the formyl substituent into the hydroxyl
found in naphthol (33) was then accomplished by using
a Baeyer–Villiger oxidation via the intermediate for-
mate. Treatment of (32) with meta-chloroperoxybenzoic
1
integration of the H n.m.r. spectrum. Replacement of
the ortho-methoxy group failed to give any signi cant
improvement in the yield of the stannane with protona-
tion still being a major problem. Similarly, treatment of
acetonide (28) with (Me3Sn)2 in the presence of dichloro-
bis(triphenylphosphine)palladium(II) a orded an insep-
arable mixture of stannane (34), naphthalene (35) and
unreacted bromide (28).

26
M. A. Brimble and L. J. Duncalf
J8,7 9 0 Hz, H 8. 13C n.m.r. (100 MHz, CDCl3) 55 7, OCH3;
61 9, OCH3; 72 7, OCH2; 104 2, CH, C 2; 110 2, CH, C 3;
116 4, quat., C 6; 119 6, CH, C 8; 122 7, quat., C 4a; 127 6,
CH, C 40; 127 7, CH, C 30; 128 0, quat., C 8a; 128 4, CH, C 20;
129 9, CH, C 7; 137 3, quat., C 10; 148 1, 150 1, quat., C 4,
C 5; 152 8, quat., C 1. Mass spectrum m/z 372/374 (M, 30%),
281/283 (M CH2Ph, 100), 202 (M CH2PhBr, 48).
In summary, the inherent basicity of alkoxy-
substituted naphthyl anions precludes an e cient
reaction with sterically bulky tin electrophiles. Fur-
thermore, the presence of an ortho-methoxy group
has been shown to create undesirable steric crowding
around the reaction centre; however, the use of a less
sterically bulky acetonide proved to be equally unsuc-
cessful. Whilst syntheses of stannanes (23) and (25),
which are precursors to the actinorhodins, have been
achieved in moderate yield, these compounds failed
to undergo palladium(0)-mediated cross-coupling with
the corresponding bromides (11) and (24) respectively.
It is therefore now evident that the use of a less
sterically hindered organometallic reagent is required,
namely a boronic acid. With the boronic acid in
hand, a Suzuki coupling could then be employed to
construct the biaryl linkage required for the synthesis
of the dimeric actinorhodins. Work towards this end
is now in progress.
3-Bromo-1,4,5-trimethoxynaphthalene (15)
To 2-bromo-4,8-dimethoxy-1-naphthol16 (300 mg, 1 06
mmol), dimethyl sulfoxide (0 5 ml) and tetrahydrofuran
(1 0 ml) at 0 C was added with stirring dimethyl sulfate
(0 20 ml, 2 12 mmol). After 10 min potassium hydroxide
(238 mg, 4 24 mmol) in water (0 3 ml) was added dropwise
and the resultant purple solution stirred for 1 h at 0 C, then
stirred a further 2 h upon reaching room temperature. The
reaction mixture was poured into ethyl acetate (20 ml), washed
with water (3 4 ml) and dried over sodium sulfate. Removal
of the solvent under reduced pressure and puri cation of
the residue by ash chromatography with hexane/ethyl acetate
(95 : 5) as eluent a orded 3-bromo-1,4,5-trimethoxynaphthalene
(15) (214 mg, 68%) as a white crystalline solid, m.p. 84–85 5 C.
The 1H n.m.r. data were consistent with those reported in the
literature.38
Experimental
1,4,5-Trimethoxy-3-(tributylstannyl)naphthalene (17)
General Details
To a solution of 3-bromo-1,4,5-trimethoxynaphthalene (15)
(32 mg, 0 11 mmol) in dry tetrahydrofuran (8 ml), cooled to
100 C under a nitrogen atmosphere, was added butyllithium
(0 067 ml of a 2 46 M solution in hexane, 0 17 mmol), and the
resultant solution stirred for 10 s. To this solution was added
tributyltin chloride (0 045 ml, 0 17 mmol) and the reaction
mixture stirred at 100 C for 1 h then warmed to room tem-
perature for 1 h. The reaction mixture was quenched by the
addition of saturated ammonium chloride solution (10 ml) and
extracted with ethyl acetate (3 10 ml). The organic phase was
washed with water (15 ml), brine (15 ml) and dried over mag-
nesium sulfate. Removal of the solvent under reduced pressure
a orded a dark oil which was puri ed by ash chromatography
with hexane/ethyl acetate (8 : 2) as eluent to yield the naph-
Melting points were determined by using a Ko er hot stage
apparatus or a Reichert heating stage with microscope and
are uncorrected. Infrared spectra were recorded on a Perkin
Elmer 1600 Fourier-transform i.r. spectrometer as thin lms,
Nujol mulls or solutions (in the solvent speci ed) between
sodium chloride plates. 1H and 13C n.m.r. spectra were
obtained by using either a Bruker AC 200, a Bruker AM 400,
a Bruker AMX 400 or a Bruker DRX 400 spectrometer. 13C
n.m.r. spectra were interpreted with the aid of DEPT spectra.
Low-resolution mass spectra were recorded on an AEI MS902
double-focusing magnetic sector mass spectrometer operating
with an ionization potential of 70 eV. High-resolution mass
spectra were recorded at nominal resolution of 5000 or 10000
as appropriate. Elemental analyses were carried out at the
Microanalytical Laboratory, University of Otago, Dunedin,
New Zealand, or the Microanalytical Laboratory, University of
New South Wales, Sydney, Australia. Flash chromatography
was performed by using Merck Kieselgel 60 or Riedel-de Haen
Kieselgel S silica gel (both 230–400 mesh) with the indicated
solvents.
thyl stannane (17) (4 mg, 7%) as a dark oil (Found: M+
,
506 1981.
C
25H40O3118Sn requires M+ , 506 1993. Found:
M+ , 508 1989. C25H40O3120Sn requires M+ , 508 1999).
1
( lm) 2934 (C–H), 1606 (C=C), 1462, 1278, 1069 cm
max
(C–O). 1H n.m.r. (400 MHz, CDCl3) 0 87–1 38, m, SnBu3;
3 72, s, OCH3; 3 95, s, OCH3; 4 00, s, OCH3; 6 80, s, H 2;
6 91, d, J6,7 8 4 Hz, H 6; 7 36, t, J7,6 8 4, J7,8 8 4 Hz,
H 7; 7 86, d, J8,7 8 4 Hz, H 8. Mass spectrum m/z 508
(M, 8%), 451 [M (CH2)3CH3, 100], 219 (M SnBu3, 35),
191 (84). 1,4,5-Trimethoxynaphthalene (18) (14 mg, 58%) was
also obtained as a colourless solid, m.p. 115–117 C (lit.18
116–117 C). The 1H n.m.r. data were in agreement with those
reported in the literature.18
4-Benzyloxy-6-bromo-1,5-dimethoxynaphthalene (11)
To a solution of 7-bromo-4,8-dimethoxy-1-naphthol15 (13)
(818 mg, 2 89 mmol) in dimethylformamide (15 ml) cooled
to 0 C under an atmosphere of nitrogen was added sodium
hydride (231 mg of a 60% dispersion in oil, 5 78 mmol). The
resultant suspension was allowed to warm to room temper-
ature for 15 min. After cooling the mixture to 0 C, benzyl
bromide (0 34 ml, 2 89 mmol) was added dropwise and the
mixture stirred at room temperature for 12 h. The solution was
quenched with ice-cold water (15 ml) and the reaction mixture
extracted with dichloromethane (4 50 ml). The combined
extracts were washed with water (100 ml), brine (100 ml) and
dried (sodium sulfate). Removal of the solvent under reduced
pressure a orded an oily solid which was puri ed by ash
chromatography with hexane/ethyl acetate (99 : 1) as eluent
to yield the benzyl ether (11) (949 mg, 88%) as a colourless
solid, m.p. 79–80 C (Found: C, 61 2; H, 4 6%. C19H17BrO3
5-Benzyloxy-1,4-dimethoxy-3-(tributylstannyl)naphthalene
(19)
To a solution of 5-benzyloxy-3-bromo-1,4-dimethoxynaph-
thalene (16) (25 mg, 0 067 mmol) in dry tetrahydrofuran
(5 ml), cooled to 100 C under an atmosphere of nitrogen,
was added butyllithium (0 08 ml of a 1 1 M solution in hex-
ane, 0 087 mmol), followed immediately by tributyltin chloride
(0 024 ml, 0 087 mmol). The reaction mixture was stirred at
100 C for 45 min, warmed to room temperature for 15 min
and quenched by the addition of saturated ammonium chloride
(10 ml). After extraction into ethyl acetate (3 10 ml), the
organic phase was washed with water (15 ml), brine (15 ml)
and dried over magnesium sulfate. Removal of the solvent
under reduced pressure a orded a brown oil which was puri ed
by ash chromatography with hexane/ethyl acetate (9 : 1) as
requires C, 61 1; H, 4 6%).
(C O). 1H n.m.r.
(Nujol) 1616 (C=C), 1376,
(200 MHz, CDCl3) 3 78, s,
max
1
1054 cm
5-OCH3; 3 93, s, 1-OCH3; 5 11, s, OCH2; 6 71, d, J3,2
8 4 Hz, H 3; 6 89, d, J2,3 8 4 Hz, H 2; 7 35–7 43, m, H 30,
H 40; 7 54–7 57, m, H 20; 7 59, d, J7,8 9 0 Hz, H 7; 7 92, d,

Naphthyl Stannanes in Stille Coupling Reactions
27
eluent to yield the naphthyl stannane (19) (4 mg, 10%) as a dark
was added butyllithium (0 15 ml of a 1 5 M solution in hex-
ane, 0 23 mmol), followed immediately by trimethyltin chloride
(0 23 ml of a 1 M solution in tetrahydrofuran, 0 23 mmol).
The reaction mixture was stirred at 78 C for 45 min, warmed
to room temperature for 15 min and quenched by the addition
of saturated ammonium chloride (10 ml). After extraction into
ethyl acetate (3 10 ml), the organic phase was washed with
water (15 ml), brine (15 ml) and dried over magnesium sulfate.
Removal of the solvent under reduced pressure a orded an
orange oil which was puri ed by ash chromatography with hex-
ane/ethyl acetate (99 : 1) as eluent to yield the naphthyl stannane
(22) (24 mg, 35%) as an o -white solid, m.p. 75–77 C (Found:
oil (Found: M+ , 582 2295. C31H44O3118Sn requires M+
,
582 2307. Found: M+ , 584 2309. C31H44O3120Sn requires
M+ , 584 2312).
( lm) 2930 (C H), 1600 (C=C), 1452,
max
(C O). 1H n.m.r. (200 MHz, CDCl3) 0 89,
1
1263, 1064 cm
t, J 7 2 Hz, (CH2)3CH3; 1 12–1 56, m, (CH2)3CH3; 3 84, s,
OCH3; 3 91, s, OCH3; 5 21, s, OCH2; 6 84, s, H 2; 7 93, m,
H 6; 7 26–7 41, m, H 20, H 30, H 40, H 7; 7 61, d, J8,7 8 2 Hz,
H 8. Mass spectrum m/z 584 (M, 10%), 527 [M (CH2)3CH3,
80], 307 (22), 91 (100). 5-Benzyloxy-1,4-dimethoxynaphthalene
(20) (12 mg, 61%) was also obtained as a colourless solid,
m.p. 143–144 C (lit.39 145 C). The 1H n.m.r. data were in
agreement with those reported in the literature.39
M+ , 458 0905. C22H26O3Sn requires M+ , 458 0904).
max
1
( lm) 1593 (C=C), 1454, 1275 cm
.
1H n.m.r. (400 MHz,
CDCl3) 0 38, s, 2J(119Sn–1H) 56, 2J(117Sn–1H) 53 Hz, Me3Sn;
3 85, s, OCH3; 3 92, s, OCH3; 5 20, s, OCH2; 6 84, s, H 2;
6 94, d, J6,7 7 6 Hz, H 6; 7 32–7 60, m, H 20, H 30, H 40, H 7;
1,4,5-Trimethoxy-3-(trimethylstannyl)naphthalene (21)
(A) Metal–halogen exchange. To a solution of the bromo-
naphthalene (15) (32 mg, 0 11 mmol) in dry tetrahydrofuran
(9 ml) cooled to 78 C under an atmosphere of nitrogen, was
added butyllithium (0 11 ml of a 1 5 M solution in hexane,
0 16 mmol), followed immediately by trimethyltin chloride
(0 16 ml of a 1 M solution in tetrahydrofuran, 0 16 mmol).
The reaction mixture was stirred at 78 C for 45 min, warmed
to room temperature for 15 min and quenched by the addition
of saturated ammonium chloride (10 ml). After extraction into
ethyl acetate (3 10 ml), the organic phase was washed with
water (15 ml), brine (15 ml) and dried over magnesium sul-
fate. Removal of the solvent under reduced pressure a orded a
brown oil which was puri ed by ash chromatography with hex-
ane/ethyl acetate (8 : 2) as eluent to yield the naphthyl stannane
7 65, d, J8,7 8 5 Hz, H 8. 13C n.m.r.
(100 MHz, CDCl3)
7 8, CH3, SnMe3; 57 7, OCH3; 63 6, OCH3; 72 3, OCH2;
109 9, 113 5, 116 1, CH, C 2, C 6, C 8; 120 6, quat., C 4a;
127 0, CH, C 7; 127 7, CH, C 40; 128 1, CH, C 20; 128 9,
CH, C 30; 130 7, quat., C 8a; 130 8, quat., C 3; 138 3, quat.,
C 10; 153 9, 156 3, quat., C 1, C 5; 157 1, quat., C 4. Mass
spectrum m/z 458 (M, 15%), 167 (28), 149 (100), 91 (40).
5-Benzyloxy-1,4-dimethoxynaphthalene (20) (20 mg, 45%) was
obtained as a colourless solid, m.p. 143–145 C (lit.39 145 C).
The 1H n.m.r. data were in agreement with those reported in
the literature.39
(B) PdCl2(PPh3)2 and (Me3Sn)2. To a suspension of the
bromonaphthalene17 (16) (20 mg, 0 053 mmol) and dichloro-
bis(triphenylphosphine)palladium(II) (3 7 mg, 0 005 mmol) in
dry toluene (4 ml), under an atmosphere of argon, was
(21) (12 mg, 29%) as a cream solid, m.p. 61–62 C (Found: M+
,
382 0570. C16H22O3Sn requires M+ , 382 0591).
( lm)
max
1
1566 (C=C), 1069 cm (C–O). 1H n.m.r. (400 MHz, CDCl3)
0 30, s, 2J(119Sn–1H) 55, 2J(117Sn–1H) 53 Hz, Me3Sn; 3 74,
s, OCH3; 3 98, s, OCH3; 4 01, s, OCH3; 6 81, s, H 2; 6 91, d,
J6,7 7 8 Hz, H 6; 7 37, t, J7,6 7 8, J7,8 7 8 Hz, H 7; 7 87, d,
J8,7 7 8 Hz, H 8. 13C n.m.r. (100 MHz, CDCl3) 8 2, CH3,
SnMe3; 55 7, OCH3; 56 1, OCH3; 63 4, OCH3; 106 5, 110 1,
CH, C 6, C 2; 115 0, CH, C 8; 119 6, quat., C 4a; 125 5, CH, C 7;
129 6, quat., C 8a; 130 8, quat., C 3; 151 3, quat., C 1; 154 5,
155 0, quat., C 4, C 5. Mass spectrum m/z 382 (M, 65%), 367
(M CH3, 100), 352 [M (CH3)2, 92], 337 [M (CH3)3, 80],
307 (43), 203 (20). 1,4,5-Trimethoxynaphthalene (18) (14 mg,
60%) was also obtained as a colourless solid, m.p. 115–117 C
(lit.18 116–117 C). The 1H n.m.r. data were in agreement with
those reported in the literature.18
(B) PdCl2(PPh3)2 and (Me3Sn)2. To a suspension of
the bromonaphthalene (15) (31 mg, 0 11 mmol) and dichloro-
bis(triphenylphosphine)palladium(II) (7 7 mg, 0 011 mmol) in
dry toluene (5 ml), under an atmosphere of argon, was added
hexamethylditin (288 mg, 0 88 mmol) in toluene (0 5 ml). The
reaction mixture was heated under re ux for 72 h. After the
mixture was cooled to room temperature, potassium uoride
(51 mg, 0 88 mmol) was added and the reaction mixture stirred
for 2 h. The resultant white precipitate was ltered through
Celite and the solvent removed under reduced pressure to
a ord a dark oil. Puri cation by ash chromatography with
hexane/ethyl acetate (9 : 1) as eluent a orded the naphthyl
stannane (21) (6 mg, 15%) as a cream solid, m.p. 61–62 C, for
which the 1H n.m.r. data were consistent with those reported
above, and 1,4,5-trimethoxynaphthalene (18) (16 mg, 66%) as
a colourless solid, m.p. 115–117 C (lit.18 116–117 C), for which
the 1H n.m.r. data were also in agreement with those reported
in the literature.18
added hexamethylditin (140 mg, 0 43 mmol).
tion mixture was heated under re ux for 48 h.
The reac-
Addi-
tional dichlorobis(triphenylphosphine)palladium(II) (3 7 mg,
0 005 mmol) was added and the reaction mixture heated
under re ux for a further 24 h. After the mixture was cooled
to room temperature, potassium uoride (25 mg, 0 43 mmol)
was added and the reaction mixture stirred for 1 h. The
resultant white precipitate was ltered through Celite and
the solvent removed under reduced pressure to a ord a dark
oil. Puri cation by ash chromatography with hexane/ethyl
acetate (99 : 1) as eluent yielded the naphthyl stannane (22)
(5 mg, 20%) as an o -white solid, m.p. 75–76 C, for which the
1H n.m.r. data were in agreement with those reported above.
5-Benzyloxy-1,4-dimethoxynaphthalene (20) (11 mg, 69%) was
also obtained as a colourless solid, m.p. 143–144 C (lit.39
145 C), for which the 1H n.m.r. data were also in agreement
with those reported in the literature.39
4-Benzyloxy-1,5-dimethoxy-6-(trimethylstannyl)naphthalene
(23) and 4-Benzyloxy-1,5-dimethoxynaphthalene (14)
(A) Metal–halogen exchange. To a solution of 4-benzyloxy-
6-bromo-1,5-dimethoxynaphthalene (11) (40 mg, 0 11 mmol)
in dry tetrahydrofuran (9 ml), cooled to 100 C under an
atmosphere of argon, was added butyllithium (0 069 ml of a
1 56 M solution in hexane, 0 11 mmol), followed immediately
by trimethyltin chloride (0 11 ml of a 1 M solution in tetrahy-
drofuran, 0 11 mmol). The reaction mixture was stirred at
100 C for 1 h, then gradually warmed to room temperature
for 1 h and quenched by the addition of saturated ammo-
nium chloride (10 ml). After extraction into ethyl acetate
(3 10 ml), the organic phase was washed with water (15 ml),
brine (15 ml) and dried over magnesium sulfate. Removal
of the solvent under reduced pressure a orded an oily solid
which was puri ed by ash chromatography with hexane/ethyl
acetate (99 : 1) as eluent to yield the naphthyl stannane (23)
5-Benzyloxy-1,4-dimethoxy-3-(trimethylstannyl)naphthalene
(22)
(A) Metal–halogen exchange. To a solution of the naphthyl
bromide17 (16) (58 mg, 0 15 mmol) in dry tetrahydrofuran
(10 ml) cooled to 78 C under an atmosphere of nitrogen
(13 mg, 26%) as an o -white solid, m.p. 82–83 C (Found: M+
,
458 0922. C22H26O3Sn requires M+ , 458 0904).
( lm)
max
1
1586 (C=C), 1407, 1073 cm
(C–O). 1H n.m.r. (400 MHz,

28
M. A. Brimble and L. J. Duncalf
CDCl3) 0 43, s, 2J(119Sn–1H) 56, 2J(117Sn–1H) 53 Hz, Me3Sn;
3 71, s, 5-OCH3; 3 95, s, 1-OCH3; 5 13, s, OCH2; 6 69, d,
quat., C 7; 137 4, CH, C 6; 147 3, quat., C 1; 158 0, quat.,
C 4; 164 1, quat., C 8; 203 4, quat., C=O. Mass spectrum
m/z 410 (M, 22%), 395 (M CH3, 100), 335 (20), 231 (18).
The starting naphthol (24) (4 2 mg, 17%) was also obtained
as a yellow solid, m.p. 136–138 C (lit.15 136–138 C), for which
the 1H n.m.r. data were consistent with those reported in the
literature,15 and 2-acetyl-4,8-dimethoxy-1-naphthol (27) (3 mg,
16%) was also obtained as a yellow solid, m.p. 133–136 C (lit.40
133–135 C), for which the 1H n.m.r. data were also consistent
with those reported in the literature.40
J3,2 8 4 Hz, H 3; 6 87, d, J2,3 8 4 Hz, H 2; 7 34, d, J4 ,3
0
0
7 3 Hz, H 40; 7 38–7 40, m, H 30; 7 50, d, J7,8 8 2 Hz, H 7;
7 54–7 56, m, H 20; 8 02, d, J8,7 8 2 Hz, H 8. 13C n.m.r.
(100 MHz, CDCl3) 8 3, CH3, Me3Sn; 55 8, OCH3; 63 7,
OCH3; 73 2, OCH2; 103 9, CH, C 2; 110 0, CH, C 3; 118 1,
CH, C 8; 120 7, quat., C 4a; 127 6, CH, C 40; 127 7, CH, C 30;
128 4, CH, C 20; 130 0, quat., C 8a; 132 6, CH, C 7; 132 9,
quat., C 6; 137 7, quat., C 10; 148 1, quat., C 4; 150 6, quat.,
C 1; 161 0, quat., C 5. Mass spectrum m/z 458 (M, 26%), 367
(M CH2Ph, 14), 352 [M (CH2Ph) CH3, 20], 335 (30), 187
(64), 149 (80), 91 (100). 4-Benzyloxy-1,5-dimethoxynaphthalene
(14) (22 mg, 68%) was also obtained as a colourless solid, m.p.
7-Bromo-4-methoxynaphthalene-1,8-carbolactone (31)
To a solution of 7-bromo-8-hydroxy-4-methoxynaphthalene-
1-carbaldehyde15 (29) (68 mg, 0 24 mmol) in dichloromethane
(7 ml) was added meta-chloroperoxybenzoic acid (84 mg,
0 49 mmol) and the reaction mixture heated under re ux
for 30 h. After the mixture was cooled to room tempera-
ture, anhydrous potassium uoride (28 mg, 0 49 mmol) was
added and stirring continued for a further 3 h. The resul-
tant white precipitate was ltered o , the residue washed
with dichloromethane, and the solvent removed under reduced
pressure to a ord an orange oil. Puri cation by ash chro-
matography with hexane/ethyl acetate (8 : 2 then 6 : 4) as
eluent a orded the lactone (31) (9 mg, 13%) as an orange
solid, m.p. 138–140 C (Found: M+ , 277 9573. C12H7BrO3
63–64 C (Found: M+ , 294 1259. C19H18O3 requires M+
,
(Nujol) 1591 (C=C), 1403, 1053 cm (C–O).
(200 MHz, CDCl3) 3 95, s, 2 OCH3; 5 13, s,
1
294 1256).
1H n.m.r.
max
OCH2; 6 72, d, J3,2 8 4 Hz, H 3; 6 89, d, J2,3 8 4 Hz, H 2;
6 93, dd, J6,7 9 6, J6,8 1 0 Hz, H 6; 7 33–7 45, m, H 20, H 30,
H 40; 7 58–7 62, m, H 7; 8 02, dd, J8,7 9 6, J8,6 1 0 Hz, H 8.
13C n.m.r.
(50 MHz, CDCl3) 55 7, OCH3; 56 2, OCH3;
73 1, OCH2; 104 2, CH, C 2; 107 0, CH, C 6; 110 4, CH, C 3;
114 6, CH, C 8; 119 2, quat., C 4a; 125 8, CH, C 7; 127 2,
CH, C 20; 127 4, CH, C 40; 128 3, CH, C 30; 128 7, quat., C 8a;
138 0, quat., C 10; 149 6, 150 1, quat., C 4, C 5; 156 7, quat.,
C 1. Mass spectrum m/z 294 (M, 33%), 203 (M CH2Ph,
100), 175 (38), 91 (22).
requires M+ , 277 9579).
1495, 1059 cm
(CH2Cl2 solution) 1790 (C=O),
max
(C–O). 1H n.m.r. (200 MHz, CDCl3) 4 12,
1
(B) PdCl2(PPh3)2 and (Me3Sn)2. To a suspension of
the naphthyl bromide (11) (60 mg, 0 16 mmol) and dichloro-
bis(triphenylphosphine)palladium(II) (11 mg, 0 016 mmol) in
dry toluene (6 ml), under an atmosphere of argon, was added
hexamethylditin (419 mg, 1 28 mmol). The reaction mix-
ture was heated under re ux for 48 h. Additional dichloro-
bis(triphenylphosphine)palladium(II) (11 mg, 0 016 mmol) was
added and the reaction mixture heated under re ux for a fur-
ther 24 h. After the mixture was cooled to room temperature,
potassium uoride (74 mg, 1 28 mmol) was added and the
reaction mixture stirred for 2 h. The resultant white precipi-
tate was ltered through Celite and the solvent removed under
reduced pressure to a ord a dark oil. Puri cation by ash chro-
matography with hexane/ethyl acetate (99 : 1) as eluent yielded
the naphthyl stannane (23) (16 mg, 22%) as an o -white
solid, m.p. 82–83 C. 4-Benzyloxy-1,5-dimethoxynaphthalene
(14) (35 mg, 75%) was also obtained as a colourless solid,
m.p. 63–64 C. The 1H n.m.r. data for (23) and (14) were in
agreement to those reported above.
s, OCH3; 7 07, d, J3,2 7 9 Hz, H 3; 7 55, d, J6,5 8 9 Hz,
H 6; 7 68, d, J5,6 8 9 Hz, H 5; 8 10, d, J2,3 7 9 Hz, H 2.
13C n.m.r.
(100 MHz, CDCl3) 56 5, OCH3; 108 5, CH,
C 3; 112 2, quat., C 7; 118 2, CH, C 5; 120 1, 128 1, quat.,
C 4a, C 8a; 130 1, CH, C 2; 131 5, CH, C 6; 135 0, quat., C 1;
146 8, quat., C 8; 161 5, quat., C 4; 164 9, quat., C=O. Mass
spectrum m/z 278/280 (M, 100%), 263/265 (M CH3, 25),
209/207 (15), 139 (70).
8-Benzyloxy-7-bromo-4-methoxynaphthalene-1-
carbaldehyde (32)
A solution of the naphthalenol (29) (501 mg, 1 78 mmol)
in dimethylformamide (20 ml) was cooled to 0 C under an
atmosphere of nitrogen. To this was added sodium hydride
(143 mg of a 60% dispersion in oil, 3 57 mmol) and the resul-
tant suspension stirred for 15 min at room temperature. After
the mixture was cooled to 0 C, benzyl bromide (0 43 ml,
3 57 mmol) was then added and the suspension stirred for 6 h
at room temperature. Ice-cold water (10 ml) was added and the
reaction mixture extracted with dichloromethane (4 80 ml).
The combined extracts were washed with water (2 100 ml),
brine (100 ml) and dried over sodium sulfate. Removal of
the solvent under reduced pressure a orded an orange solid.
Puri cation by ash chromatography with hexane/ethyl acetate
(7 : 3) as eluent a orded the benzyl ether (32) (573 mg, 87%) as
a colourless solid, m.p. 115–116 C (Found: C, 61 8; H, 4 3%;
2-Acetyl-4,8-dimethoxy-7-(trimethylstannyl)-1-naphthol (25)
To a suspension of 2-acetyl-7-bromo-4,8-dimethoxy-1-naph-
thol15 (24) (25 mg, 0 078 mmol) and dichlorobis(triphenylphos-
phine)palladium(II) (5 5 mg, 0 0078 mmol) in dry toluene
(4 ml), under an atmosphere of argon, was added hexa-
methylditin (206 mg, 0 63 mmol). The reaction mixture was
heated under re ux for 40 h. After the mixture was cooled
to room temperature, potassium uoride (36 mg, 0 63 mmol)
was added and the reaction mixture stirred for 3 h. The
resultant white precipitate was ltered through Celite and
the solvent removed under reduced pressure to a ord a dark
oil. Puri cation by ash chromatography with hexane/ethyl
acetate (8 : 2) as eluent yielded the naphthyl stannane (25) (9 mg,
28%) as a yellow oil (Found: M+ , 410 0557. C17H22O4Sn
M+ , 370 0202. C19H15BrO3 requires C, 61 5; H, 4 1%;
1
M+ , 370 0205).
(Nujol) 1662 (C=O), 1330, 1043 cm
max
(C–O). 1H n.m.r. (200 MHz, CDCl3) 4 06, s, OCH3; 4 94,
s, OCH2; 6 91, d, J3,2 8 3 Hz, H 3; 7 36–7 57, m, Ph; 7 70,
d, J6,5 9 0 Hz, H 6; 8 05, d, J5,6 9 0 Hz, H 5; 8 10, d, J2,3
8 3 Hz, H 2; 11 00, s, CHO. 13C n.m.r. (50 MHz, CDCl3)
56 1, OCH3; 75 7, OCH2; 104 1, CH, C 3; 118 0, quat., C 7;
120 6, CH, C 5; 126 4, 126 5, quat., C 8a, C 4a; 128 6, CH,
C 40; 128 9, CH, C 20, C 30; 130 3, 130 8, CH, C 2, C 6; 135 4,
quat., C 10; 151 9, quat., C 8; 159 2, quat., C 1; 159 9, quat.,
C 4; 193 6, quat., C=O. Mass spectrum m/z 370/372 (M, 9%),
342/344 (M CO, 14), 278/280 (M CH2Ph, 28), 91 (100).
requires M+ , 410 0540).
1248, 1053 cm
( lm) 3333 (OH), 1621 (C=O),
max
(C–O). 1H n.m.r. (200 MHz, CDCl3) 0 36,
1
s, 2J(119Sn–1H) 56, 2J(117Sn–1H) 54 Hz, Me3Sn; 2 71, s,
COCH3; 3 87, s, OCH3; 3 98, s, OCH3; 6 89, s, H 3; 7 67, d,
J6,5 8 2 Hz, H 6; 7 99, d, J5,6 8 2 Hz, H 5; 14 48, s, OH. 13C
n.m.r. (100 MHz, CDCl3) 8 31, CH3, SnMe3; 27 5, COCH3;
55 9, OCH3; 63 8, OCH3; 101 9, CH, C 3; 112 6, quat., C 8a;
118 0, CH, C 5; 119 3, quat., C 4a; 133 8, quat., C 2; 134 3,
8-Benzyloxy-7-bromo-4-methoxy-1-naphthol (33)
To a solution of the aldehyde (32) (423 mg, 1 14 mmol) in
dichloromethane (20 ml) was added meta-chloroperoxybenzoic

Naphthyl Stannanes in Stille Coupling Reactions
29
4
5
acid (394 mg, 2 28 mmol) and the reaction mixture stirred
for 30 h at room temperature. Anhydrous potassium uoride
(133 mg, 2 28 mmol) was added and stirring continued for
a further 3 h. The resultant white precipatate was ltered
o , the residue washed with dichloromethane, and the solvent
removed under reduced pressure to a ord an orange oil. To
this oil was added tetrahydrofuran/water (9 : 1, 10 ml) and p-
toluenesulfonic acid (2 mg) and the resultant reaction mixture
heated under re ux for 20 h. Ethyl acetate (30 ml) was added
and the organic layer washed with water (2 10 ml), brine
(15 ml), dried (magnesium sulfate) and the solvent removed
under reduced pressure to a ord a brown oil. Puri cation
by ash chromatography with hexane/ethyl acetate (7 : 3) as
eluent a orded the naphthol (33) (266 mg, 65%) as a tan solid,
Brockmann, H., Zeeck, A., van der Merwe, K., and Mueller,
W., Justus Liebigs Ann. Chem., 1966, 698, 209.
Brockmann, H., and Hieronymus, E., Chem. Ber., 1955,
88, 1379.
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249.
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Trans. 1, 1990, 881.
Brimble, M. A., and Lynds, S. J., J. Chem. Soc., Perkin
Trans. 1, 1994, 493.
Brimble, M. A., Phythian, S. J., and Prabaharan, H., J.
Chem. Soc., Perkin Trans. 1, 1995, 2855.
Brimble, M. A., Duncalf, L. J., and Phythian, S. J., J.
Chem. Soc., Perkin Trans. 1, 1997, 1399.
Stille, J. K., Angew. Chem., Int. Ed. Engl., 1986, 25, 508,
and references therein.
Brimble, M. A., Nairn, M. R., Prabaharan, H., and Walters,
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Chem., 1979, 44, 2153.
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1889.
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6289.
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Am. Chem. Soc., 1991, 113, 6982.
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M., J. Organomet. Chem., 1976, 117, C55.
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Chem., 1981, 215, 49.
Kosugi, M., Shimizu, K., Ohtani, A., and Migita, T., Chem.
Lett., 1981, 829.
Kelly, T. R., Xu, W., Ma, Z., Li, Q., and Bhushan, V.,
J. Am. Chem. Soc., 1993, 115, 5843.
Kelly, T. R., Li, Q., and Bhushan, V., Tetrahedron Lett.,
1990, 31, 161.
Farina, V., and Krishnan, B., J. Am. Chem. Soc., 1991,
113, 9585.
Farina, V., Krishnan, B., Marshall, D. R., and Roth, G.
P., J. Org. Chem., 1993, 58, 5434.
Beletskaya, I. P., J. Organomet. Chem., 1983, 250, 551.
Liebeskind, L. S., and Fengl, R. W., J. Org. Chem., 1990,
55, 5359.
Liebeskind, L. S., and Riesinger, S. W., J. Org. Chem.,
1993, 58, 408.
Farina, V., Kapadia, S., Krishnan, B., Wang, C., and
Liebeskind, L. S., J. Org. Chem., 1994, 59, 5905.
Kelly, T. R., and Kim, M. H., J. Org. Chem., 1992, 57,
1593.
Hoye, T. R., and Chen, M., J. Org. Chem., 1996, 61, 7940.
Kato, N., and Miyaura, N., Tetrahedron, 1996, 52, 13347.
Bo e, F., Rao Tunoori, A., Niestroj, A. J., Gronwald, O.,
and Maier, M. E., Tetrahedron, 1996, 52, 9485.
Friesen, R. W., Loo, R. W., and Sturino, C. F., Can.
J. Chem., 1994, 72, 1262.
6
7
8
9
10
11
12
13
14
15
16
m.p. 60–61 C (Found: C, 59 8; H, 4 5. C18H15BrO3 requires
1
C, 60 1; H, 4 2%).
(Nujol) 3389 (OH), 1394, 1040 cm
max
(C–O). 1H n.m.r. (200 MHz, CDCl3) 3 93, s, OCH3; 5 16,
s, OCH2; 6 77, d, J2,3 8 5 Hz, H 2; 6 85, d, J3,2 8 5 Hz, H 3;
7 37–7 47, m, H 30, H 40; 7 56, d, J6,5 9 1 Hz, H 6; 7 61–7 66,
m, H 20; 7 94, d, J5,6 9 1 Hz, H 5; 8 86, s, OH. 13C n.m.r.
(50 MHz, CDCl3) 55 5, OCH3; 76 1, OCH2; 105 8, CH, C 3;
110 3, CH, C 2; 112 7, quat., C 8a; 119 0, quat., C 7; 120 6,
CH, C 5; 126 6, quat., C 4a; 128 1, CH, C 40; 128 5, 128 8,
CH, C 20, C 30; 129 3, CH, C 6; 134 5, quat., C 10; 145 9, quat.,
C 1; 148 2, quat., C 8; 150 3, quat., C 4. Mass spectrum m/z
358/360 (M, 40%), 279 (M Br, 5), 251/253 (M OCH2Ph,
18), 91 (100).
17
18
6-Bromo-4,5-(isopropylidenedioxy)-1-methoxynaphthalene
(28)
19
20
21
22
23
24
25
26
27
To a solution of the naphthol (33) (51 mg, 0 14 mmol) in
dry ethyl acetate (15 ml) was added palladium on charcoal
(15 mg). The reaction mixture was stirred at room temperature
under an atmosphere of hydrogen for 2 h, then ltered through
Celite. The solvent was removed under reduced pressure
a ording the crude diol (30) (28 mg) as a brown oil. To a
solution of the crude diol (30) in dry acetone (1 ml) were added
2,2-dimethoxypropane (0 078 ml, 0 63 mmol) and perchloric
acid (4 drops of a 70% aqueous solution) and the reaction
mixture was stirred at room temperature for 6 h. The solvent
was removed under reduced pressure and the resultant residue
redissolved in ethyl acetate (6 ml). The organic phase was
washed with water (3 10 ml), brine (10 ml), dried (sodium
sulfate) and the solvent removed under reduced pressure to
yield a dark oil. Puri cation by ash chromatography with
hexane/ethyl acetate (7 : 3) as eluent a orded the acetonide
(28) (26 mg, 60%) as a yellow oil (Found: M+ , 308 0036.
28
29
C
1202, 1054 cm
14H13BrO3 requires M+ , 308 0048).
( lm) 1584, 1369,
max
1
(C–O). 1H n.m.r. (200 MHz, CDCl3) 1 41,
30
31
32
s, 2 CH3; 3 95, s, OCH3; 6 73, d, J3,2 8 2 Hz, H 3; 6 81,
d, J2,3 8 2 Hz, H 2; 7 53, d, J7,8 8 9 Hz, H 7; 7 65, d, J8,7
8 9 Hz, H 8. 13C n.m.r.
(50 MHz, CDCl3) 25 9, 2 CH3;
56 4, OCH3; 103 2, quat., C 10; 104 4, quat., C 4a; 106 0,
CH, C 2; 110 0, CH, C 3; 115, quat., C 6; 116 8, CH, C 7;
125 3, quat., C 8a; 130 9, CH, C 8; 141 2, 145 5, quat., C 4,
C 5; 150 7, quat., C 1. Mass spectrum m/z 308/310 (M, 58%),
250/252 [M OC(CH3)2, 52], 91 (65), 83 (80), 73 (100).
33
34
35
References
36
37
1
Brockmann, H., and Pini, H., Naturwissenschaften, 1947,
34, 190.
Brockmann, H., Pini, H., and von Plotho, O., Chem. Ber.,
1950, 83, 161.
Brockmann, H., and Loeschcke, V., Chem. Ber., 1955, 88,
778.
Kometani, T., Takeuchi, Y., and Yoshii, E., J. Org. Chem.,
1983, 48, 2311.
Dotz, K. H., and Popall, M., Chem. Ber., 1988, 121, 665.
Laatsch, H., Liebigs Ann. Chem., 1985, 1847.
Uno, H., J. Org. Chem., 1986, 51, 350.
2
38
39
40
3