Synthesis of natural cytotoxic camphorataimides B and C

Article abstract of DOI:10.1055/s-2006-926354

Recently isolated camphorataanhydride A and cytotoxic camphorataimides B and C have been synthesized using chemoselective S_N2′ Grignard coupling reaction of p-methoxyphenyl-magnesium bromide with dimethyl bromomethylfumarate and chemoselective

Full text of DOI:10.1055/s-2006-926354

PAPER
1005
Synthesis of Natural Cytotoxic Camphorataimides B and C1
S
ynthesisof Camphoradtaimides 1
B
a
.
nd
C
Merajuddin Baag, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25893153; E-mail: np.argade@ncl.res.in
Received 23 September 2005; revised 14 October 2005
O
Abstract: Recently isolated camphorataanhydride A and cytotoxic
R
camphorataimides B and C have been synthesized using chemo-
selective SN2¢ Grignard coupling reaction of p-methoxyphenyl-
magnesium bromide with dimethyl bromomethylfumarate and
X
O
chemoselective allylic substitution of bromide in bromoanhydride 9
with 2-propylmagnesium bromide as the key reactions. The present
approach is general in nature and can be easily used to design the
congeners of camphorataanhydrides/imides for structure–activity
relationship studies.
O
camphorataanhydride A [1a, X = O, R = CH2CH(CH3)2]2
camphorataimide B [1b, X = NH, R = CH2CH(CH3)2]2
camphorataimide C [1c, X = NOH, R = CH2CH(CH3)2]2
himanimide A [1d, X = NH, R = CH2Ph]3
Key words: dimethyl bromomethylfumarate, SN2¢ Grignard cou-
pling reaction, functionalized maleic anhydrides, bioactive natural
product synthesis, camphorataimides B and C
himanimide C [1e, X = NOH, R = CH2Ph]3
O
H
R
HO
N
Recently camphorataanhydride/imides were isolated from
the mycelium of Antrodia camphorata and the imides
1b,c showed appreciable cytotoxic effects on LLC tumor
cells.2 The analogous himanimides A–D possessing anti-
microbial and antifungal activities were recently isolated
from basidomycete culture of Serpata himantoides3
(Figure 1). The biological screening studies of these natu-
rally occurring anhydrides/imides 1–4 revealed that their
activity is linked to the N-hydroxylated maleimide moi-
ety.2,3 In 2005, Patrice Selles reported4 a flexible approach
to the himanimide scaffold using a copper-mediated tan-
dem vicinal difunctionalization of dimethyl acetylenedi-
carboxylate (DMAD) as a key step.5,6 We feel that these
simple natural products 1–4 are of interest as new leads.
To study the structure–activity relationship of these types
of natural and unnatural molecules, a flexible synthetic
approach that will allow mono/dialkyl/allyl/benzyl/aryl
functionalization of both the available carbons with sever-
al types of heteroatoms in the five-membered ring is es-
sential. Our strategy for the synthesis of 1a–c
incorporating the above aspects is described in
Scheme 1.7
H
O
O
camphorataimide D [2a, R = CH2CH(CH3)2]2
himanimide D [2b, R = CH2Ph]3
O
H
HO
N
H
O
O
camphorataimide E (3)2
O
CH2Ph
HN
O
OH
O
We envisaged dimethyl bromomethylfumarate (5)7b as a
potential starting material for the stepwise construction of
natural products 1a–c and their various analogues. The
OH
himanimide B (4))3
Figure
1
Naturally occurring bioactive camphorata/himan-
chemoselective SN2¢ coupling reaction of p-methoxyphe- anhydride/-imides 1–42,3
nylmagnesium bromide with 5 exclusively gave the de-
sired arylalkylidenesuccinic diester 6 in 73% yield. To the
ring closure gave the expected anhydride 8 in nearly
best of our knowledge this is the first arylmagnesium bro-
mide coupling with 5. The base catalyzed hydrolysis of di-
ester 6 to diacid 7 followed by acetic anhydride-induced
100% yield. In this reaction, both the formation of succin-
ic anhydride intermediate and C–C double bond migration
took place in one pot. The NBS-mediated bromination of
the allylic carbon in the anhydride 8 furnished the re-
quired bromoanhydride 9 in 80% yield. We did not ob-
serve any ring bromination or demethylation of methoxy
group in 8/9 under our reaction conditions. The chemose-
SYNTHESIS 2006, No. 6, pp 1005–1008
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x
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x
x
.2
0
0
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Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926354; Art ID: Z17505SS
© Georg Thieme Verlag Stuttgart · New York

1006
M. M. Baag, N. P. Argade
PAPER
Br
Br
O
O
O
O
O
OMe
v
OMe
i
iv
ii
iii
OH
O
O
MeO
MeO
HO
O
O
O
O
OMe
O
5
OMe
9
7
8
OMe
OMe
6
O
O
O
O
viii
vi
vii
HN
O
O
O
O
O
O
O
O
OMe
O
OH
11
10
camphorataanhydride (1a)
camphorataimide (1b)
O
HO
N
ix
O
1a
O
camphorataimide (1c)
Scheme 1 Reagents and conditions: (i) p-CH3OC6H4MgBr (1.5 equiv), THF, HMPA, –20 °C, 0.5 h (73%); (ii) (a) LiOH (10 equiv), THF +
H2O (3:1), r.t., 18 h, (b) H+/HCl (92%); (iii) Ac2O, reflux, 1.5 h (ca. 100%); (iv) NBS (1.5 equiv), DBP (10 mol%), CCl4, reflux, 12 h (80%);
(v) C3H7MgBr (5 equiv), CuI (0.1 equiv), THF, HMPA, –5 to 0 °C, 8 h (45%); (vi) BBr3 (5 equiv), CH2Cl2, –78 to 0 °C 12 h (91%); (vii) 3,3-
dimethylallyl bromide (1.2 equiv), K2CO3 (10 equiv), acetone, reflux, 2 h (90%); (viii) urea (1.2 equiv), 130 °C , 1 h (81%); (ix) NH2OH·HCl,
pyridine, reflux, 2 h (76%).
lective allylic substitution of bromine atom in anhydride 9 of anhydride to a variety of N-substituted maleimides is
with isopropylmagnesium bromide gave the 2-(p-meth- possible. Hence, we feel that our present approach is gen-
oxyphenyl)-3-isobutylmaleic anhydride (10) in 45% eral in nature and will be useful to design congeners of
yield. Boron tribromide induced demethylation of 10 pro- camphorataimides in search of new lead molecules with
vided the corresponding 2-(p-hydroxyphenyl)-3-isobutyl- better activity.
maleic anhydride (11) in 91% yield. Allylation of
anhydride 11 with 3,3-dimethylallyl bromide in the pres-
ence of K2CO3 furnished the naturally occurring campho-
rataanhydride A (1a) in 90% yield. The anhydride 1a was
heated with urea at 130 °C for one hour to obtain the nat-
ural bioactive camphorataimide B (1b) in 81% yield.
Treatment of anhydride 1a with hydroxylamine hydro-
chloride in refluxing pyridine gave the desired third bio-
active natural product camphorataimide C (1c) in 76%
yield. The analytical and spectral data obtained for these
three natural products 1a–c were in complete agreement
with the reported data.2
Melting points are uncorrected. The 1H NMR spectra were recorded
on Bruker AC 200 NMR spectrometer using TMS as an internal
standard. The 13C NMR spectra were recorded on either Bruker AC
200 NMR spectrometer (50 MHz), Bruker AC 300 NMR spectrom-
eter (75 MHz) or Bruker AC 500 NMR spectrometer (125 MHz).
The FT-IR spectra were recorded on a FT-IR-8300 Shimadzu spec-
trometer. Column chromatographic separations were carried out on
silica gel (60–120 mesh) and flash chromatographic separation was
carried out using 230–400 mesh size silica gel. Commercially avail-
able citraconic anhydride, 4-bromoanisole, 2-bromopropane, mag-
nesium turnings, HMPA, CuI, N-bromosuccinimide, dibenzoyl
peroxide, Ac2O, BBr3, 3,3-dimethylallyl bromide, urea and
NH4OH·HCl were used. Petroleum ether (PE) refers to the fraction
boiling in the range 60–80 °C.
In summary, we have reported the first synthetic approach
to natural camphorataanhydride (1a) (7-steps, 20%) and
bioactive camphorataimides (1b,c) (8 steps, 16 and 15%,
respectively). In our present approach the stepwise func-
tionalization and generation of anhydride moiety with a
variety of alkyl/allyl/benzyl/aryl groups and conversion
2-(4-Methoxyphenyl)-3-methylenesuccinic Acid Dimethyl Ester
(6)
A fresh solution of 4-methoxyphenylmagnesium bromide in THF
was prepared as follows. A solution of 4-bromoanisole (4.49 g, 24
Synthesis 2006, No. 6, 1005–1008 © Thieme Stuttgart · New York

PAPER
Synthesis of Camphorataimides B and C
1007
mmol) in anhyd THF (30 mL) was added at r.t. to Mg (1.73 g, 72
mmol) in THF (10 mL) under argon with constant stirring in three
equal portions at an interval of 10 min. The mixture was further
stirred at r.t. for 4 h. This freshly generated Grignard reagent was
added dropwise to a solution of HMPA (14.34 g, 80 mmol) and 5
(3.79 g, 16 mmol) in anhyd THF (30 mL) under argon at 0 °C and
the mixture was further stirred at the same temperature for 30 min.
The reaction was quenched by the addition of a sat. aq NH4Cl solu-
tion (30 mL). EtOAc (50 mL) was added to the mixture and the or-
ganic layer was separated. The aqueous layer was extracted with
EtOAc (3 × 40 mL). The combined EtOAc extracts were washed
with H2O and brine, dried (Na2SO4) and concentrated in vacuo. The
obtained residue was chromatographed over silica gel using PE–
EtOAc (9:1) to give 6 as a thick oil; yield: 3.07 g (73%).
mL), the combined organic layers were washed with H2O, brine,
dried (Na2SO4) and concentrated in vacuo to furnish the crude com-
pound. Purification by silica gel column chromatography using PE–
EtOAc (9:1) afforded the desired compound 9 as a yellow solid;
yield: 1.18 g (80%); mp 78 °C.
IR (Nujol): 1840, 1811, 1761, 1725, 1636, 1601 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.91 (s, 3 H), 4.36 (s, 2 H), 7.09
(d, J = 8 Hz, 2 H), 7.86 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 18.7, 55.6, 115.0, 119.2, 130.1,
132.0, 132.8, 140.5, 162.7, 164.3.
Anal. Calcd for C12H9BrO4: C, 48.51; H, 3.05. Found: C, 48.65; H,
3.16.
IR (neat): 1736, 1720, 1632, 1611 cm–1.
3-(4-Methoxyphenyl)-4-isobutylfuran-2,5-dione (10)
1H NMR (CDCl3, 200 MHz): d = 3.71 (s, 3 H), 3.77 (s, 3 H), 3.80
(s, 3 H), 4.77 (s, 1 H), 5.43 (s, 1 H), 6.39 (s, 1 H), 6.89 (d, J = 10
Hz, 2 H), 7.19 (d, J = 10 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 52.1 (2 C), 52.3, 55.2, 114.2,
127.6, 127.8, 130.0, 139.1, 159.1, 166.8, 172.5.
A fresh solution of isopropylmagnesium bromide in THF was pre-
pared as follows. A solution of 2-bromopropane (1.23 g, 10 mmol)
in anhyd THF (20 mL) was added at r.t. to Mg turnings (1.20 g, 50
mmol) in THF (5 mL) under argon with constant stirring in three
equal portions at an interval of 10 min. The mixture was further
stirred at r.t. for 4 h. This freshly generated Grignard reagent was
added dropwise to the solution of 9 (594 mg, 2 mmol) and CuI (38
mg, 0.2 mmol) in THF (10 mL) and HMPA (2 mL) under argon at
–5 to 0 °C over 15 to 20 min under stirring. The mixture was al-
lowed to reach r.t. and further stirred for 8 h. It was then diluted with
EtOAc (10 mL) and acidified with 4 N H2SO4 (20 mL) and the aque-
ous layer was further extracted with EtOAc (3 × 30 mL). The com-
bined organic layers were washed with H2O, brine, dried (Na2SO4)
and concentrated in vacuo. The obtained residue was chromato-
graphed over silica gel using PE–EtOAc (9.5:0.5) to give 10 as a
thick oil; yield: 234 mg (45%).
Anal. Calcd for C14H16O5: C, 63.63; H, 6.10. Found: C, 63.78; H,
6.18.
2-(4-Methoxyphenyl)-3-methylenesuccinic acid (7)
A solution of LiOH (2.40 g) in H2O (20 mL) was added to a solution
of 6 (2.64 g, 10 mmol) in THF (30 mL) at r.t. and the mixture was
stirred for 18 h. The mixture was concentrated in vacuo, EtOAc (50
mL) was added and then it was acidified to pH 2 with 2 N HCl. The
organic layer was separated and the aqueous layer was further ex-
tracted with EtOAc (3 × 25 mL). The combined organic layers were
washed with H2O and brine, dried (Na2SO4) and concentrated in
vacuo. The obtained residue was chromatographed over silica gel
using PE–EtOAc (6:4) to give 7 as a white solid; yield: 2.17 g
(92%); mp 158 °C.
IR (CHCl3): 1844, 1825, 1763, 1736, 1607 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.95 (d, J = 6 Hz, 6 H), 2.13 (sep-
tet, J = 6 Hz, 1 H), 2.60 (d, J = 8 Hz, 2 H), 3.88 (s, 3 H), 7.02 (d,
J = 8 Hz, 2 H), 7.64 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 22.6, 27.9, 33.6, 55.4, 114.5,
120.1, 131.1, 140.0, 140.2, 161.7, 165.4, 166.3.
IR (Nujol): 2700–2500, 1713, 1693, 1634, 1611 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.82 (s, 3 H), 4.73 (s, 1 H), 5.42
(s, 1 H), 6.54 (s, 1 H), 6.92 (d, J = 8 Hz, 2 H), 7.24 (d, J = 8 Hz, 2
Anal. Calcd for C15H16O4: C, 69.22; H, 6.20. Found: C, 69.20; H,
6.13.
H).
13C NMR (acetone-d6, 75 MHz): d = 52.8, 55.5, 114.8, 127.3,
129.3, 131.0, 141.4, 160.0, 167.8, 173.4.
3-(4-Hydroxyphenyl)-4-isobutylfuran-2,5-dione (11)
Anal. Calcd for C12H12O5: C, 61.02; H, 5.12. Found: C, 60.88; H,
5.19.
To a stirred solution of 10 (160 mg, 0.62 mmol) in anhyd CH2Cl2
(10 mL) at –78 °C, was added a solution of BBr3 in CH2Cl2 (1 M,
3.10 mL, 3.10 mmol) over a period of 15 min. The mixture was then
allowed to warm up to r.t., and stirred for further 12 h. The reaction
was then quenched with H2O (5 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (3 × 15 mL).
The combined organic layers were washed with H2O, brine, dried
(Na2SO4) and concentrated in vacuo. The obtained residue was pu-
rified by silica gel column chromatography using PE and EtOAc
(8:2) to give 11 as a thick oil; yield: 138 mg (91%).
3-(4-Methoxyphenyl)-4-methylfuran-2,5-dione (8)
A solution of 7 (1.89 g, 8 mmol) in Ac2O (15 mL) was gently re-
fluxed for 1.5 h and the mixture was concentrated in vacuo at 50 °C.
The residue was diluted with EtOAc (40 mL) and the organic layer
was washed with H2O and brine, dried (Na2SO4) and concentrated
in vacuo to obtain 8 as a yellow solid; yield: 1.74 g (ca. 100%); mp
112 °C.
IR (Nujol): 1840, 1811, 1759, 1726, 1635, 1605 cm–1.
IR (CHCl3): 3391, 1832, 1765, 1719, 1709, 1609 cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.32 (s, 3 H), 3.89 (s, 3 H), 7.04
(d, J = 8 Hz, 2 H), 7.70 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 10.8, 55.4, 114.5, 120.1, 131.3,
135.8, 139.2, 161.8, 165.2, 166.5.
1H NMR (CDCl3, 200 MHz): d = 0.95 (d, J = 6 Hz, 6 H), 2.12 (sep-
tet, J = 6 Hz, 1 H), 2.60 (d, J = 8 Hz, 2 H), 6.98 (d, J = 8 Hz, 2 H),
7.58 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 22.6, 27.9, 33.6, 116.1, 120.0,
131.3, 140.1, 140.3, 158.1, 165.5, 166.5.
Anal. Calcd for C12H10O4: C, 66.05; H, 4.62. Found: C, 65.92; H,
4.80.
Anal. Calcd for C14H14O4: C, 68.28; H, 5.73. Found: C, 68.33; H,
5.89.
3-Bromomethyl-4-(4-methoxyphenyl)furan-2,5-dione (9)
A mixture of 8 (1.09 g, 5 mmol), N-bromosuccinimide (1.34 g, 7.5
mmol) and a catalytic amount of DBP (122 mg, 10 mol%) in CCl4
(50 mL) was gently refluxed for 12 h. The mixture was left over-
night at r.t. and then filtered. The residue was washed with CCl4 (25
3-[4-(3-Methylbut-2-enyloxy)phenyl]-4-isobutylfuran-2,5-di-
one (Camphorataanhydride A, 1a)
A solution of 11 (100 mg, 0.41 mmol) in acetone (10 mL) was add-
ed to 3,3-dimethylallyl bromide (73.3 mg, 0.49 mmol) and K2CO3
Synthesis 2006, No. 6, 1005–1008 © Thieme Stuttgart · New York

1008
M. M. Baag, N. P. Argade
PAPER
(566 mg, 4.10 mmol) and the mixture was refluxed for 2 h. The mix-
ture was concentrated in vacuo and diluted with H2O (5 mL). The
aqueous layer was extracted with EtOAc (3 × 15 mL) and the com-
bined organic layers were washed with brine, dried (Na2SO4) and
concentrated in vacuo. The obtained residue was purified by silica
gel column chromatography using PE and EtOAc mixture (9.5:0.5)
to give camphorataanhydride A (1a) as a thick yellow oil; yield: 115
mg (90%).
(5 mL) was added. The aqueous layer was extracted with EtOAc
(3 × 15 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated in vacuo. The obtained residue
was purified by silica gel column chromatography using PE and
EtOAc mixture (8:2) to give camphorataimide C (1c) as a yellow
oil; yield: 32 mg (76%).
IR (neat): 3306, 1782, 1722, 1713, 1605 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89 (d, J = 8 Hz, 6 H), 1.76 (s, 3
H), 1.81 (s, 3 H), 2.06 (septet, J = 6 Hz, 1 H), 2.51 (d, J = 8 Hz, 2
H), 4.56 (d, J = 6 Hz, 2 H), 5.51 (br t, J = 6 Hz, 1 H), 6.98 (d, J = 8
Hz, 2 H), 7.51 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 18.2, 22.7, 25.8, 28.1, 33.0, 64.9,
114.9, 119.1, 120.7, 131.0, 135.9, 136.0, 138.8, 160.2, 168.0, 168.7.
IR (neat): 1836, 1825, 1763, 1605 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.95 (d, J = 8 Hz, 6 H), 1.77 (s, 3
H), 1.82 (s, 3 H), 2.13 (septet, J = 6 Hz, 1 H), 2.61 (d, J = 6 Hz, 2
H), 4.59 (d, J = 6 Hz, 2 H), 5.50 (br t, J = 6 Hz, 1H), 7.03 (d, J = 10
Hz, 2 H), 7.63 (d, J = 10 Hz, 2 H).
13C NMR (CDCl3, 50 MHz): d = 18.2, 22.7, 25.8, 27.9, 33.6, 65.0,
115.1, 118.9, 119.9, 131.1, 139.0, 139.8, 140.2, 160.9, 165.4, 166.4.
Anal. Calcd for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C,
69.39; H, 6.92; N, 4.37.
Anal. Calcd for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.66; H,
7.10.
Acknowledgment
3-[4-(3-Methylbut-2-enyloxy)phenyl]-4-isobutylpyrrole-2,5-di-
one (Camphorataimide B, 1b)
M.M.B. thanks CSIR, New Delhi, for the award of a research fel-
lowship.
A mixture of 1a (40 mg, 0.13 mmol) and urea (9 mg, 0.15 mmol)
was heated to 130–135 °C for 1 h. The mixture was allowed to cool
to r.t., then H2O (10 mL) was added and the aqueous layer was ex-
tracted with EtOAc (3 × 15 mL). The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated in vacuo. The
obtained residue was purified by silica gel column chromatography
using PE and EtOAc mixture (8.5:1.5) to give camphorataimide B
(1b) as a yellow solid; yield: 32 mg (81%); mp 110 °C.
References
(1) NCL Communication No. 6688.
(2) Nakamura, N.; Hirakawa, A.; Gao, J.-J.; Kakuda, H.; Shiro,
M.; Komatsu, Y.; Sheu, C.-C.; Hattori, M. J. Nat. Prod.
2004, 67, 46.
(3) Aqueveque, P.; Anke, T.; Sterner, O. Z. Naturforsch. 2002,
57c, 257.
(4) Selles, P. Org. Lett. 2005, 7, 605.
(5) Ratemi, E. S.; Dolence, J. M.; Poulter, C. D.; Vederas, J. C.
J. Org. Chem. 1996, 61, 6296.
(6) Adlington, R. M.; Baldwin, J. E.; Cox, R. J.; Pritchard, G. J.
Synlett 2002, 820; and references cited therein.
(7) For our contributions towards cyclic anhydrides to bioactive
natural and unnatural products, see: (a) Mhaske, S. B.;
Argade, N. P. J. Org. Chem. 2001, 66, 9038. (b) Kar, A.;
Argade, N. P. J. Org. Chem. 2002, 67, 7131. (c) Kar, A.;
Argade, N. P. Tetrahedron 2003, 59, 2991. (d) Kar, A.;
Gogoi, S.; Argade, N. P. Tetrahedron 2005, 61, 5297.
(e) Argade, N. P.; Balasubramaniyan, V. Heterocycles 2000,
53, 475; and references 7a–e cited therein.
IR (CHCl3): 3435, 1773, 1717, 1715, 1605 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.91 (d, J = 8 Hz, 6 H), 1.77 (s, 3
H), 1.82 (s, 3 H), 2.06 (septet, J = 6 Hz, 1 H), 2.52 (d, J = 6 Hz, 2
H), 4.57 (d, J = 6 Hz, 2 H), 5.51 (br t, J = 6 Hz, 1 H), 7.00 (d, J = 8
Hz, 2 H), 7.32 (br s, 1 H), 7.52 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3, 125 MHz): d = 18.2, 22.7, 25.8, 28.1, 32.8, 64.9,
114.8, 119.2, 121.1, 130.9, 138.7, 138.8, 139.1, 160.1, 171.0, 171.7.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.72; H, 7.51; N, 4.53.
3-[4-(3-Methylbut-2-enyloxy)phenyl]-4-isobutyl-N-hydroxy-
pyrrole-2,5-dione (Camphorataimide C, 1c)
A mixture of 1a (40 mg, 0.13 mmol) and NH2OH·HCl (18 mg, 0.26
mmol) was refluxed in pyridine (5 mL) for 2 h. The mixture was al-
lowed to cool to r.t., pyridine was removed in vacuo and then H2O
Synthesis 2006, No. 6, 1005–1008 © Thieme Stuttgart · New York