New syntheses of the benzoquinone primin and its water-soluble analog primin acid via Heck reactions

Article abstract of DOI:10.1055/s-1999-3515

The syntheses of primin, 2-methoxy-6-pentylbenzoquinone (1), a major allergen of Primula obconica, and its water-soluble acid analog primin acid (2) are reported. The key steps were ortho-lithiation reactions of protected hydroquinones, palladium coupling (Heck) reactions, and salcomine-catalyzed oxidations of phenols to quinones.

Full text of DOI:10.1055/s-1999-3515

PAPER
1127
New Syntheses of the Benzoquinone Primin and its Water-Soluble Analog
Primin Acid via Heck Reactions
Stéphane Mabic,a* Lucile Vaysse,b Claude Benezra,b Jean-Pierre Lepoittevinb
a Peters Center, Chemistry Department, Virginia Tech, Blacksburg, VA 24061-0212, USA
Fax +1(540)2318890; E-mail: mabic@vt.edu
b Laboratoire de Dermatochimie associé au CNRS, U.R.A. 31, Clinique Dermatologique, C.H.U., F-67091, Strasbourg, France
Fax +33(3)88140447
Received 23 December 1998; revised 11 February 1999
Dedicated to the memory of Professor Claude Benezra
of the molecule and is not expected to modify the reactiv-
ity of the quinone moiety.
Abstract: The syntheses of primin, 2-methoxy-6-pentylbenzo-
quinone (1), a major allergen of Primula obconica, and its water-
soluble acid analog primin acid (2) are reported. The key steps were
ortho-lithiation reactions of protected hydroquinones, palladium
coupling (Heck) reactions, and salcomine-catalyzed oxidations of
phenols to quinones.
The synthesis of primin (1) was first reported by Schild-
knecht et al. in 19671 and later by de Lima et al.5 Primin
(1) and some of its homologous alkyl analogs were subse-
quently prepared for structure-biological activity relation-
ships.14–16 Key steps in recent syntheses (Scheme 1)
involved the addition of an alkyl Grignard to 2-hydroxy-
3-methoxybenzaldehyde (3) to form the benzyl alcohol
4,5,14 and ortho-lithiation of tetrahydropyranyl guaiacol
(5) yielding 6 (ca. 60% overall yield to 1).16
Key words: primin, quinone, ortho-lithiation, palladium coupling,
salcomine
Primin, 2-methoxy-6-pentylbenzoquinone (1), has been
isolated from a variety of plants, including Primula ob-
conica (primrose)1,2 and Miconia sp.3,4 In addition to its
4
antimicrobial5 and insect feeding activities, this benzo-
OH
OH OH
MeO
CHO
MeO
quinone is also known for its allergenic properties. Primin
is indeed a strong sensitizer and has long been recognized
to induce contact dermatitis.6,7 Synthetic primin has been
included for some time in the European standard patch
testing series, which is used to identify plant sources in
people subject to contact dermatitis.8–11 The immune re-
sponse is believed to be mediated by the formation of an-
tigenic adducts resulting from the Michael addition of the
nucleophilic protein residues to the quinone.12 In order to
investigate in more detail the type of amino acids involved
in this process, the position of nucleophilic addition, and
the structures of the adducts, the synthesis of primin was
of interest to us. Although some information can be as-
sessed by chemical reactions run in organic solvents, bio-
logically relevant in vitro experiments are best performed
in aqueous medium. A fundamental requirement, howev-
er, to run in vitro tests is to have molecules that are soluble
in the aqueous cell culture media.13 The limited solubility
of primin (LogP 2.99) in aqueous media prompted us to
design a more water-soluble analog. Primin acid (2)
(LogP 0.96, i.e. about 100 times more hydrophilic) was
selected. The carboxylic functionality at the terminal po-
sition of the alkyl chain is away from the reactive center
C4H9MgBr
4
3
1
OTHP
OTHP
MeO
MeO
1- n-BuLi
2- C5H11Br
6
5
Scheme 1
p-Benzoquinones can be efficiently prepared by oxidation
of either protected hydroquinone or phenol derivatives.
Methods for the oxidation of p-dimethoxybenzene with
nitric acid,18 silver oxide in acidic medium,18 and CAN19
have been reported. More recently, CAN in combination
with pyridine dicarboxylic acid derivatives was shown to
be a very mild and efficient method of oxidation.20 We
first focused our effort on the synthesis of 1 and 2 via the
protected hydroquinones 7 and 8, which could be pre-
pared using an ortho-lithiation/alkylation sequence from
the correctly protected methoxyhydroquinone 9 (Scheme
2). This efficient route to primin (1) was unsuccessful,
however, in preparing the analog primin acid (2), as de-
tailed below. This prompted us to develop an alternative
synthetic pathway via phenols 10 and 11, emphasizing a
palladium-catalyzed coupling reaction between a bro-
moaromatic and an alkene. Phenols can be efficiently ox-
idized to benzoquinones in a homogenous phase reaction
O
O
MeO
MeO
CO2H
O
O
Primin (1)
Primin acid (2)
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

1128
S. Mabic et al.
PAPER
using the cobalt(II) complex salcomine under an oxygen
atmosphere.21,22 Primin (1) and primin acid (2) were both
prepared via this methodology, using alkenes 12 or 13.
OMOM
OH
OMOM
H3CO
H3CO
H3CO
b, c, d
a
CHO
CHO
OR
OR
15
14
R = H 16
OH
MeO
Br
R = TBDMS 9
OMOM
MeO
R
H3CO
1, 2
f
e
1
R = CH3 10
R: see text
R = CO2H 11
R
OTBDMS
R = CH3 12
R = CO2Et 13
7
OMOM
OMOM
Reagents and conditions: a) NaH/MOMCl/DMF, 91%; b) m-CPBA/
CH2Cl2, 94%; c) KOH/EtOH/H2O, 78%; d) TBDMSCl/imidazole/
DMF, 90%; e) i. TMEDA/s-BuLi/THF, –78°C, ii. MgBr2/Et2O, iii.
C5H11Br, 73%; f) CAN/2,6-pyridinedicarboxylic acid/MeCN/H2O,
90%
MeO
R
MeO
OTBDMS
R = CH3
R = CO2H 8
OTBDMS
7
9
Scheme 3
with methyl 5-bromovalerate failed, as well as attempts of
alkylation via cuprate derivatives33 generated from the
lithium salt using CuBr•Me2S or CuCN. This synthetic
pathway was abandoned and efforts were pursued to pre-
pare primin acid (2) via a palladium-catalyzed coupling
reaction.
Scheme 2
1.
ortho-Lithiation Directed Reactions
ortho-Directing groups have been widely used in aromatic
chemistry to introduce substituents regioselectively.23–26
The methoxymethoxy (MOM) protecting group was se-
lected based on the high yields of introduction and remov-
al as well as its good ortho-directing properties.27–29 The
MOM group was quantitatively introduced by the reaction
of vanillin (14) with MOMCl (Scheme 3). The vanillin de-
rivative 15 was further reacted in a Dakin reaction,30,31 fol-
lowed by base hydrolysis of the intermediate formate ester
to phenol 16. The protection of the resulting hydroxy
group was achieved using tert-butyldimethylsilyl chloride
(TBDMSCl) and yielded 9.
2.
Heck Reactions
Palladium-mediated carbon-carbon coupling reactions
have found an extremely wide use in organic chemistry
and many methods and conditions are now available.34–40
The early reactions developed by Heck allow the coupling
between a bromo- or iodo-aromatic and an alkene, result-
ing in trans-styrenyl systems, with the exo double bond
isomers as byproducts.34,41,42 A large variety of groups is
tolerated on the aromatic moiety, although terminal alk-
enes are more reactive than internal alkenes due to steric
interactions in the intermediate palladium complexes. The
catalyst Pd(0) is generated in situ from Pd(OAc)2 and
triphenylphosphine or an analogous phosphine, affording
a homogenous catalytic reaction. The Heck reaction be-
tween ethyl pent-4-enoate (13) and 6-bromoguaiacol (18),
prepared in 65% yield by Pearson bromination of guaiacol
(17) (Scheme 4),43 gave low yields of coupling (Table).
This result was consistent with literature precedents, and
Alkylation of the lithium salt of 9 did not proceed in good
yields (s-BuLi/THF, 33%; BuLi/TMEDA/Et2O, 18%;
BuLi/THF/TMEDA, 26%). The conversion of the lithium
salt to an intermediate Grignard using MgBr2, followed by
alkylation,32 however, afforded the alkylated product 7 in
72% yield. Both the methoxy and the methoxymethylene
groups are effective ortho-directing groups. The MOM
group is expected, however, to be more efficient because
the lithium cation is more tightly complexed to the oxygen
in a six member ring. ortho-Lithiation was therefore ex-
pected at the position ortho to the MOM group. No regio-
isomer was isolated. NMR data, however, were not
conclusive for the structure of 7, because the two aromatic
protons coincidentally had the same chemical shift (d =
6.25, s) and showed no coupling constant. The conversion
of 7 to primin (1), which is a known compound, by oxida-
tion with CAN in combination with 2,6-pyridine di-
carboxylic acid (90% yield) 20 can be argued as proof of
the regioselective ortho-lithiation.
Table Heck Reactions with Ester 13
Substrate
R
Product
Yield
(%)
endo/exo
(%)
18
27b
20
21
19
H
Me
CH2OMe
COMe
CONEt2
29
10
90
93
92
85
not determined
75:25b
80:20
86:14
100: 0
28a/28b
24a/24b
25a/25b
26
a Yields after purification by chromatography on silica gel.
b Experimental results and structures not given in this paper. Please
see Ref. 45.
Attempts to prepare the analog primin acid (2) via a simi-
lar sequence of ortho lithiation/alkylation were unsuc-
cessful. The alkylation of the Grignard or lithium salt of 9
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Syntheses of the Benzoquinone Primin via Heck Reactions
1129
the lack of reaction is presumably due to the competitive duce a higher steric hindrance in the formation of the in-
quaternarization of the phosphorus ligands.41
termediate palladium complex, favoring the approach of
the alkene with the methylene group toward the aromatic
ring and the R chain away.
Three protected bromophenols, 19–21, were prepared us-
ing various functional groups, namely a carbamate, a
methoxymethyl, and an acetyl (Scheme 4). The bromocar-
bamate derivative 19 was easily prepared by reaction of
17 with diethylcarbamyl chloride followed by ortho-di-
rected bromination of the aromatic 22.44 A similar path-
way was attempted to prepare the 3-bromo-1-methoxy-2-
methoxymethoxybenzene (20), but the bromination of 23
did not proceed in good yield. Several conditions were
tried, including varying the temperature of formation of
the anion, the base (BuLi or s-BuLi), the solvent (THF or
Et2O), and the brominating agent (Br2 or BrCN), but the
best yield obtained was only 38%. Moreover, the reaction
yield dropped to 20% when the reaction was run on a scale
larger than 4 mmoles. Introduction of the bromine atom
first, leading to 6-bromoguaiacol (18), followed by pro-
tection of the phenol group revealed, however, a much
easier route to 20. The 2-acetoxy-3-bromo-1-methoxy-
benzene (21) was easily obtained by acetylation of 18.
OR
MeO
MeO
CO2Et
OR
CO2Et
endo
exo
MeO
Br
13
Pd(OAc)2,
P(o-Tol)3,
NEt3
OR
CO2Et
R: see Table 1
Scheme 5
R
H
H
H
H
H
R
H
O
O
H3CO
H3CO
Pd Br
Pd Br
L
L
OH
OR
exo
endo
MeO
MeO
b or c
c) R = CONEt2 22
b) R = MOM 23
Figure. Formation of the intermediate palladium complex
17
What was defined above as the endo isomer was actually
a mixture of three different alkenes, resulting from the mi-
gration of the double bond along the alkyl chain. Using
the acetyl protected derivatives 25, we were able to iso-
a
e or f
OR
OH
1
MeO
Br
MeO
Br
late, quantify, and identify by H NMR the various iso-
b or d
e) R = CONEt2 19
b) or f) R = MOM 20
d) R = COCH3 21
mers (Scheme 6) obtained in a typical Heck reaction
(100°C, 28 h). The separation of each isomer was
achieved by chromatography on silica gel pre-treated with
aqueous 10% AgNO3 solution. The ratio of exo 25b and
18
Reagents and conditions: a) i. t-BuNH2/toluene, ii. Br2, 65%; b) i.
NaH/Et2O, ii. MOMBr, 97%; c) i. NaH/Et2O, ii. ClCONEt2, 93%; d) three endo isomeric alkenes 25a, 25c, and 25d are shown
MeCOCl/pyridine/DMAP (cat.)/CH2Cl2, 99%; e) i. s-BuLi/TMEDA/
Et2O, ii. Br2, 87%; f) i. BuLi/TMEDA/Et2O, ii. Br2, 38%
in Scheme 6. As expected the major isomer was the alkene
25a resulting directly from the coupling. The two other
endo isomers 25c, and 25d were observed in significant
Scheme 4
amounts (24 and 9% respectively). The deprotected phe-
nol 29 was also isolated as a byproduct (ca. 2% yield).
Heck reactions with all three protected phenols 19–21
(Scheme 5) proceeded in high yields (85–93% after puri-
fication, Table). The ratio of endo (a mixture of endo iso-
mers is actually obtained, as discussed below, but only the
main isomer is shown in Scheme 5) to exo double bond
was dependent on the bulkiness of the protecting group
(Table). While the MOM derivative 20 yielded an 80:20
mixture of benzylic alkenes 24a/24b (endo/exo), the
Similar migration of the double bond was observed by 1H
NMR with the carbamate and MOM analogs 26 and 24a,
although no attempt was made to separate the various iso-
mers. The next step of our synthesis consisted in the re-
duction of the alkene, so the position of the double bond
was therefore of relatively minor importance.
After catalytic hydrogenation of the double bond, the es-
ters 30–32 were converted to the corresponding acids 33,
acetyl derivative 21 afforded a 86:14 ratio of alkenes 25a/
34, and 11, by deprotection with Ba(OH)2 in a water/THF
25b, and the diethylcarbamate 19 gave the endo isomer 26
mixture (Scheme 7).46 The acetyl protective group from
only. Independent results obtained with 3-bromo-1,2-
31 was removed simultaneously. The MOM protective
dimethoxybenzene (27) showed a 75:25 ratio of alkenes
group was quantitatively removed from 33 using a meth-
28a and 28b.45 The endo/exo selectivity can be rational-
ized by looking at the transition state of formation of the
complex between the alkene and the aromatic-palladium
compound (Figure). Large groups on the aromatic ring in-
anolic solution of 10% HCl47 and the carbamate group
was removed from 34 in 70% yield using ethanolic
NaOH.48 The phenol 11 was then oxidized to the benzo-
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

1130
S. Mabic et al.
PAPER
1-ene (12). Pent-1-ene was volatile under the conditions
of the reaction and 5 equivalents were necessary to
achieve the reaction. Catalytic hydrogenation of alkene 35
to the corresponding n-alkyl 36 followed by deprotection
of the carbamate with ethanolic NaOH afforded the phe-
nol 10, which was oxidized to primin (1) with salcomine.
OCOCH3
Br
MeO
21
CO2Et
13
1-
Pd(OAc)2,
P(o-Tol)3,
NEt3
OCONEt2
1- H2, Pd/C -> 36
MeO
2- SiO2, 10% AgNO3
2- NaOH, EtOH
12
19
10
1
Pd(OAc)2,
P(o-Tol)3,
NEt3
90%
OCOCH3
CH3COO
MeO
80%
CO2Et
35
CO2Et
25b, 24%
25a, 51%
Scheme 8
OCOCH3
MeO
OCOCH3
CO2Et
CO2Et
In conclusion, two new syntheses of primin (1) from gua-
iacol (52% overall yield) and vanillin (40% overall yield)
are described. Although the overall yield of synthesis via
the Heck reaction is lower than the overall yield of the
synthesis proceeding via ortho-lithiation reaction from
guaiacol (60%),16 it allows more flexibility regarding the
groups than can be introduced. The hydrophilic analog
primin acid (2) was prepared via a Heck reaction. The best
pathway proceeds via the acetyl derivative for it allows
the simplest and most reproducible deprotection reac-
tions. Biological tests are currently in progress to evaluate
the fate and behavior of primin acid (2) in in vitro testing.
25d, 9%
25c, 14%
OH
MeO
CO2Et
29, 2%
Scheme 6
OR
R = MOM 24
CAUTION! Primin (1) is a strong sensitizer and should be handled
MeO
CO2Et
R = COCH3 25
R = CONEt2 26
with care, avoiding skin contact.
Reagents and starting materials were obtained from commercial
suppliers and were used without further purification. THF and Et2O
were distilled over sodium/benzophenone ketyl. Toluene and
CH2Cl2 were distilled under nitrogen from P2O5. All reactions were
conducted using flame dried glassware under an atmosphere of dry
N2. Chromatography refers to flash column chromatography on sil-
R = MOM 30
1- H2, Pd/C 5%
R = COCH3 31
R = CONEt2 32
2- Ba(OH)2, H2O, THF
> 94%
1
ica gel unless otherwise noted. H and 13C NMR spectra were re-
corded on a Bruker WP 200-MHz SY spectrometer. Chemical shifts
d are expressed in ppm downfield from internal TMS. Coupling
constant values (J) are given in Hertz (Hz). IR spectra were record-
ed on a Perkin-Elmer 1600 FT-IR. Melting points were obtained us-
ing a Büchi-Tottoli 510 apparatus and are uncorrected. Elemental
analyses were performed by Centre de Recherche des Macromolé-
cules de Strasbourg. LogP calculations were obtained using ACD
LogP software (ACD/Labs). Silica gel chromatography were done
using Kieselgel Merck (040–0.063 mm) and with unpurified sol-
vents unless otherwise indicated. The following compounds are
known compounds: 1,1 10,1 23,29 18,49 21,50 22,50 27.51
OR
MeO
CO2H
R = MOM 33
R =H 11
HCl 10%, MeOH, ∆, 99%
NaOH, EtOH, ∆, 72%
R = CONEt2 34
Salcomine, O2, DMF from 11, 70%
2
Methoxymethoxyvanillin (15)
Scheme 7
Under anhydrous conditions and an atmosphere of argon, NaH (7.2
g, 300 mmol) was added portionwise at 0°C to a solution of vanillin
(14; 38.0 g, 250 mmol) in anhyd DMF (350 mL). After stirring for
15 min at 0°C, chloromethyl methyl ether (28.5 mL, 375 mmol) was
added and the mixture was stirred for 14 h at 25°C. H2O (100 mL)
was then added and the solution was extracted with CH2Cl2 (3 × 150
mL). The combined organic phases were washed with brine, dried
(MgSO4), and evaporated under reduced pressure. The crude was
quinone 2 in 70% yield using salcomine in DMF under an
atmosphere of oxygen.
Primin (1) also was synthesized via a Heck reaction
(Scheme 8) by reaction of bromocarbamate 19 with pent-
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Syntheses of the Benzoquinone Primin via Heck Reactions
1131
recrystallized from EtOAc/hexane to give 15 (45 g, 92%) as white
and evaporated under reduced pressure. The crude product was pu-
crystals; mp 39°C.
rified by silica gel chromatography (hexane/Et2O, 9:1) to give 7
(0.45 g, 73%) as a colorless liquid.
1H NMR (CDCl3): d = 3.45 (s, 3 H), 3.85 (s, 3 H), 5.25 (s, 2 H), 7.32
(m, 3 H), 9.80 (s, 1 H).
1H NMR (CDCl3): d = 0.19 (s, 6 H), 0.86 (t, 3 H, J = 6.8 Hz), 0.98
(s, 9 H), 1.30 (m, 6 H), 2.60 (t, 2 H, J = 7.7 Hz), 3.68 (s, 3 H), 3.78
(s, 3 H), 4.99 (s, 2 H), 6.25 (s, 2 H).
IR (CHCl3): n = 982 cm–1 (Si–O).
IR (CHCl3): n = 1688 cm–1 (C=O).
Anal. Calcd for C10H12O4: C, 61.22, H, 6.16. Found C, 60.99, H,
5.96.
Anal. Calcd for C9H12O4: C, 65.17, H, 9.84. Found C, 65.37, H,
10.06.
3-Methoxy-4-methoxymethoxyphenol (16)
Under anhydrous conditions, m-CPBA (recrystallized, 45.0 g, 262
mmol) was added portionwise at 0°C to a solution of aldehyde 15
(21.3 g, 128 mmol) in anhyd CH2Cl2 (250 mL). After stirring for 5
h at 25°C, the mixture was filtered and the filtrate was washed with
an aq solution of NaHCO3 and then with brine. The organic phase
was dried (MgSO4) and evaporated under reduced pressure to give
an intermediate formate (25.5 g, 94%, colorless oil), that was used
as such. This intermediate was hydrolyzed using a solution of 10%
KOH (120 mL) and EtOH (60 mL) at 50°C for 10 min. The mixture
was washed with Et2O (100 mL) and the aqueous phase was acidi-
fied with 1 N HCl and extracted with Et2O (2 × 100 mL). The com-
bined organic phase was washed with brine, dried (MgSO4), and
evaporated under reduced pressure. The crude mixture was recrys-
tallized (EtOAc/hexane) to give 16 (17.24 g, 78%) as white crystals;
mp 69°C.
3-Bromo-1-methoxy-2-methoxymethoxybenzene (20)
NaH (264 mg, 11 mmol) was added portionwise to a solution of bro-
moguaiacol 18 (2.0 g, 10 mmol) in anhyd THF (60 mL) at 0°C. Af-
ter stirring the mixture for 30 min a 25°C, MOMBr (1.0 mL, 12
mmol) was added at 0°C. The mixture was stirred for 16 h at 25°C,
neutralized using a satd aq solution of NH4Cl, and extracted with
Et2O (3 × 30 mL). The combined organic phases were washed with
brine and dried (MgSO4). After evaporation of the solvent, the crude
material was purified by silica gel chromatography (hexane/EtOAc,
85:15) to yield 20 (2.4 g, 96%) as a colorless oil.
1H NMR (CDCl3): d = 3.65 (s, 3 H), 3.83 (s, 3 H), 5.16 (s, 2 H), 6.84
(dd, 1 H, J = 8.4 Hz), 6.92 (t, 1 H), 7.14 (dd, 1 H, J = 8.0, 1.6 Hz).
13C NMR (CDCl3): d = 56.0, 57.9, 98.6, 111.8, 117.8, 125.0, 125.2,
143.2, 153.6.
1H NMR (CDCl3): d = 3.53 (s, 3 H), 3.80 (s, 3 H), 5.12 (s, 2 H), 5.49
(s, 1 H), 6.29 (dd, 1 H, J = 2.8, 8.6 Hz), 6.45 (d, 1 H, J = 2.8 Hz),
6.96 (d, 1 H, J = 8.6 Hz).
IR (CHCl3): n = 3580 cm–1 (OH).
IR (CHCl3): n = 1481 (O–CH2–O), 1218 (C–O), 758 cm–1 (C–Br).
Anal. Calcd for C9H11BrO3: C, 43.75, H, 4.48, Br, 32.34. Found C,
43.67, H, 4.48, Br, 32.43.
Anal. Calcd for C9H12O4: C, 58.69, H, 6.56. Found C, 58.63, H,
6.39.
2-Acetoxy-3-bromo-1-methoxybenzene (21)
Phenol 18 (2.0 g, 10 mmol) was dissolved in anhyd CH2Cl2 (30
mL). Pyridine (3.0 mL, 30 mmol) was then added at 0°C, followed
by addition of a catalytic amount of DMAP and acetyl chloride (1.5
mL, 15 mmol), and the mixture was stirred for 2.5 h at 25°C. After
filtration, the organic phase was washed with a solution of 2 N HCl
(3 × 25 mL) and dried (MgSO4). The crude mixture was purified by
silica gel chromatography (hexane/EtOAc, 85:15) to yield 21 (2.43
g, 99%) as white crystals; mp 39°C.
1H NMR (CDCl3): d = 2.36 (s, 3 H), 3.82 (s, 3 H), 6.90 (dd, 1 H, J
= 8.0, 1.4 Hz), 7.07 (t, 1 H), 7.18 (dd, 1 H, J = 8.2, 1.4 Hz).
13C NMR (CDCl3): d = 20.5, 56.3, 111.5, 117.3, 124.5, 127.4, 138.0,
152.7, 167.9.
4-tert-Butyldimethylsilyloxy-2-methoxy-1-methoxymethoxy-
benzene (9)
Under anhydrous conditions, imidazole (6.1 g, 89.6 mmol) fol-
lowed by TBDMSCl (13.5 g, 89.6 mmol) were added to a solution
of 16 (11 g, 60 mmol) in anhyd DMF (100 mL). The reaction was
over in 7 h and the precipitate formed during the reaction was fil-
tered. The DMF was evaporated under reduced pressure and the
precipitate was dissolved in Et2O. The organic phase was washed
with brine, dried (MgSO4) and evaporated to give a crude mixture
that was purified by silica gel chromatography (hexane/EtOAc, 8:2)
to give 9 (16 g, 90%) as a colorless liquid.
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.97 (s, 9 H), 3.52 (s, 3 H), 3.83
(s, 3 H), 5.14 (s, 2 H), 6.34 (dd, 1 H, J = 8.6, 2.7 Hz), 6.43 (d, 1 H,
J = 2.7 Hz), 6.98 (d, 1 H, J = 8.6 Hz).
IR (CHCl3): n = 980 cm–1(Si–O).
IR (CHCl3): n = 1769 (C=O), 1271, 1201 (C-O), 1039 (C-O (Ac)),
759 cm–1 (C-Br).
Anal. Calcd for C9H9BrO3: C, 44.11, H, 3.70, Br, 32.60. Found C,
44.19, H, 3.63, Br, 32.81.
Anal. Calcd for C15H26O4Si: No good elemental analysis could be
obtained despite many attempts.
Heck Coupling Reactions of Bromoaromatics 18–21, 27 with the
Alkene 13 (Table); General Procedure
In a one-neck flask closed using a septum and tighted up with a hose
connector clamp, the appropriate bromoaromatic (1 equiv),
Pd(OAc)2 (0.02 equiv), tri-o-tolylphosphine (0.08 equiv) and the
alkene 13 (2.5 equiv) were stirred until dissolved. Et3N (minimum
2.5 equiv) was then added. The mixture was then heated up to
100°C for 12 to 36 h. After cooling down, the mixture was diluted
with Et2O and filtered over Celite. The solvent was evaporated and
the crude material was purified by silica gel chromatography.
In most cases only 1H NMR spectra are reported because a mixture
of isomeric alkenes was obtained. The purity of the reduced com-
pounds, however, supports the proposed structures.
4-tert-Butyldimethylsilyloxy-2-methoxy-1-methoxymethoxy-6-
pentylbenzene (7)
Under anhydrous conditions, TMEDA (0.28 mL, 1.84 mmol) and
sec-BuLi (1.3 mL, 1.84 mmol) were dissolved in THF (50 mL) and
the mixture was cooled down to –78°C. A solution of 9 (0.50 g, 1.67
mmol) in THF (6 mL) was added dropwise. After 30 min, MgBr2
(1.3 g, 5.02 mmol) was added. After 15 min, the mixture was
warmed up to 25°C until a clear solution was obtained and the mix-
ture was then cooled down to –78°C for 40 min, during which bro-
mopentane (0.42 mL, 3.35 mmol) was added. The mixture was
allowed to warm up to 25°C and was then heated to reflux for 4 h.
After cooling down, the reaction was hydrolyzed by addition of an
aq solution of 10% NH4Cl and extracted with Et2O (3 × 50 mL). The
combined organic phase was washed with brine, dried (MgSO4),
Ethyl 5-(2’-Methoxymethoxy-3’-methoxyphenyl)pent-4-enoate
(24, mixture of isomers, major one described)
Colorless oil.
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

1132
S. Mabic et al.
PAPER
1H NMR (CDCl3): d = 1.22 (t, 3 H), 2.48 (m, 4 H), 3.57 (s, 3 H),
3.83 (s, 3 H), 4.12 (q, 2 H, J = 7.2 Hz), 5.14 (s, 2 H), 6.22 (dt, 1 H,
J = 16.0, 7.0 Hz), 6.80 (m, 3 H), 7.00 (t, 1 H, J = 7.8 Hz).
IR (CHCl3): n = 1734 (C=O), 1254, 1168 cm–1 (C–O).
(s, 2 H), 6.70 (dd, 1 H, J = 7.2, 1.6 Hz), 6.74 (dd, 1 H, J = 7.0, 1.6
Hz), 6.97 (t, 1 H).
Anal. Calcd for C16H24O5: C, 64.84, H, 8.16. Found C, 65.17, H,
8.32.
Ethyl 5-(2’-Acetoxy-3’-methoxyphenyl)pent-4-enoate (25a)
Ethyl 5-(2’-acetoxy-3’-methoxyphenyl)pentanoate (31)
Colorless oil.
Colorless oil.
1H NMR (CDCl3): d = 1.22 (t, 3 H), 2.34 (s, 3 H), 2.48 (m, 4 H),
3.80 (s, 3 H), 4.10 (q, 2 H, J = 7.2 Hz), 6.21 (m, 1 H), 6.44 (d, 1 H,
J = 16.0 Hz), 6.81 (dd, 1 H, J = 7.2, 2.4 Hz), 7.13 (m, 2 H).
1H NMR (CDCl3): d = 1.22 (t, 3 H), 1.60 (m, 4 H), 2.34 (s, 3 H),
2.51 (m, 4 H), 3.80 (s, 3 H), 4.10 (q, 2 H, J= 7.2 Hz), 6.80 (m, 2 H),
7.10 (t, 1 H, J = 8.0 Hz).
IR (CHCl3): n = 1762, 1732 (C=O), 1470, 1274, 1170 cm–1 (C–O).
13C NMR (CDCl3): d = 14.3, 20.5, 24.8, 29.5, 29.8, 34.1, 55.9, 60.2,
110.0, 121.6, 126.3, 135.3, 138.2, 151.2, 168.8, 173.4.
Ethyl 4-(2’-Acetoxy-3’-methoxyphenyl)pent-4-enoate (25b)
Colorless oil.
IR (CHCl3): n = 3022, 2939 (CH), 1765, 1729 (C=O), 1478, 1275,
1174 cm–1 (C–O).
1H NMR (CDCl3): d = 1.22 (t, 3 H), 2.26 (s, 3 H), 2.36 (t, 2 H), 2.69
(td, 2 H, J = 7.0 Hz), 3.81 (s, 3 H), 4.09 (q, 2 H, J = 7.2 Hz), 5.02
(m, 1 H), 5.18 (m, 1 H, J = 1.2 Hz), 6.80 (dd, 1 H, J = 8.0 Hz), 6.87
(dd, 1 H, J = 8.2, 1.2 Hz), 7.15 (t, 1 H).
Anal. Calcd for C16H22O5: C, 65.29; H, 7.53. Found C, 65.05, H,
7.69.
Ethyl 5-(2’-N,N-Diethylcarbamato-3’-methoxyphenyl)pen-
tanoate (32)
Colorless oil.
1H NMR (CDCl3): d = 1.20 (t, 9 H), 1.65 (m, 4 H), 2.30 (t, 2 H), 2.58
(m, 4 H), 3.40 (m, 4 H), 3.80 (s, 3 H), 4.14 (q, 2 H, J= 7.2 Hz), 6.78
(m, 2 H), 7.06 (t, 1 H, J = 8.0 Hz).
13C NMR (CDCl3): d = 13.4, 14.2, 24.8, 29.6, 29.9, 34.2, 42.2, 55.9,
60.1, 110.1, 121.5, 125.5, 135.8, 139.0, 152.0, 153.8, 173.5.
IR (CHCl3): n = 1760, 1730 (C=O), 1476, 1280, 1172 cm–1 (C–O).
Ethyl 5-(2’-Acetoxy-3’-methoxyphenyl)pent-3-enoate (25c)
Colorless oil.
1H NMR (CDCl3): d = 1.25 (t, 3 H), 2.34 (s, 3 H), 3.02 (m, 2 H),
3.27 (m, 2 H), 3.82 (s, 3 H), 4.14 (q, 2 H, J= 7.2 Hz), 5.65 (m, 2 H),
6.85 (m, 2 H), 7.13 (t, 1 H, J = 7.6 Hz).
IR (CHCl3): n = 1760, 1728 (C=O), 1471, 1276, 1170 cm–1 (C–O).
IR (CHCl3): n = 2977, 2937 (CH), 1732, 1721 (C=O), 1276, 1087
Ethyl 5-(2’-Acetoxy-3’-methoxyphenyl)pent-2-enoate (25d)
Colorless oil.
cm–1 (C–O).
Anal. Calcd for C19H29NO5: C, 64.93, H, 7.95, N, 3.98. Found C,
65.11, H, 8.11, N, 3.92.
1H NMR (CDCl3): d = 1.25 (t, 3 H), 2.32 (s, 3 H), 2.47 (m, 2 H),
2.66 (m, 2 H), 3.80 (s, 3 H), 4.16 (q, 2 H, J= 7.2 Hz), 5.63 (m, 1 H),
5.83 (dt, 1 H, J = 15.6, 1.4 Hz), 6.82 (m, 2 H), 7.12 (t, 1 H, J = 7.6
Hz).
5-(2’-Methoxymethoxy-3’-methoxyphenyl)pentanoic Acid (33)
The ester 30 (3 mmol) was dissolved in THF (20 mL) and a satd so-
lution of Ba(OH)2 (40 mL) was added. The reaction was complete
in about 4 h and 1 N HCl was then added dropwise until pH 2. The
aqueous phase was extracted with EtOAc (5 × 50 mL) and the com-
bined organic phases were washed with brine, dried (MgSO4), and
evaporated under reduced pressure. The crude material was purified
by silica gel chromatography to give the acid in yields over 90%.
IR (CHCl3): n = 1756, 1712 (C=O), 1476, 1280, 1172 cm–1 (C–O).
Ethyl 5-(2’-N,N-Diethylcarbamato-3’-methoxyphenyl)pent-4-
enoate (26, mixture of isomers, major one described)
Colorless oil.
1H NMR (CDCl3): n = 1.08 (br m, 6 H), 1.25 (t, 3 H), 2.48 (m, 4 H),
3.45 (m, 4 H), 3.80 (s, 3 H), 4.14 (q, 2 H, J = 7.1 Hz), 6.32 (d, 1 H,
J = 0.8 Hz), 6.52 (dt, 1 H, J = 16.0, 6.5 Hz), 6.90 (m, 3 H).
Colorless oil.
1H NMR (CDCl3): d = 1.58 (qn, 2 H), 1.69 (qn, 2 H), 2.32 (t, 2 H),
2.76 (t, 2 H), 3.44 (m, 4 H), 3.83 (s, 3 H), 5.07 (s, 2 H), 7.02,
(m, 3 H).
IR (CHCl3): n = 1732, 1720 (C=O), 1264, 1160 cm–1 (C-O).
Ethyl 5-(2’-Hydroxy-3’-methoxyphenyl)pent-4-enoate (29, mix-
ture of isomers, major one described)
Colorless oil.
5-(2’-Hydroxy-3’-methoxyphenyl)pentanoic Acid (11)
To a solution of the carbamate 34 (4.45 mmol) in EtOH (50 mL)
was added NaOH (1.78 g, 44.5 mmol) in large excess. The mixture
was refluxed for 12 h. The excess of NaOH was neutralized at 0°C
using a solution of 1 N HCl, and the aqueous solution was extracted
with EtOAc (3 × 100 mL). The combined organic phase was
washed with brine, dried (MgSO4), and evaporated under reduced
pressure. The crude was purified by silica gel chromatography to
give the deprotected product (80%) as white crystals; mp 123–
124°C (Lit.52 mp 125–126°C).
1H NMR (acetone-d6): d = 1.63 (m, 4 H), 2.30 (t, 2 H, J = 7.0 Hz),
2.62 (t, 2 H, J = 7.0 Hz), 6.60 (m, 3 H), 7.00 (s, 1 H), 8.18 (s, 1 H).
13C NMR (CDCl3): d = 24.5, 29.2, 29.3, 34.0, 56.1, 108.5, 119.3,
128.0, 143.6, 146.6, 180.3.
1H NMR (CDCl3): d = 1.22 (t, 3 H), 2.48 (m, 4 H), 3.86 (s, 3 H),
4.11 (q, 2 H, J= 7.2 Hz), 5.70 (m, 1 H), 5.84 (s, 1 H), 6.20 (m, 1 H),
6.76 (m, 2 H), 6.97 (dd, 1 H, J = 8.2, 1.2 Hz).
IR (CHCl3): n = 3320 (OH), 1730 (C=O), 1258, 1164 cm–1 (C–O).
Catalytic Hydrogenation of Alkenes 24-26; General Procedure
The mixture of alkenes obtained as above from the Heck coupling
reaction was dissolved in EtOAc together with 5% Pd/C and the
heterogeneous solution was stirred vigorously for 2 h under an at-
mosphere of H2. After one equivalent of gas was consumed, the
mixture was filtered over Celite and the reaction was rerun with less
catalyst for 1 h. After filtration and evaporation of the solvent, the
reduced product was obtained quantitatively in pure form.
Ethyl 5-(2’-Methoxymethoxy-3’-methoxyphenyl)pentanoate
(30)
IR (CHCl3): n = 3540, 3200–2950 (OH), 1756, 1711 cm–1 (C=O).
Colorless oil.
5-(3’-Methoxy-p-benzoquinone)pentanoic Acid (2)
1H NMR (CDCl3): d = 1.24 (t, 3 H), 1.65 (m, 4 H), 2.28 (t, 2 H), 2.60
(m, 2 H), 3.55 (s, 3 H), 3.80 (s, 3 H), 4.11 (q, 2 H, J = 7.2 Hz), 5.03
Salcomine Oxidation: In dry glassware purged with oxygen, phenol
11 (1.0 mmol) was dissolved in anhyd DMF (5 mL) and salcomine
was added (0.1 mmol). The mixture was vigorously stirred and the
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Syntheses of the Benzoquinone Primin via Heck Reactions
1133
reaction was followed by TLC. After consumption of the starting
material (6 h), DMF was evaporated under vacuum and the crude
mixture was purified by chromatography, using degassed silica gel
and solvents (hexane/EtOAc, 5:5), and using N2 pressure to flash
the solvent. The quinone 2 was obtained as yellow crystals in 70%
yield; mp 98°C.
1H NMR (CDCl3): d = 1.67 (m, 4 H), 2.40 (m, 4 H), 3.84 (s, 3 H),
5.85 (d, 1 H), 6.50 (d, 1 H, J = 2.4 Hz).
13C NMR (CDCl3): d = 25.1, 30.8, 34.0, 37.3, 56.0, 107.1, 132.7,
145.2, 158.5, 179.7, 182.0, 187.5.
References
(1) Schildknecht, H.; Schmidt, H. Z. Naturforsch. 1967, 22b, 287.
(2) Bloch, B.; Karrer, P. Vjschr. naturforsch. Ges., Zurich, 1927,
72, 1; Chem. Abstr. 1928, 22, 2784.
(3) Marini-Bettolo, G. B.; Monache, F. D.; da Lima, O. G.;
Coelho, S. B. Gazz. Chim. Ital. 1971, 101, 41.
(4) Bernays, E.; Lupi, A.; Bettolo, R. M.; Mastrofrancesco, C.;
Tagliatesta, P. Experentia 1984, 40, 1010.
(5) de Lima, O. G.; Marini-Bettolo, G. B.; Delle Monache, F.;
Coelho, J. S.; d'Albuquerque, L. I.; Maciel, G. M.; Lacerda,
A.; Martins, D. G. Rev. Inst. Antibiot. 1970, 10, 29; Chem
Abstr. 1970, 77, 29622.
(6) Fregert, S.; Hjorth, N. Contact Dermatitis 1977, 3, 172.
(7) Schulz, K. H.; Garbe, I.; Hausen, B. M.; Simatupang, M. H.
Arch. Dermatol. Res. 1979, 264, 275.
IR (CHCl3): n = 3400-2700 (OH), 1734, 1680, 1604 (C=O), 1436,
1252 cm–1 (C–O).
Anal. Calcd for C12H14O5: C, 60.50, H, 5.92. Found: C, 60.78, H,
6.14.
(8) Ducombs, G. Allerg. Immunol. 1990, 22, 280.
(9) Fregert, S.; Hjorth, N.; Schulz, K. H. Arch. Dermatol. 1968,
98, 144.
(10) Ingber, A.; Menne, T. Contact Dermatitis 1990, 23, 15.
(11) Tabar, A. I.; Quirce, S.; Garcia, B. E.; Rodriguez, A.;
Olaguibel, J. M. Contact Dermatitis 1994, 30, 47.
(12) Dupuis, G.; Benezra, C. Allergic Contact Dermatitis to Simple
Chemicals: A Molecular Approach; M. Deckert: New York,
1982.
Oxidation with CAN: The protected hydroquinone 7 (1.6 mmol)
and 2,6-pyridinedicarboxylic acid (0.67 g, 4 mmol) were dissolved
in MeCN/H2O (10 mL, 7:3), and a solution of CAN (2.19 g, 4
mmol) in MeCN/H2O (10 mL, 1:1) was added dropwise at 0°C. The
mixture was stirred 40 min at 0°C and 10 min at 25°C. H2O (10 mL)
was then added and the mixture was extracted using CH2Cl2 (3 × 30
mL). The combined organic phases were washed with brine, dried
(MgSO4), and evaporated under reduced pressure, to yield a crude
mixture that was purified by silica gel chromatography (EtAOc/
hexane, 1:1). The solvent and the silica gel were degassed prior to
the chromatography. The quinone 2 was recovered in 62% yield.
(13) In Meeting report and highlights; Williams, D. C. M., L., Ed.;
Commission of the European Commnunities, Bruxelle:
Dublin, 1992.
(14) König, W. A.; Faasch, H.; Heitsch, H.; Colberg, C.; Hausen,
B. M. Z. Naturforsch. B. 1993, 48, 387.
(15) Hausen, B. M.; Heitsch, H.; Borrmann, B.; Koch, D.;
Rathmann, R.; Richter, B.; König, W. A. Contact Dermatitis
1995, 33, 12.
(16) Bieber, L. W.; De Andrade Chiapetta, A.; De Moraes e Souza,
M. A.; Generino, R. M. J. Nat. Prod. 1990, 53, 706.
(17) Snyder, C. D.; Rapoport, H. J. Am.. Chem. Soc. 1974, 96,
8046.
(18) Rao, D. V.; Ulrich, H.; Sayigh, A. A. R. J. Org. Chem. 1975,
40, 2548.
(19) Jacob, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. Jr. J.
Org. Chem. 1976, 41, 3627.
(20) Syper, L.; Kloc, K.; Miochowski, J.; Szulc, Z. Synthesis 1979,
521.
(21) Van Dort, H. M.; Geursen, H. J. Recl. Trav. Chim. Pays Bas
1967, 86, 520.
(22) De Jonge, C. R. H. I.; Hageman, H. J.; Hoentjen, G.; Mijs, W.
J. Org. Synth. 1977, 57, 78.
N,N-Diethylcarbamato-2-methoxy-6-(pent-1’-enyl)benzene(35,
mixture of isomers)
General procedure described for Heck coupling was adopted for 19
with 5 equiv of the alkene 12 instead of 2.5 equiv; Colorless liquid.
1H NMR (CDCl3): d = 0.94 (t, 3 H, J = 7.2 Hz), 1.21 (m, 6 H), 2.00
(m, 4 H), 3.47 (m, 4 H), 3.81 (s, 3 H), 6.21 (d, 1 H, J = 15.9 Hz),
6.46 (dd, 1 H, J = 15.9, 6.6 Hz), 6.90 (m, 3 H).
IR (CHCl3): n = 1722 cm–1 (C=O).
N,N-Diethylcarbamato-2-methoxy-6-pentylbenzene (36)
Hydrogenation of 35 following the general procedure gave 36; col-
orless liquid.
1H NMR (CDCl3): d = 0.89 (t, 3 H), 1.25 (m, 6 H), 1.59 (m, 6 H),
2.54 (t, 2 H, J = 7.1 Hz), 3.47 (m, 4 H), 3.81 (s, 3 H), 6.75 (m, 3 H).
IR (CHCl3): n = 1714 cm–1 (C=O).
Anal. Calcd for C17H27NO3: C, 69.59, H, 9.26, N, 4.77. Found C,
69.75, H, 9.20, N, 4.70.
(23) Gilman, H. Org. React. 1954, 8, 258.
(24) Snieckus, V. Bull. Soc. Chim. 1988, 1, 67.
(25) Saa, J. M.; Martorell, G.; Frontera, A. J. Org. Chem. 1996, 61,
5194.
(26) Bauer, W.; von Ragué Schleyer, P. J. Am. Chem. Soc. 1989,
111, 7191.
6-Pentylguaiacol (10)
Same hydrolysis procedure as described for 11 from the diethylcar-
bamate 34 was used; Colorless liquid.
1H NMR (CDCl3): d = 0.92 (t, 3 H), 1.38 (m, 4 H), 1.65 (m, 2 H),
2.65 (t, 2 H), 3.89 (s, 3 H), 5.71 (s, 1 H), 6.75 (m, 3 H).
13C NMR (CDCl3): d = 14.2, 22.8, 29.7, 29.8, 32.0, 56.0, 108.3,
119.3, 122.5, 128.9, 143.7, 146.5.
(27) Townsend, C. A.; Bloom, L. M. Tetrahedron Lett. 1981, 22,
3923.
(28) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; 2nd ed.; Wiley: New York, 1991.
(29) Ronald, R. C.; Winkle, M. R. Tetrahedron 1982, 39, 2031.
(30) Dakin, H. D. Am. Chem. J. 1909, 42, 477.
(31) Baker, W.; Bondy, H. F.; Gumb, J.; Miles, D. J. Chem. Soc.
1953, 1615.
IR (CHCl3): n = 3432 (OH), 3010, 2931, 2866 (CH), 1264, 1077
cm–1 (C–O).
Acknowledgement
(32) Sibi, P.; Jahil Miah, R. A.; Snieckus, V. J. Org. Chem. 1984,
49, 737.
LV and SM were both financially supported by MRE fellowships
from the French Government.
(33) Keinan, E.; Eren, D. J. Org. Chem. 1987, 52, 3872.
(34) Heck, R. F. Pure Applied Chem. 1978, 50, 691.
(35) Collum, D. B. Tet. Lett. 1995, 36, 3111.
(36) Larock, R. C.; Tu, C. Tetrahedron 1995, 51, 6635.
(37) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York

1134
S. Mabic et al.
PAPER
(38) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem.
1996, 61, 2346.
(47) Auerbach, J.; Weinreb, S. M. J. Chem. Soc., Chem. Commun.
1974, 298.
(39) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi,
U. J. Org. Chem. 1997, 62, 7170.
(40) Jutand, A.; Molesh, A. J. Org. Chem. 1997, 62, 261.
(41) Heck, R. F. Org. React. 1982, 345.
(42) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941.
(43) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem.
1967, 32, 2358.
(48) Jäger, G.; Geiger, R.; Siedel, W. Chem. Ber. 1968, 101, 2762.
(49) Drake, N. L.; Harris, H. C.; Bjaeder, C. Am. Soc. 1948, 70,
168.
(50) Sibi, P.; Snieckus, V. J. Org. Chem. 1983, 48, 3923.
(51) Stevens, R. V.; Bisacchi, G. S. J. Org. Chem. 1982, 47, 2393.
(52) Carpenter, P. D.; Humphreys, D. J.; Proctor, G. R.; Rees, L. G.
J. Chem. Soc. Perkin Trans. I 1974, 1527.
(44) Sibi, M. P.; Chattopadhyay, S.; Dankwardt, J. W.; Snieckus,
V. J. Am.Chem. Soc. 1985, 107, 6312.
(45) Mabic, S.; Paré, M.; Stampf, J.-L.; Benezra, C.; Lepoittevin,
J.-P. Chem. Res. Toxicol. 1998, In press.
Article Identifier:
1437-210X,E;1999,0,07,1127,1134,ftx,en;C07498SS.pdf
(46) Inoue, K.; Sakai, K. Tetrahedron Lett. 1977, 18, 4063.
Synthesis 1999, No. 7, 1127–1134 ISSN 0039-7881 © Thieme Stuttgart · New York