Towards the rubromycins: An efficient synthesis of a suitable isocoumarin precursor, its lactam analogue, and palladium-catalyzed couplings

Article abstract of DOI:10.1055/s-2005-918417

6-Iodoisocoumarin 4 and its aza-analogue, 6-iodo-1-oxo-isoquinoline 29, were efficiently prepared from vanillin in seven and six steps, respectively. Key transformations in their syntheses were achieved by directed ortho-lithiation and variations of Horne

Full text of DOI:10.1055/s-2005-918417

PAPER
3571
Towards the Rubromycins: An Efficient Synthesis of a Suitable Isocoumarin
Precursor, its Lactam Analogue, and Palladium-Catalyzed Couplings
An
E
fficient Synthesis
a
of
a
Suitab
l
le Isoc
tePrecursor Brasholz,* Xiaosong Luan, Hans-Ulrich Reissig
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 18 May 2005; revised 23 June 2005
coumarin subunit, palladium-catalyzed coupling reactions
Abstract: 6-Iodoisocoumarin 4 and its aza-analogue, 6-iodo-1-
oxo-isoquinoline 29, were efficiently prepared from vanillin in sev-
en and six steps, respectively. Key transformations in their synthe-
ses were achieved by directed ortho-lithiation and variations of
Horner–Wadsworth–Emmons reactions. Both 6-iodoisocoumarin 4
and its aza-analogue were designed for insertion into syntheses of
rubromycin type target structures via palladium-catalyzed coupling
reactions. For the isocoumarin subunit, this plan could be confirmed
through Heck, Sonogashira, and Suzuki reactions of our building
block with various substrates.
with appropriate naphthoquinone moieties appear to be a
very suitable synthetic strategy for rubromycin type target
compounds.
Our generalized retrosynthetic analysis of the rubromycin
spiroketal core A involves a Heck reaction10 between an
enone fragment B and an aryl iodide unit C as one key
step (Scheme 1).11 In this illustration the aryl iodide C
serves as a model compound for a fully functionalized iso-
coumarin coupling precursor 4.
Key words: isocoumarins, rubromycins, ortho-lithiation, Horner–
Wadsworth–Emmons reaction, palladium catalysis
R
R
O
O
The isocoumarin nucleus is an abundant structural motif
in natural products.1 Many constituents of the steadily
growing class of known isocoumarins exhibit valuable bio-
logical properties such as antifungal,2 antitumor or cyto-
toxic,3 and enzyme inhibitory4 activity. The rubromycin
family of antibiotics5 are a structurally distinguished spe-
cies of more complex isocoumarin-containing natural
products. These compounds consist of a 5,6-spiroketal
core fused to hydroxynaphthoquinone and isocoumarin 3-
carboxylate subunits (Figure 1). This intriguing molecular
architecture as well as their highly attractive biological
properties6 have spurred a number of research groups to
R
A
R
MeO
O
OPG
O
PGO
PGO
I
O
R
R
+
I
CO2Me
R
B
C
4
Scheme 1 Retrosynthetic analysis of benzannulated spiroketals11
(PG = protecting group)
develop synthetic strategies for rubromycin type Initially, we attempted to prepare the targeted isocou-
compounds7 and their subunits.8
marin building block 4 from the known opianic acid (5)12
derived isocoumarin 68a,b,13 (Scheme 2). Compound 6 was
subjected to a number of halogenation protocols but un-
fortunately, we were unable to achieve substitution at the
6-position.
Here we disclose our progress in the synthesis of a 6-iodo-
isocoumarin building block9 designed for employment in
rubromycin syntheses. From the perspective of the iso-
Instead, we found that NBS, in combination with
HBF4·OEt2 in acetonitrile14 gave the undesired 5-bromo
derivative 7. In order to effect substitution at the 6-posi-
tion of 6, we turned our attention to selective liberation of
the 7-hydroxyl group prior to halogenation. This transfor-
mation could not be achieved within a single step. When
0.30 equivalents of boron tribromide (CH2Cl2, –78 °C)15
were employed, the 8-methoxy group of 6 was selectively
attacked due to complexation of the Lewis acid with the
neighboring carbonyl function. Cleavage of both methyl
ethers and subsequent site-selective alkylation of the 8-
position was considered but soon eliminated due to the
large number of expected steps.
O
O
MeO
OH
HO
O
CO2Me
HO
O
O
O
O
HO
OMe
O
R3
R1
R2
L-Cymarose
1 γ-Rubromycin
2 Purpuromycin
R1 = R2 = R3 = H
R1 = R2 = H, R3 = OH
3 Heliquinomycin R1 = L-Cymarose, R2 = OH, R3 = H
Figure 1 Antibiotics of the rubromycin family
These preliminary results led us to conceive a new synthe-
sis. During the synthesis the ability to differentiate be-
tween the two neighboring phenolic hydroxyl groups of 4
SYNTHESIS 2005, No. 20, pp 3571–3580
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918417; Art ID: T06405SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

3572
M. Brasholz et al.
PAPER
MeO
O
MeO
O
12 could be achieved, 8 would be accessible from 9 in
three steps only. The ortho-lithiation and carboxylation of
acetal 12 was optimized on a 0.5 mmol scale (Table 1).
Initial experiments in diethyl ether and THF gave low
conversions and yields of the protected ester 13 were
poor. Among the conditions we applied, n-BuLi·TMEDA
in diethyl ether was the least effective system (Table 1,
entry 1). A series of experiments in cyclohexane was more
productive (Table 1, entries 2–5). Under optimized condi-
tions, the metalation of 12 was carried out using 1.2
equivalents of n-BuLi at 0 °C for 5.5 hours followed by
the addition of an excess of methyl chloroformate. Ester
13 was formed regioselectively and obtained in satisfacto-
ry 56% yield. Upon scale-up, however, metalation of 12
for three hours at room temperature turned out to be more
reliable. Hence, a clear-cut temperature effect on the met-
alation of 12 could not be observed. The one-step conver-
sion of acetal 12 into ester 8 was achieved under these
conditions in 58% yield, when the intermediate 13 was not
isolated but directly deprotected under acidic conditions.
MeO
MeO
X
O
O
CO2Me
CO2Me
Br
7
a
X = Br, I
61%
MeO
O
O
MeO
O
MeO
MeO
O
[Refs. 8a,b, 13]
CO2Me
OH
5
6
b
H
O
O
MeO
O
O
MeO
HO
O
not
CO2Me
CO2Me
Scheme 2 Attempted functionalization of Chatterjea’s isocoumarin
6. Reagents and conditions: a) HBF4⋅OEt2, NBS, MeCN, r.t., over-
night, b) BBr3 (0.30 equiv), CH2Cl2, –78 °C, 3 h15
OMe
OMe
MOMO
Br
O
HO
Br
O
a, b
O
11
10
at C-7 and C-8 would be advantageous. Therefore, we
chose vanillin (9) as a starting material which readily ful-
fills this prerequisite. The new route to isocoumarin 4 is
outlined in Scheme 3. Starting from vanillin (9), the key
intermediate 8 should be accessible in a reasonably short
sequence. Subsequent transformations of ester 8 into iso-
coumarin 4 would involve iodination, a Horner–Wads-
worth–Emmons olefination,16 and intramolecular
condensation to the lactone.
4 steps
[Refs. 17a,b]
c
56% (3 steps)
OMe
TBSO
d
e
97%
82%
f
9
8
O
58%
O
12
conditions
see Table 1
MeO
O
OMe
OMe
PGO
I
HO
CO2Me
HO
O
OMe
CO2Me
TBSO
CO2Me
O
O
4
9
8
O
O
Scheme 3 Retrosynthetic plan for isocoumarin 4
13
Scheme 4 Routes to ester 8 starting from vanillin (9). Reagents and
conditions: a) ethylene glycol, p-TsOH, PhH, reflux, b) NaH, MOM-
Cl, DMF, 0 °C → r.t., overnight, c) i: n-BuLi (2 equiv), THF, –78 °C,
1 h, ii: ClCO2Me, –78 °C → r.t., overnight, iii: 3 N HCl (aq), 60 °C,
1.5 h, d) TBSCl, Et3N, DMAP, CH2Cl2, r.t., 24 h, e) 1,3-propanediol,
n-Bu4NBr3, HC(OMe)3, CH2Cl2, r.t., 2.5 h, f) i: n-BuLi (1.2 equiv),
cyclohexane, r.t., 3 h, ii: ClCO2Me, 0 °C → r.t., overnight, iii: HCl
(37%, aq), KF, THF, r.t., 6–24 h
Thus, different routes to the vanillin 6-carboxylate 8 were
investigated (Scheme 4). Vanillin (9) was first converted
into its 6-bromo-derivative 10 according to known proce-
dures (four steps).17 Compound 10 was protected as 1,3-
dioxolane and MOM-ether providing fully protected in-
termediate 11. This bromide was subjected to bromine–
metal exchange, carboxylation with methyl chlorofor-
mate, and deprotection to 8 under acidic conditions. Fol-
lowing this route, intermediate ester 8 was prepared from
vanillin (9) in seven steps in moderate overall yield. On a
larger scale, the preparation of vanillin derivative 10 pro-
ceeded less efficiently. In order to circumvent this diffi-
culty and to reduce the number of steps, we modified the
conversion of vanillin into ester 8 by protecting vanillin as
TBS-ether and subsequently as 1,3-dioxane giving inter-
mediate acetal 12. If a regioselective ortho-lithiation18 of
Ester 8 was then readily converted into isocoumarin deriv-
ative 17 within three steps (Scheme 5). Iodination of 8
with tetramethylammonium dichloroiodate19 was fol-
lowed by a Horner–Wadsworth–Emmons reaction of the
resulting aldehyde 14 with phosphonate 15.20 The olefina-
tion reaction proceeded in good yield despite the presence
of the free hydroxyl group. Two equivalents of NaHMDS
were used and the desired enol ether 16 was obtained as a
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of a Suitable Isocoumarin Precursor
3573
Table 1 Directed ortho-Lithiation and Carboxylation of Acetal 12
OMe
MeO
O
BnO
I
CO2Me
O
BnO
I
d
a
Entry
1
RLi
Equiv Solvent
Conditions
0 °C, 2 h
Yield
16%
O
14
81%
77%
OH
n-BuLi
TMEDA
2.3
Et2O
18
21
2
3
4
5
n-BuLi
n-BuLi
t-BuLi
n-BuLi
1.2
3.0
1.2
1.2
C6H12
C6H12
C6H12
C6H12
r.t., 3 h
40%
29%
20%
56%
O
P
O
O
P
O
b
91%
MeO
MeO
r.t., 3 h
MeO
MeO
OMe
OMe
OTBS
r.t., 3 h
N2
19
22
0 °C, 5.5 h
e
14%
OMe
BnO
CO2Me
CO2Me
c
mixture of diastereoisomers (E/Z, 35:65).21 In the subse-
quent intramolecular condensation step, cleavage of the
methyl ester at C-3 had to be avoided. This was achieved
by refluxing enol ether 16 in a 1:1 mixture of methanol
and concentrated aqueous HBr solution, providing iso-
coumarin 17 as a highly polar precipitate with excellent
purity. This method of converting aldehyde 14 into iso-
coumarin 17 is of advantage because the phosphonate re-
agent 15 is readily available in large quantities and the
free hydroxyl group in 17 can be protected with different
groups.
4
95%
I
OTBS
20
E:Z > 95:5
Scheme 6 Attempts to improve the ring closure protocol employing
phosphonates 19 and 22. Reagents and conditions: a) BnBr, DIPEA,
DMF, 65 °C, 20 h, b) 19, LiHMDS, THF, –78 °C → r.t., c) MeOH–
HCl (37%, aq), 100:1, reflux, 2 h, d) i: BnBr, DIPEA, DMF, 65 °C,
26 h, ii: 3 N NaOH, 65 °C, 15 h, e) i: 22, Rh2(OAc)4, PhCH3, 80 °C,
3 h, ii: DBU, r.t., 1.5 h
tected phosphonate 1922 to afford silyl enol ether 20 (E/Z
> 95:5). The intramolecular condensation of 20 occurred
under considerably milder acidic conditions and isocou-
marin 4 was isolated in excellent yield after these two
steps. However, the known preparation of phosphonate 19
was a limiting factor in this sequence. Therefore we
checked an alternative approach involving diazophospho-
nate 22,23 which was prepared in one step from commer-
cially available trimethyl phosphonoacetate. Phenol
derivative 14 was benzylated and the methyl ester was
subsequently hydrolyzed furnishing ortho-formyl benzoic
acid derivative 21 exclusively as its isobenzofuranone
tautomer 21a (Figure 2). This was exposed to the car-
benoid derived from phosphonate 22, assuming that at el-
evated temperatures a sufficient amount of 21b is in
equilibrium with 21a. After intramolecular olefination of
O
P
O
MeO
MeO
OMe
OMe
OMe
15
HO
I
CO2Me
O
a
8
82%
91%
b
14
OMe
MeO
O
HO
I
CO2Me
RO
I
c
O
OMe
55–68%
CO2Me
CO2Me
16
E:Z = 35:65
17: R = H
4: R = Bn 81%
d
Scheme 5 Completion of the synthesis of isocoumarin 17 using the resulting carbene insertion product24 isocoumarin de-
phosphonate reagent 15. Reagents and conditions: a) Me4NICl2,
NaHCO3, CH2Cl2, r.t., 4 h, b) 15, NaHMDS (2 equiv), THF, –78 °C
→ r.t., c) HBr (47%, aq)–MeOH, 1:1, reflux, 12 h, d) BnBr, DIPEA,
rivative 4 was isolated in a disappointingly low yield of
14% which is of no synthetic use.
DMF, 65 °C, 24 h
MeO
MeO
O
O
BnO
I
BnO
I
OH
O
In their approaches to rubromycin syntheses, de Koning et
al. passed through spiroketal precursors with benzyl pro-
tected phenolic hydroxyl groups.7a These could elegantly
be cyclized by hydrogenation in acidic medium. Follow-
ing this precedence, we continued our investigations em-
ploying benzyl protected isocoumarin 4 which was
OH
O
21a
21b
Figure 2 The tautomerism of pseudo-acid 21
prepared from 17 in 81% yield. However, we felt that fur- With a good procedure for the preparation of isocoumarin
ther modifications in its synthesis would be advantageous, derivative 4 in hand, we turned our attention to its palladi-
in particular an improvement in the intramolecular con- um-catalyzed coupling reactions (Scheme 7). It was anti-
densation step. Consequently, phenol derivative 14 was cipated that the base lability of either the unsaturated
first protected as benzyl ether 18 (Scheme 6). This com- lactone system or the methyl ester of 4 might complicate
pound smoothly underwent olefination with the TBS-pro- this objective. Gratifyingly, Sonogashira25 and Heck cou-
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

3574
M. Brasholz et al.
PAPER
Table 2 Attempted Suzuki Reaction of Isocoumarin Derivative 4
with p-Methoxyphenylboronic Acid
plings of 4 were easily achieved under standard condi-
tions. The 6-alkynyl derivatives 23 and 24 as well as the
a,b-unsaturated carbonyl compounds 25 and 26 were pre-
pared in high yields. The Heck reaction of isocoumarin 4
with methyl vinyl ketone served as a model experiment
for analogous reactions of 4 with enone building blocks of
type B. We were pleased that Jeffery’s conditions26 were
very effective here and no optimization was required for
these substrates. Surprisingly, a clean Suzuki reaction27 of
isocoumarin derivative 4 with p-methoxyphenylboronic
acid was difficult to achieve which was in contrast to the
positive results obtained in Heck and Sonogashira reac-
tions (Table 2). A number of protocols were examined but
they resulted in product mixtures. While isocoumarin de-
rivative 4 was stable to amine bases and NaHCO3 under
anhydrous conditions, the Suzuki reactions with the bo-
ronic acid and different bases such as CsF,28 K2CO3, and
K3PO4 afforded mixtures of saponification products of ei-
ther the lactone or the methyl ester at C-3. Finally, adap-
tation of conditions reported by Beletskaya et al. for
Suzuki reactions of coumarin 4-triflates29 afforded biaryl
derivative 27 cleanly although in only a moderate 51%
yield. This result may be improved in future experiments.
Catalyst
Base
Conditions
Yield
Pd(OAc)2, PPh3
K2CO3
DMF, 70 °C,
8.5 h
mixture
Pd(PPh3)4
Pd(PPh3)4
CsF
DMSO, 85 °C,
20 h
mixture
mixture
K3PO4
DMSO, 85 °C,
22 h
PdCl2(dppf)·CH2Cl2 K3PO4,
MeCN, 110 °C, 51%
10% Bu4NBr 6.5 h
O
P
O
a
MeO
MeO
22
OMe
NHAc
28
MeO
O
BnO
I
H
N
b
18
42%
CO2Me
29
Scheme 8 Preparation of the 1-oxo-isoquinoline derivative 29.
Reagents and conditions: a) CH3CONH2, Rh2(OAc)4, PhCH3, 110 °C,
3.5 h, b) i: DBU, MeCN, r.t., 30 min, ii: 18, 0 °C → r.t., 22 h
MeO
O
BnO
O
O
O
CO2Me
R
acetamide31 and subsequent olefination of 18 with DBU
furnished target compound 29 in reasonable overall yield.
84%
91%
23: R = Ph
24: R = CH2OMe
a
In conclusion, the synthesis of a suitable 6-iodo isocou-
marin precursor for rubromycin-type compounds was ac-
MeO
O
BnO
b or c
complished in
a
concise and efficient manner.
4
R
Isocoumarin 4 as well as 1-oxo-isoquinoline 29 were rap-
idly accessed by the protocols presented here and 4 clean-
ly underwent several typical palladium-catalyzed
coupling reactions. Thus, our synthetic concept for the
synthesis towards rubromycins has been confirmed by
these results. We are confident that current and future ef-
forts will pave the way to these natural products and their
analogues.
CO2Me
O
71%
91%
25: R = Ot-Bu
26: R = CH3
MeO
BnO
O
conditions
see Table 2
CO2Me
27
MeO
Reactions involving moisture-sensitive reactants were performed in
flame dried glassware under an atmosphere of argon, reagents being
added via syringe. Purchased chemicals were used without further
purification. DMSO, CH2Cl2, cyclohexane, and MeCN were dis-
tilled from calcium hydride, toluene from sodium. THF was dis-
tilled from sodium benzophenone ketyl. Anhyd DMF was
purchased from Aldrich and stored over 4 Å molecular sieves. Ben-
zene was used as received from vendors. NMR spectra were record-
ed on Bruker (AM 270, AC 500) and JEOL (Eclipse 500)
instruments. Chemical shifts are reported relative to CHCl3 (1H:
d = 7.24, 13C: d = 77.0 ppm), DMSO (1H: d = 2.49, 13C: d = 39.7
ppm) and SiMe4 (1H: d = 0.00 ppm). Signal sets in which assign-
ments are based on HMQC experiments are marked with an asterisk
(*). IR spectra were obtained from a Nicolet spectrometer
(FTIR 5 SXC), MS spectra (EI, FAB) from Finnigan instruments
(MAT 711, MAT CH7A and CH5DF). CHN-analyses were per-
formed on a Perkin-Elmer elemental analyzer. Reported melting
Scheme 7 Palladium-catalyzed coupling reactions of isocoumarin
4. Reagents and conditions: a) R-C≡CH, Pd(OAc)2, PPh3, CuI, Et3N,
DMF, r.t., 8 h, b) tert-butyl acrylate, Pd(OAc)2, PPh3, LiCl, NEt3,
DMF, 85 °C, 8 h, c) 3-buten-2-one, Pd(OAc)2, n-Bu4NCl, NaHCO3,
DMF, r.t., 72 h
We also prepared an aza-derivative of isocoumarin build-
ing block 4 which should open an access to lactam ana-
logues of rubromycin-type compounds (Scheme 8).
The 1-oxo-isoquinoline derivative 29 was prepared in a
straightforward one-pot procedure from aldehyde 18 by
olefination with the amido-phosphonate 28 and cycliza-
tion of the intermediate eneamide.30 Phosphonate 28 was
generated by carbene insertion of 22 into the N–H bond of
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of a Suitable Isocoumarin Precursor
3575
points (determined with a Büchi MP 510 apparatus) are uncorrect-
ed.
1H NMR (500 MHz, CDCl3): d = 3.50, 3.87 (2 s, 2 × 3 H, 2 × OMe),
4.11 (mc, 4 H, 4¢-H, 5¢-H), 5.23 (s, 2 H, CH2), 6.07 (s, 1 H, 2¢-H),
7.13, 7.31 (2 d, J = 8.8 Hz, 2 × 1 H, 5-H, 6-H).
Methyl 5-Bromo-7,8-dimethoxy-1-oxo-1H-isochromene-3-car-
boxylate (7)
13C NMR (126 MHz, CDCl3): d = 56.3, 60.6 (2 q, 2 × OMe), 65.4
(t, C-4¢, C-5¢), 95.1 (t, CH2), 102.6 (d, C-2¢), 115.2, 123.0 (2 d, C-5,
C-6), 118.8, 131.0, 147.1, 151.7 (4 s, Ar).
Isocoumarin derivative 68a,b,13 (80 mg, 0.30 mmol) was suspended
in MeCN (1 mL). At 0 °C, HBF4 (50% soln in Et2O; 60 mg, 0.34
mmol) and NBS (60 mg, 0.34 mmol) were added and the mixture
was stirred at r.t. overnight. After quenching with a soln of NaHSO4
(38% aq, 1 mL), the mixture was extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried with MgSO4, filtered, and
evaporated. Column chromatography (silica gel; EtOAc–
hexane, 2:1) provided 7 as a colorless solid.
MS (EI, 80 eV, 90 °C): m/z (%) = 320, 318 ([M]+, 10, 11), 89 (20),
73 (20), 59 (11), 45 ([CH2OCH3]+, 100).
Anal.Calcd for C12H15BrO5 (319.2): C, 45.16; H, 4.74. Found: C,
45.02; H, 4.67.
Methyl 6-formyl-3-hydroxy-2-methoxybenzoate (8)
Crude acetal 11 (4.30 g, max. 13.5 mmol) was dissolved in THF (80
mL). n-BuLi (2.50 M in hexanes; 10.8 mL, 27.0 mmol) was added
at –78 °C. After 1 h, methyl chloroformate (5.14 g, 4.20 mL, 54.4
mmol) was introduced and the reaction was warmed to r.t. over-
night. Aq HCl (3 N; 60 mL) was added and the mixture was heated
to 60 °C for 1.5 h. NaCl was added until the mixture was saturated
and then extracted with EtOAc (3 × 60 mL). The combined organic
layers were dried with MgSO4, filtered, and evaporated. Column
chromatography (silica gel; EtOAc–hexane, 1:2) provided 8 as a
yellow solid.
Yield: 63 mg (61%); mp 228–230 °C.
IR (KBr): 3110–2860 (=CH, CH), 1760, 1730 (C=O), 1575, 1550
(C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.93, 3.94, 3.95 (3 s, 3 × 3 H,
2 × OMe, CO2Me), 7.56 (s, 1 H, Ar), 7.67 (s, 1 H, 4-H).
13C NMR (126 MHz, CDCl3): d = 52.9, 56.7, 61.7 (3 q, 2 × OMe,
CO2Me), 111.0 (d, C-4), 123.2 (d, C-6), 117.0, 118.0, 128.0, 142.0,
151.1, 155.0 (6 s, C-3, Ar), 156.5, 160.7 (2 s, CO); the substitution
pattern of 7 was confirmed by an HMBC experiment.
Yield: 1.70 g (56% over 3 steps from 10); mp 102–104 °C.
MS (EI, 80 eV, 120 °C): m/z (%) = 344, 342 ([M]+, 99, 100), 329,
327 ([M – CH3]+, 24, 26), 313, 311 (29, 32), 257, 255 (38, 42), 229,
227 (20, 29).
IR (KBr): 3150 (O–H), 3005–2840 (=CH, CH), 1740, 1660 (C=O),
1600, 1560, 1505 (C=C) cm–1.
HRMS (EI, 80 eV, 120 °C): m/z calcd for C13H1179BrO6, 341.9739;
found, 341.9753.
1H NMR (500 MHz, CDCl3): d = 3.90, 3.98 (2 s, 2 × 3 H, OMe,
CO2Me), 6.45 (br s, 1 H, OH), 7.11, 7.55 (2 d, J = 8.4 Hz, 2 × 1 H,
4-H, 5-H), 9.79 (s, 1 H, CHO).
2-(2-Bromo-3-methoxy-4-methoxymethoxyphenyl)-[1,3]diox-
olane (11)
13C NMR (126 MHz, CDCl3): d = 53.0, 62.5 (2 q, OMe, CO2Me),
116.6, 129.9 (2 d, Ar), 127.0, 127.6, 144.4, 154.4 (4 s, Ar), 166.9 (s,
CO), 189.0 (d, CHO).
MS (EI, 80 eV, 170 °C): m/z (%) = 210 ([M]+, 99), 195 ([M –
CH3]+, 57), 182 (46), 179 ([M – OCH3]+, 71), 151 ([M – CO2CH3]+,
100), 136 (62), 121 (91), 107 (49), 92 (36), 80 (50), 65 (44), 51 (55),
39 (32).
Aldehyde 1017a,b (2.00 g, 8.66 mmol), p-TsOH·H2O (0.05 g, 0.26
mmol), and ethylene glycol (0.81 g, 0.73 mL, 13.1 mmol) were dis-
solved in benzene (50 mL). The mixture was refluxed with a Dean–
Stark trap fitted. After the formation of H2O had ceased, the reaction
was cooled to r.t., Na2CO3 (0.50 g) was added, and the solvent was
evaporated. The residue was dissolved in Et2O (80 mL) and the mix-
ture was washed with a sat. aq soln of NaHCO3 (2 × 10 mL). The
organic layer was dried with MgSO4, filtered, and evaporated. Dry-
ing at high vacuum provided the crude 1,3-dioxolane as a yellow
oil.
Anal. Calcd for C10H10O5 (210.2): C, 57.14; H, 4.80. Found: C,
56.86; H, 4.54.
tert-Butyl-(4-[1,3]dioxan-2-yl-2-methoxyphenoxy)dimethylsi-
lane (12)
Yield (crude): 2.21 g (93%).
Et3N (6.10 g, 8.40 mL, 60.3 mmol) was added at r.t. to a mixture of
vanillin (7.56 g, 49.7 mmol), TBDMSCl (8.92 g, 59.2 mmol), and
DMAP (0.93 g, 7.61 mmol) in CH2Cl2 (240 mL). After stirring at
r.t. for 24 h, a sat. aq soln of Na2CO3 (150 mL) was added. The lay-
ers were separated and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were dried with MgSO4,
filtered, and evaporated. Column chromatography (silica gel;
EtOAc–hexane, 1:4) provided TBS-protected vanillin as a yellow
oil.
1H NMR (270 MHz, CDCl3): d = 3.90 (s, 3 H, OMe), 4.07 (mc, 4 H,
4¢-H, 5¢-H), 5.75 (s, 1 H, OH), 6.04 (s, 1 H, 2¢-H), 6.95, 7.31 (2 d,
J = 8.3 Hz, 2 × 1 H, 5-H, 6-H).
13C NMR (126 MHz, CDCl3): d = 61.0 (q, OMe), 65.3 (t, C-4¢, C-
5¢), 102.6 (d, C-2¢), 114.7, 124.0 (2 d, C-5, C-6), 117.1, 132.1,
144.4, 150.6 (4 s, Ar).
The crude product (1.80 g, max. 6.54 mmol) was dissolved in DMF
(20 mL). This soln was added at 0 °C to a suspension of NaH (0.53
g, 60% suspension in mineral oil, 13.3 mmol) in DMF (5 mL). The
mixture was stirred at r.t. for 30 min and MOMCl (0.72 g, 0.68 mL,
8.95 mmol) was introduced. After stirring at r.t. overnight, the reac-
tion was quenched with a soln of NH4Cl (sat. aq, 20 mL). The mix-
ture was extracted with Et2O (3 × 40 mL). The combined organic
layers were dried with MgSO4, filtered, and evaporated. Drying at
high vacuum provided crude 11 as a yellow oil, which was suffi-
ciently pure for further conversion. An analytically pure sample was
obtained by column chromatography (silica gel; EtOAc–
hexane, 1:8).
Yield: 12.8 g (97%).
1H NMR (500 MHz, CDCl3): d = 0.17, 0.98 (2 s, 6 H, 9 H, SiMe2t-
Bu), 3.85 (s, 3 H, OMe), 6.94 (d, J = 8.0 Hz, 1 H, 5-H), 7.35 (dd,
J = 1.9, 8.0 Hz, 1 H, 6-H), 7.38 (d, J = 1.9 Hz, 1 H, 2-H), 9.82 (s, 1
H, CHO).
13C NMR (126 MHz, CDCl3): d = –4.6, 18.5, 25.6 (q, s, q, SiMe2t-
Bu), 55.4 (q, OMe), 110.2, 120.7, 126.2 (3 d, Ar), 131.0, 151.3,
151.6 (3 s, Ar), 190.9 (d, CHO).
The analytical data were comparable with those previously report-
ed.32
Yield (crude): 2.10 g (100%).
IR (film): 3020–2830 ( =CH, CH), 1595, 1535 (C=C) cm–1.
This product (926 mg, 3.48 mmol) was dissolved in CH2Cl2 (5 mL).
1,3-Propanediol (1.00 g, 0.95 mL, 13.1 mmol), trimethyl orthofor-
mate (586 mg, 600 mL, 5.52 mmol) and n-Bu4NBr3 (88 mg, 0.18
33
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

3576
M. Brasholz et al.
PAPER
mmol) were added and the resulting mixture was stirred at r.t. for
2.5 h. A sat. aq soln of Na2CO3 (7 mL) was added and the layers
were separated. The aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried with MgSO4,
filtered, and evaporated. Column chromatography (silica gel;
EtOAc–hexane, 1:4) provided 12 as a colorless oil.
ture was stirred at r.t. until TLC indicated complete conversion (6–
24 h). The mixture was washed with brine (20 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were dried with MgSO4, filtered,
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:1) provided 8 as a pale reddish solid.
Yield: 923 mg (82%).
Yield: 0.47 g (58%).
IR (film): 3070–3050 (=CH), 2955–2855 (CH), 1610, 1590, 1520
(C=C) cm–1.
Methyl 6-Formyl-3-hydroxy-4-iodo-2-methoxybenzoate (14)
NaHCO3 (1.05 g, 12.5 mmol) was suspended in a soln of phenol de-
rivative 8 (1.25 g, 5.95 mmol) in CH2Cl2 (40 mL). Tetramethylam-
monium dichloroiodate (1.79 g, 6.58 mmol) was added and the
mixture was stirred at r.t. for 4 h. After addition of aq HCl (5%, 20
mL) under rapid stirring, the mixture was washed with a sat. aq soln
of Na2S2O3 (20 mL). The layers were separated and the aqueous lay-
er was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried with MgSO4, filtered, and evaporated. Column
chromatography (silica gel; EtOAc–hexane, 1:1) provided 14 as a
yellow oil, which solidified upon storage in the refrigerator.
1H NMR (500 MHz, CDCl3): d = 0.11, 0.96 (2 s, 6 H, 9 H, SiMe2t-
Bu), 1.41, 2.21 (2 mc, 2 × 1 H, 5¢-H), 3.80 (s, 3 H, OMe), 3.96, 4.24
(2 mc, 2 × 2 H, 4¢-H, 6¢-H), 5.42 (s, 1 H, 2¢-H), 6.81 (d, J = 8.1 Hz,
1 H, 6-H), 6.90 (dd, J = 2.1, 8.1 Hz, 1 H, 5-H), 7.00 (d, J = 2.1 Hz,
1 H, 3-H).
13C NMR (126 MHz, CDCl3): d = –4.7, 18.4, 25.71 (q, s, q, SiMe2t-
Bu), 25.70 (t, C-5¢), 55.4 (q, OMe), 67.4 (t, C-4¢, C-6¢), 101.7 (d, C-
2¢), 109.7, 118.7, 120.6 (3 d, Ar), 132.4, 145.5, 150.9 (3 s, Ar).
MS (EI, 80 eV, 40 °C): m/z (%) = 324 ([M]+, 4), 267 ([M – C4H9]+,
72), 209 ([M – SiC6H15]+, 100), 194 ([M – SiC6H15 – CH3]+, 97), 91
(36), 28 (29).
Yield: 1.83 g (91%); mp 106 °C.
IR (KBr): 3310 (OH), 3020–2845 (=CH, CH), 1740, 1680 (C=O),
1570 (C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.92, 3.97 (2 s, 2 × 3 H, OMe,
CO2Me), 6.59 (s, 1 H, OH), 7.96 (s, 1 H, Ar-H), 9.74 (s, 1 H, CHO).
13C NMR (126 MHz, CDCl3): d = 53.1, 62.6 (2 q, OMe, CO2Me),
83.8, 127.8, 128.1, 143.6, 154.3 (5 s, Ar), 138.1 (d, Ar), 166.1 (s,
CO), 187.6 (d, CHO); the substitution pattern of 14 was confirmed
by NOESY and HMBC experiments.
MS (EI, 80 eV, 90 °C): m/z (%) = 336 ([M]+, 100), 321 ([M –
CH3]+, 23), 308 (93), 305 ([M – OCH3]+, 40), 277 ([M – CO2CH3]+,
74), 247 (56), 163 (44), 134 (45), 91 (33), 78 (64), 28 (88).
Anal. Calcd for C17H28O4Si (324.5): C, 62.92; H, 8.70. Found: C,
63.08; H, 8.52.
Methyl 3-(tert-Butyldimethylsiloxy)-6-[(1,3)dioxan-2-yl]-2-
methoxybenzoate (13)
n-BuLi (2.50 M in hexanes; 0.25 mL, 0.63 mmol) was added at 0 °C
to a soln of acetal 12 (168 mg, 0.52 mmol) in cyclohexane (5 mL).
The mixture was stirred at 0 °C for 5.5 h and methyl chloroformate
(0.18 g, 0.15 mL, 1.94 mmol) was introduced. The mixture was
warmed to r.t. overnight. After quenching with a sat. aq soln of
NH4Cl (5 mL), the layers were separated and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic layers were
dried with MgSO4, filtered, and evaporated. Column chromatogra-
phy (silica gel; EtOAc–hexane, 1:4) provided 13 as a colorless sol-
id.
Anal. Calcd for C10H9IO5 (336.1): C, 35.74; H, 2.70. Found: C,
35.79; H, 2.67.
(E,Z)-Methyl-3-hydroxy-4-iodo-2-methoxy-6-(2-methoxy-2-
methoxycarbonylethenyl)benzoate (16)
Yield: 111 mg (56%); mp 76–78 °C.
NaHMDS (5.00 mL, 2.00 M in THF, 10.0 mmol) was added at
–78 °C to a soln of phosphonate 1520 (1.31 g, 6.18 mmol) in THF
(18 mL). After 20 min at this temperature, a soln of aldehyde 14
(1.69 g, 5.03 mmol) in THF (7 mL) was introduced. The mixture
was gradually warmed to r.t. over 45 min and stirred for an addition-
al 2.5 h. A sat. aq soln of NH4Cl (15 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried with MgSO4, filtered,
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:4) provided (E,Z)-16 as a yellow oil, which solidified
upon storage in the refrigerator.
IR (KBr): 2990–2860 (=CH, CH), 1725 (C=O), 1600, 1585 (C=C)
cm–1.
1H NMR (500 MHz, CDCl3): d = 0.15, 0.98 (2 s, 6 H, 9 H, SiMe2t-
Bu), 1.38, 2.14 (2 mc, 2 × 1 H, 5¢-H), 3.80, 3.88 (2 s, 2 × 3 H, OMe,
CO2Me), 3.89, 4.19 (2 mc, 2 × 2 H, 4¢-H, 6¢-H), 5.53 (s, 1 H, 2¢-H),
6.86, 7.22 (2 d, J = 8.5 Hz, 2 × 1 H, 4-H, 5-H).
13C NMR (126 MHz, CDCl3): d = –4.6, 18.2, 25.7 (q, s, q, SiMe2t-
Bu), 25.6 (t, C-5¢), 52.1, 61.3 (2 q, OMe, CO2Me), 67.3 (t, C-4¢, C-
6¢), 99.1 (d, C-2¢), 121.9, 122.1 (2 d, Ar), 127.9, 129.6, 148.3, 149.1
(4 s, Ar), 167.7 (s, CO).
MS (EI, 80 eV, 100 °C): m/z (%) = 382 ([M]+, 2), 367 ([M – CH3]+,
2), 351 ([M – OCH3]+, 4), 325 ([M – C4H9]+, 100), 251 ([M –
OSiC6H15]+, 36), 73 (28).
The E/Z ratio of 35:65 was determined after HPLC separation of the
diastereoisomers as well as by NMR analysis of the crude product
mixture. Stereochemical assignment was made on the basis of
NOESY experiments.
Anal. Calcd for C19H30O6Si (382.5): C, 59.66; H, 7.90. Found: C,
59.55; H, 7.85.
Yield: 1.74 g (82%); mp 109 °C (mixture of diastereoisomers).
IR (KBr): 3430 (OH), 3100, 3005 (=CH), 2950, 2940, 2850 (CH),
1735, 1725, 1700 (C=O), 1575, 1565 (C=C) cm–1.
Conversion of 12 into 8
n-BuLi (2.50 M in hexanes; 1.86 mL, 4.65 mmol) was added at 0 °C
to a soln of acetal 12 (1.26 g, 3.88 mmol) in cyclohexane (25 mL).
The mixture was stirred at r.t. for 3 h, recooled to 0 °C, and methyl
chloroformate (1.22 g, 1.00 mL, 12.9 mmol) was added. Stirring
was continued overnight and the reaction was warmed to r.t. After
quenching with a sat. aq soln of Na2CO3 (10 mL), the layers were
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were concentrated in vacuo and
the residue was dissolved in THF (25 mL). Aq HCl (37%, 4 mL),
KF (0.70 g, 12.1 mmol), and H2O (5 mL) were added and the mix-
(E)-16
1H NMR (500 MHz, CDCl3): d = 3.62, 3.83 (2 s, 2 × 3 H, OMe),
3.67, 3.84 (2 s, 2 × 3 H, CO2Me), 5.27 (s, 1 H, OH), 6.03 (s, 1 H, 1¢-
H), 7.29 (s, 1 H, 5-H).*
13C NMR (126 MHz, CDCl3): d = 52.3, 52.4 (2 q, CO2Me), 56.0,
62.2 (2 q, OMe), 105.8 (d, C-1¢), 84.6, 126.9, 127.4, 143.3, 148.1,
148.2 (6 s, Ar, C-2¢), 134.6 (d, Ar), 163.4, 166.7 (2 s, CO).*
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of a Suitable Isocoumarin Precursor
3577
(Z)-16
Anal. Calcd for C19H15IO6 (466.2): C, 48.95; H, 3.24. Found: C,
48.91; H, 3.16.
1H NMR (500 MHz, CDCl3): d = 3.70, 3.83 (2 s, 2 × 3 H, OMe),
3.79, 3.92 (2 s, 2 × 3 H, CO2Me), 6.24 (br s, 1 H, OH), 6.74 (s, 1 H,
1¢-H), 8.21 (s, 1 H, 5-H).*
Methyl 3-Benzyloxy-6-formyl-4-iodo-2-methoxybenzoate (18)
Phenol derivative 14 (461 mg, 1.37 mmol) was dissolved in DMF
(6 mL). DIPEA (0.45 g, 0.60 mL, 3.44 mmol) and BnBr (0.36 g,
0.25 mL, 2.10 mmol) were added and the soln was stirred at 65 °C
for 20 h. After addition of aq HCl (5%, 1.50 mL), the mixture was
diluted with EtOAc (7 mL) and washed with brine (2 × 15 mL). The
layers were separated and the aqueous layer was re-extracted with
EtOAc (15 mL). The combined organic layers were dried with
MgSO4, filtered, and evaporated. Column chromatography (silica
gel; EtOAc–hexane, 1:4) provided 18 as a yellow oil.
13C NMR (126 MHz, CDCl3): d = 52.2, 52.6 (2 q, CO2Me), 59.4,
62.2 (2 q, OMe), 85.5, 125.2, 128.6, 143.5, 146.2, 149.2 (6 s, Ar, C-
2¢), 117.8 (d, C-1¢), 135.6 (d, Ar), 164.3, 166.6 (2 s, CO).*
MS (EI, 80 eV, 110 °C): m/z (%) = 422 ([M]+, 100), 391 ([M –
OCH3]+, 20), 363 ([M – CO2CH3]+, 66), 331 (33), 59 (29), 45 (30),
43 (33), 28 (43).
Anal. Calcd for C14H15IO7 (422.2): C, 39.83; H, 3.58. Found: C,
40.02; H, 3.40.
Yield: 473 mg (81%).
Methyl 7-Hydroxy-6-iodo-8-methoxy-1-oxo-1H-isochromene-
3-carboxylate (17)
A soln of enol ether (E,Z)-16 (148 mg, 0.35 mmol) in MeOH (3 mL)
and HBr (47% aq, 3 mL) was refluxed for 12 h. After 4 h and after
12 h, the precipitates were filtered off, washed with Et2O (3 × 10
mL), and dried at high vacuum to afford 17 as a colorless solid.
IR (film): 3110–2840 (=CH, CH), 1740, 1700 (C=O), 1570, 1555
(C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.90 (s, 3 H, OMe), 3.98 (s, 3 H,
CO2Me), 5.11 (s, 2 H, CH2), 7.32–7.56 (m, 5 H, Ph), 8.03 (s, 1 H,
5-H), 9.80 (s, 1 H, CHO).*
Combined yield: 90 mg (68%).
13C NMR (126 MHz, CDCl3): d = 53.0 (q, CO2Me), 62.2 (q, OMe),
76.7 (t, CH2), 94.6, 130.5, 130.7, 135.7, 150.2, 156.9 (6 s, Ar, Ph),
128.6, 128.7, 128.8 (3 d, Ph), 137.6 (d, C-5), 166.0 (s, CO), 187.7
(d, CHO).*
In an analogous experiment on a larger scale (E,Z)-16 (1.36 g, 3.22
mmol) gave 0.67 g (55%) of 17.
Mp 249 °C (dec.).
MS (EI, 80 eV, 140 °C): m/z (%) = 426 ([M]+, 4), 91 ([C7H7]+, 100).
IR (KBr): 3450 (OH), 3090–2940 (=CH, CH), 1740, 1715 (C=O),
1570, 1555 (C=C) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.79 (s, 3 H, OMe), 3.84 (s, 3
H, CO2Me), 7.57 (s, 1 H, 4-H), 8.14 (s, 1 H, 5-H), 10.81 (br s, 1 H,
OH).*
13C NMR (126 MHz, DMSO-d6): d = 52.8 (q, CO2Me), 62.1 (q,
OMe), 96.6, 116.0, 129.0, 140.6, 147.0, 153.0 (6 s, Ar, C-3), 111.9
(d, C-4), 134.0 (d, C-5), 156.9, 160.3 (2 s, CO).*
Anal. Calcd for C17H15IO5 (426.2): C, 47.91; H, 3.55. Found: C,
47.99; H, 3.32.
(E,Z)-Methyl 3-Benzyloxy-4-iodo-2-methoxy-6-(2-methoxy-
carbonyl-2-tert-butyldimethylsiloxyethenyl)benzoate (20)
Phosphonate 1922 (240 mg, 0.77 mmol) was dissolved in THF (7
mL). At –78 °C, LiHMDS (0.70 mL, 1.00 M in THF, 0.70 mmol)
was added. After 15 min at this temperature, a soln of aldehyde 18
(221 mg, 0.52 mmol) in THF (3 mL) was added and the mixture was
warmed to r.t. overnight. After the addition of a sat. aq soln of
NH4Cl (10 mL) the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried with MgSO4, filtered, and evaporated. Column chroma-
tography (EtOAc–hexane, 1:6) provided 20 as a yellow oil.
MS (EI, 80 eV, 150 °C): m/z (%) = 376 ([M]+, 100), 358 (75), 317
([M – CO2CH3]+, 13), 299 (53), 289 (43), 261 (45), 44 (35), 28 (74).
Anal. Calcd for C12H9IO6 (376.1): C, 38.32; H, 2.41. Found: C,
38.15; H, 2.41.
Methyl 7-Benzyloxy-6-iodo-8-methoxy-1-oxo-1H-isochromene-
3-carboxylate (4)
An E/Z ratio of >95:5 was determined by 1H NMR analysis of the
purified product. The diastereoisomers were tentatively assigned by
comparison of the vinylic and aromatic signals (1¢-H and 5-H) with
those of (E,Z)-16.
Isocoumarin derivative 17 (587 mg, 1.56 mmol) was dissolved in
DMF (15 mL). DIPEA (0.41 g, 0.55 mL, 3.17 mmol) and BnBr
(0.43 g, 0.30 mL, 2.52 mmol) were added and the mixture was
stirred at 65 °C for 24 h. After addition of aq HCl (5%, 1.5 mL), the
mixture was diluted with EtOAc (10 mL), and washed with brine
(2 × 10 mL). The layers were separated and the aqueous layer was
re-extracted with EtOAc (10 mL). The combined organic layers
were dried with MgSO4, filtered, and evaporated. Column chroma-
tography (silica gel; EtOAc–hexane, 1:2) provided 4 as a colorless
solid.
Yield: 288 mg (91%).
IR (film): 3090–2860 (=CH, CH), 1735 (C=O), 1630, 1575, 1545
(C=C) cm–1.
(E)-20
1H NMR (500 MHz, CDCl3): d = 0.19, 0.95 (2 s, 6 H, 9 H, SiMe2t-
Bu), 3.60, 3.86, 3.88 (3 s, 3 × 3 H, OMe, 2 × CO2Me), 5.00 (s, 2 H,
CH2), 6.27, 7.41 (2 d, J = 0.8 Hz, 2 × 1 H, 5-H, 1¢-H), 7.32–7.57 (m,
5 H, Ph).
Yield: 589 mg (81%); mp 156 °C.
IR (KBr): 3090–2865 (=CH, CH), 1750, 1725 (C=O), 1570, 1565,
1540 (C=C) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.86 (s, 3 H, CO2Me), 3.88 (s,
3 H, OMe), 5.05 (s, 2 H, CH2), 7.34–7.58 (m, 5 H, Ph), 7.56 (s, 1 H,
4-H), 8.18 (s, 1 H, 5-H).*
13C NMR (126 MHz, DMSO-d6): d = 52.9 (q, CO2Me), 62.0 (q,
OMe), 75.1 (t, CH2), 104.5, 116.9, 133.8, 136.5, 142.2, 153.6, 153.9
(7 s, Ar, C-3, Ph), 111.1 (d, C-4), 128.49, 128.54, 128.7 (3 d, Ph),
133.7 (d, C-5), 156.4, 160.2 (2 s, CO).*
13C NMR (126 MHz, CDCl3): d = –4.9, 18.3, 25.5 (q, s, q, SiMe2t-
Bu), 51.8, 52.4, 61.9 (3 q, OMe, 2 × CO2Me), 76.8 (t, CH2), 94.3,
129.3, 130.9, 136.5, 143.6, 149.8, 150.7 (7 s, Ar, C-2¢, Ph), 115.3,
134.9 (2 d, C-5, C-1¢), 128.4, 128.5, 128.7 (3 d, Ph), 164.5, 166.8 (2
s, CO).
The following signals of (Z)-20 could be identified in the 1H NMR
spectrum of the product mixture: d = 6.65, 8.22 (2 d, J = 0.4 Hz,
2 × 1 H, 5-H, 1¢-H).
MS (FAB+): m/z (%) = 635 ([M + Na]+, 2), 613 ([M + H]+, 2), 581
MS (EI, 80 eV, 160 °C): m/z (%) = 466 ([M]+, 5), 375 ([M – C7H7]+,
([M – OCH3]+, 7), 555 (20), 91 ([C7H7]+, 58), 89 (29), 73 (100).
3), 91 ([C7H7]+, 100).
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

3578
M. Brasholz et al.
PAPER
Anal. Calcd for C26H33IO7Si (612.5): C, 50.98; H, 5.43. Found: C,
50.89; H, 5.59.
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:2) provided 23 as a brownish solid.
Yield: 92 mg (84%); mp 128 °C.
Conversion of 20 into 4
IR (KBr): 3085–2850 (=CH, CH), 2210 (C≡C), 1740, 1720 (C=O),
Silyl enol ether (E,Z)-20 (223 mg, 0.36 mmol) was dissolved in
MeOH (15 mL). Aq HCl (37%, 0.15 mL) was added and the mix-
ture was heated to 80 °C for 2 h. Upon cooling to r.t., the product
precipitated from the mixture. The mixture was diluted with EtOAc
(10 mL) resulting in a clear soln. This was dried with MgSO4, fil-
tered, and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:2) provided 4 as a colorless solid.
1590, 1540 (C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.94 (s, 3 H, CO2Me), 4.02 (s, 3
H, OMe), 5.26 (s, 2 H, CH2), 7.31–7.57 (m, 10 H, Ph), 7.33 (s, 1 H,
4-H), 7.44 (s, 1 H, 5-H).*
13C NMR (126 MHz, CDCl3): d = 52.7 (q, CO2Me), 62.0 (q, OMe),
76.0 (t, CH2), 84.2, 98.4 (2 s, C-1¢, C-2¢), 116.6, 122.1, 126.7, 132.1,
136.7, 142.8, 154.6, 155.6 (8 s, Ar, C-3, Ph), 111.4 (d, C-4), 128.2,
128.3, 128.38, 128.41, 129.2, 131.8 (6 d, Ph), 126.8 (d, C-5), 156.5,
160.5 (2 s, CO).*
Yield: 162 mg (95%).
6-Benzyloxy-3-hydroxy-5-iodo-7-methoxy-3H-isobenzofuran-
1-one (21)
MS (EI, 80 eV, 170 °C): m/z (%) = 440 ([M]+, 42), 381 ([M –
CO2CH3]+, 7), 349 ([M – C7H7]+, 28), 91 ([C7H7]+, 100), 44 (48),
28 (79).
Phenol derivative 14 (302 mg, 0.90 mmol) was dissolved in DMF
(4 mL). DIPEA (0.22 g, 0.30 mL, 1.72 mmol) and BnBr (0.29 g,
0.20 mL, 1.68 mmol) were added and the soln was stirred at 65 °C
for 26 h. Then, aq NaOH (3 N, 2.00 mL) was introduced and stirring
was continued at 65 °C for an additional 15 h. After cooling to 0 °C,
aq HCl (3 N, 2.50 mL) was added. The mixture was diluted with
EtOAc (7 mL) and washed with brine (2 × 7 mL). The layers were
separated and the aqueous layer was re-extracted with EtOAc (10
mL). The combined organic layers were dried with MgSO4, filtered,
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 3:1) provided 21 as a yellow solid.
HRMS (EI, 80 eV, 170 °C): m/z calcd for C27H20O6: 440.1260;
found: 440.1263.
Methyl 7-Benzyloxy-8-methoxy-6-(3-methoxyprop-1-ynyl)-1-
oxo-1H-isochromene-3-carboxylate (24)
To a mixture of 4 (106 mg, 0.23 mmol), 3-methoxypropyne (42 mg,
50 mL, 0.60 mmol), and Et3N (36 mg, 50 mL, 0.36 mmol) in DMF
(3 mL) were added CuI (4 mg, 0.02 mmol), PPh3 (14 mg, 0.05
mmol), and Pd(OAc)2 (5 mg, 0.02 mmol). After stirring at r.t. for 8
h, aq HCl (5%, 0.30 mL) was added. The mixture was diluted with
EtOAc (3 mL) and washed with brine (2 × 3 mL). The layers were
separated and the aqueous layer was re-extracted with EtOAc (5
mL). The combined organic layers were dried with MgSO4, filtered,
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:2) provided 24 as a colorless solid.
Yield: 284 mg (77%); mp 162 °C.
IR (KBr): 3265 (OH), 3080–2850 (=CH, CH), 1740 (C=O), 1585
(C=C) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 4.03 (s, 3 H, OMe), 5.01 (s, 2
H, CH2), 6.49 (d, J = 8.1 Hz, 1 H, 3-H), 7.34–7.59 (m, 5 H, Ph), 7.79
(s, 1 H, 4-H), 8.12 (d, J = 8.1 Hz, 1 H, OH).
13C NMR (126 MHz, DMSO-d6): d = 62.7 (q, OMe), 75.1 (t, CH2),
96.3, 119.9, 136.6, 145.8, 150.4, 152.1 (6 s, Ar, Ph), 103.2 (d, C-3),
128.3, 128.46, 128.54, 128.6 (4 d, C-4, Ph), 165.3 (s, CO).
Yield: 84 mg (91%); mp 140 °C.
IR (KBr): 3100–2830 (=CH, CH), 1730, 1720 (C=O), 1595, 1545
(C=C) cm–1; the signal of the triple bond transition could not be de-
tected.
MS (EI, 80 eV, 150 °C): m/z (%) = 412 ([M]+, 10), 91 ([C7H7]+,
1H NMR (500 MHz, CDCl3): d = 3.38 (s, 3 H, OMe), 3.90 (s, 3 H,
CO2Me), 3.97 (s, 3 H, OMe), 4.31 (s, 2 H, 3¢-H), 5.17 (s, 2 H, CH2),
7.28–7.50 (m, 5 H, Ph), 7.23, 7.33 (2 d, J = 1.7 Hz, 2 × 1 H, 4-H, 5-
H).*
100).
Anal. Calcd for C16H13IO5 (412.2): C, 46.62; H, 3.18. Found: C,
46.83; H, 3.15.
13C NMR (126 MHz, CDCl3): d = 52.8 (q, CO2Me), 57.8 (q, OMe),
60.2 (t, C-3¢), 62.0 (q, OMe), 76.0 (t, CH2), 80.9, 94.3 (2 s, C-1¢, C-
2¢), 116.8, 126.0, 132.0, 136.4, 142.7, 154.8, 155.6 (7 s, Ar, C-3,
Ph), 111.3 (d, C-4), 127.0 (d, C-5), 128.3, 128.35, 128.39 (3 d, Ph),
156.5, 160.5 (2 s, CO).*
Conversion of 21 into 4
A mixture of isobenzofuranone derivative 21 (104 mg, 0.25 mmol),
diazophosphonate 2223 (52 mg, 0.25 mmol), and Rh2(OAc)4 (3.1
mg, 7.0 mmol) in toluene (5 mL) was stirred at 80 °C for 3 h. After
cooling to r.t., DBU (102 mg, 100 mL, 0.67 mmol) was added and
the mixture was stirred at r.t. for 90 min. It was diluted with EtOAc
(5 mL) and washed with aq HCl (0.10 M, 10 mL). The layers were
separated and the aqueous layer was re-extracted with EtOAc (10
mL). The combined organic layers were dried with MgSO4, filtered,
and evaporated. Column chromatography (silica gel; EtOAc–
hexane, 1:2) provided 4 as a colorless solid.
MS (EI, 80 eV, 180 °C): m/z (%) = 408 ([M]+, 2), 376 (9), 286 (10),
317 ([M – C7H7]+, 9), 91 ([C7H7]+, 100).
HRMS (EI, 80 eV, 180 °C): m/z calcd for C23H20O7: 408.1209;
found: 408.1218.
Methyl 7-Benzyloxy-6-(2-tert-butoxycarbonylethen-1-yl)-8-
methoxy-1-oxo-1H-isochromene-3-carboxylate (25)
Yield: 17 mg (14%).
Isocoumarin derivative 4 (99 mg, 0.21 mmol), tert-butyl acrylate
(44 mg, 50 mL, 0.34 mmol) and Et3N (36 mg, 50 mL, 0.36 mmol)
were dissolved in DMF (3 mL). LiCl (26 mg, 0.61 mmol), PPh3 (3
mg, 0.01 mmol), and Pd(OAc)2 (4 mg, 0.02 mmol) were added and
the mixture was stirred at 85 °C for 8 h. After cooling to r.t., aq HCl
(5%, 0.10 mL) and EtOAc (3 mL) were added, and the mixture was
washed with brine (2 × 3 mL). The layers were separated and the
aqueous layer was re-extracted with EtOAc (5 mL). The combined
organic layers were dried with MgSO4, filtered, and evaporated.
Column chromatography (silica gel; EtOAc–hexane, 1:2) provided
25 as a yellow-brown solid.
Methyl 7-Benzyloxy-8-methoxy-1-oxo-6-phenylethynyl-1H-iso-
chromene-3-carboxylate (23)
To a mixture of 4 (117 mg, 0.25 mmol), phenylacetylene (37 mg, 40
mL, 0.36 mmol), and Et3N (36 mg, 50 mL, 0.35 mmol) in DMF
(3 mL) were added CuI (5 mg, 0.03 mmol), PPh3 (13 mg, 0.05
mmol), and Pd(OAc)2 (5 mg, 0.02 mmol). After stirring at r.t. for 8
h, aq HCl (5%, 0.20 mL) was added. The mixture was diluted with
EtOAc (3 mL) and washed with brine (2 × 3 mL). The layers were
separated and the aqueous layer was re-extracted with EtOAc (5
mL). The combined organic layers were dried with MgSO4, filtered,
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of a Suitable Isocoumarin Precursor
3579
Yield: 70 mg (71%); mp 122 °C.
IR (KBr): 3085–2840 (=CH, CH), 1740 (C=O), 1540, 1510 (C=C)
cm–1.
1H NMR (500 MHz, CDCl3): d = 3.88, 3.95, 4.07 (3 s, 3 × 3 H,
2 × OMe, CO2Me), 4.82 (s, 2 H, CH2), 6.97, 7.51 (2 d, J = 8.7 Hz,
2 × 2 H, Ar), 7.13–7.28 (m, 5 H, Ph), 7.30, 7.39 (2 s, 2 × 1 H, 4-H,
5-H).*
13C NMR (126 MHz, CDCl3): d = 52.8, 55.4, 62.1 (3 q, 2 × OMe,
CO2Me), 75.4 (t, CH2), 112.2, 124.3 (2 d, C-4, C-5), 113.8, 130.7 (2
d, Ar), 115.4, 128.4, 132.3, 136.3, 142.6, 144.2, 151.7, 156.4, 157.0
(9 s, Ar, C-3, C-1¢, C-4¢, Ph), 128.1, 128.2, 128.6 (3 d, Ph), 160.0,
160.8 (2 s, CO).*
IR (KBr): 3085–2850 ( =CH, CH), 1750, 1720, 1700 (C=O), 1645,
1595, 1545 (C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.50 (s, 9 H, t-Bu), 3.92 (s, 3 H,
CO2Me), 4.00 (s, 3 H, OMe), 5.12 (s, 2 H, CH2), 6.40 (d, J = 16.2
Hz, 1 H, 2¢-H), 7.28–7.43 (m, 5 H, Ph), 7.33 (s, 1 H, 4-H), 7.41 (s,
1 H, 5-H), 7.76 (d, J = 16.2 Hz, 1 H, 1¢-H).*
13C NMR (126 MHz, CDCl3): d = 28.1 (q, t-Bu), 52.7 (q, CO2Me),
62.0 (q, OMe), 76.4 (t, CH2), 81.0 (s, t-Bu), 111.7 (d, C-4), 117.3,
132.3, 136.1, 137.3, 142.8, 152.4, 156.5 (7 s, Ar, C-3, Ph), 121.3 (d,
C-5), 125.7 (d, C-2¢), 128.5, 128.6, 128.8 (3 d, Ph), 136.1 (d, C-1¢),
156.1, 160.6, 165.0 (3 s, CO).*
MS (EI, 80 eV, 30 °C): m/z (%) = 446 ([M]+, 31), 355 ([M – C7H7]+,
100), 296 (21), 254 (22), 91 ([C7H7]+, 50).
MS (EI, 80 eV, 190 °C): m/z (%) = 466 ([M]+, 0.4), 410 ([M –
C4H9]+, 6), 91 ([C7H7]+, 100), 57 ([C4H9]+, 20).
HRMS (EI, 80 eV, 30 °C): m/z calcd for C26H22O7: 446.1366;
found: 446.1374.
HRMS (EI, 80 eV, 190 °C): m/z calcd for C26H26O8: 466.1628;
found: 466.1625.
Methyl 7-Benzyloxy-6-iodo-8-methoxy-1-oxo-1,2-dihydro-iso-
quinoline-3-carboxylate (29)
Methyl 7-Benzyloxy-8-methoxy-1-oxo-6-(3-oxobut-1-enyl)-1H-
isochromene-3-carboxylate (26)
A mixture of diazophosphonate 2223 (157 mg, 0.75 mmol), acet-
amide (255 mg, 4.32 mmol), and Rh2(OAc)4 (7.4 mg, 16.7 mmol) in
toluene (2.50 mL) was heated to 110 °C for 3.5 h. A biphasic mix-
ture was obtained, the lower layer being a brown oil. After cooling
to r.t., MeCN (2.50 mL) was added resulting in a clear soln. DBU
was introduced (502 mg, 490 mL, 3.30 mmol) and the mixture was
stirred at r.t. for 30 min. At 0 °C, a soln of aldehyde 18 (90 mg, 0.21
mmol) in MeCN (3.00 mL) was added and the mixture was stirred
at r.t. for 22 h. The mixture was concentrated in vacuo and subjected
directly to column chromatography (silica gel; EtOAc–hexane, 2:1)
providing 29 as a colorless solid.
Isocoumarin derivative 4 (95 mg, 0.20 mmol) and freshly distilled
3-buten-2-one (34 mg, 40 mL, 0.48 mmol) were dissolved in DMF
(3 mL). TBACl (59 mg, 0.21 mmol), NaHCO3 (44 mg, 0.52 mmol),
and Pd(OAc)2 (4 mg, 0.02 mmol) were added and the mixture was
stirred at r.t. for 72 h (reaction was monitored by TLC). The mixture
was diluted with EtOAc (3 mL) and washed with brine (2 × 3 mL).
The layers were separated and the aqueous layer was re-extracted
with EtOAc (5 mL). The combined organic layers were dried with
MgSO4, filtered, and evaporated. Column chromatography (silica
gel; EtOAc–hexane, 1:1) provided 26 as a yellow solid.
Yield: 41 mg (42%); mp 212 °C.
Yield: 76 mg (91%); mp 169 °C.
IR (KBr): 3420 (N–H), 3090–2880 (=CH, CH), 1740, 1680 (C=O),
1570, 1530 (C=C) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.85, 3.86 (2 s, 2 × 3 H, OMe,
CO2Me), 5.05 (s, 2 H, CH2), 7.28 (s, 1 H, 4-H), 7.35–7.59 (m, 5 H,
Ph), 8.22 (s, 1 H, 5-H), 10.90 (s, 1 H, NH).
13C NMR (126 MHz, DMSO-d6): d = 53.0, 62.1 (2 q, OMe,
CO2Me), 75.1 (t, CH2), 101.3, 108.7, 122.7, 128.9, 133.9, 135.7,
136.8, 151.9, 153.1 (2 d, C-4, C-5, 7 s, Ar, C-3, Ph), 128.4, 128.5,
128.6 (3 d, Ph), 159.3, 161.6 (2 s, CO).
MS (EI, 80 eV, 50 °C): m/z (%) = 465 ([M]+, 10), 374 ([M – C7H7]+,
100), 342 (96), 338 ([M – I]+, 54), 91 ([C7H7]+, 81), 57 ([C4H9]+,
41), 44 (60).
IR (KBr): 3090–2850 (=CH, CH), 1750, 1730, 1675 (C=O), 1620,
1600, 1550, 1500 (C=C) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 2.23 (s, 3 H, 4¢-H), 3.86 (s, 3
H, CO2Me), 3.92 (s, 3 H, OMe), 5.13 (s, 2 H, CH2), 6.77 (d, J = 16.6
Hz, 1 H, 2¢-H), 7.33–7.46 (m, 5 H, Ph), 7.53 (s, 1 H, 4-H), 7.55 (d,
J = 16.6 Hz, 1 H, 1¢-H), 8.01 (s, 1 H, 5-H).*
13C NMR (126 MHz, DMSO-d6): d = 27.3 (q, C-4¢), 52.9 (q,
CO2Me), 61.8 (q, OMe), 76.3 (t, CH2), 112.1 (d, C-4), 117.3, 132.3,
136.37, 136.40, 142.0, 152.2, 155.2 (7 s, Ar, C-3, Ph), 122.2 (d, C-
5), 128.70, 128.71, 129.0 (3 d, Ph), 131.5 (d, C-2¢), 135.5 (d, C-1¢),
156.2, 160.3, 198.0 (3 s, CO).*
MS (EI, 80 eV, 170 °C): m/z (%) = 408 ([M]+, 5), 366 (12), 275
(12), 91 ([C7H7]+, 100), 43 (18), 28 (21).
Anal. Calcd for C19H16INO5 (465.2): C, 49.05; H, 3.47; N, 3.01.
Found: C, 48.98; H, 3.12; N, 2.87.
HRMS (EI, 80 eV, 170 °C): m/z calcd for C23H20O7: 408.1209;
found: 408.1224.
Acknowledgment
Methyl 7-Benzyloxy-8-methoxy-6-(4-methoxyphenyl)-1-oxo-
1H-isochromene-3-carboxylate (27)
The authors thank Dr. C. Azap and Dr. I. M. Lyapkalo for stimula-
ting discussions and Mr. A. Kilisli for skilful experimental contri-
butions. Financial support by the Fonds der Chemischen Industrie
(fellowship for M. B.), the Deutsche Forschungsgemeinschaft, and
Schering AG is most gratefully acknowledged. We further thank
Dr. R. Zimmer for his assistance during the preparation of this ma-
nuscript.
Isocoumarin derivative 4 (88 mg, 0.19 mmol) and 4-methoxyphe-
nylboronic acid (35 mg, 0.23 mmol) were dissolved in MeCN
(5 mL). K3PO4 (121 mg, 0.57 mmol), n-Bu4NBr (6 mg, 0.02 mmol),
and PdCl2(dppf)·CH2Cl2 (7.0 mg, 8.6 mmol) were added and the
mixture was heated to 110 °C for 6.5 h (reaction monitored by
TLC). The mixture was diluted with H2O (3 mL), brine (3 mL), and
extracted with CH2Cl2 (4 × 10 mL). The combined organic layers
were dried with MgSO4, filtered, and evaporated. Column chroma-
tography (silica gel; EtOAc–hexane, 1:2) provided 27 as a brown
sticky resin.
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Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York

3580
M. Brasholz et al.
PAPER
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Universität Berlin, Germany, 2004.
(12) Opianic acid (5) was prepared according to ref. 18c.
Synthesis 2005, No. 20, 3571–3580 © Thieme Stuttgart · New York