Synthesis of D/L-febrifugine and D/L-isofebrifugine

Article abstract of DOI:10.1055/s-1999-3583

Racemic compounds (1 and 2) of the antimalarial agents febrifugine (D-1) and isofebrifugine (D-2) were synthesized using an unusual Claisen rearrangement of allyl enol ether 6 and the stereoselective reduction of 2- allylpiperid-3-one 8. This method is widely applicable to the synthesis of febirifugine derivatives.

Full text of DOI:10.1055/s-1999-3583

1814
PAPER
Synthesis of D/L-Febrifugine and D/L-Isofebrifugine
Yasuo Takeuchi,* Mayumi Hattori, Hitoshi Abe, Takashi Harayama
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Fax +81(86)2517963; E-mail: take@pharm.okayama-u.ac.jp
Received 12 May 1999, revised 21 June 1999
known. In this paper, we describe a novel and widely ap-
plicable synthetic method of 1, 2, and those derivatives.
Abstract: Racemic compounds (1 and 2) of the antimalarial agents
febrifugine (D-1) and isofebrifugine (D-2) were synthesized using an
unusual Claisen rearrangement of allyl enol ether 6 and the stereo-
selective reduction of 2-allylpiperid-3-one 8. This method is widely
applicable to the synthesis of febirifugine derivatives.
8
5
4''
8a N
HO
N
5''
6''
7
6
2
HO
O
3''
2''
O
N
Key words: Claisen rearrangement, stereoselective reduction, feb-
rifugine, isofebrifugine, antimalarial agent
N
4
N
4a
O
2'
N
1'
3'
D
H
O
H
Isofebrifugine (D-2)
Febrifugine (
-1)
Febrifugine (D-1) is an antimalarial agent that was isolat-
ed from Dichroa febrifuga and Hydrangea umbellata
along with isofebrifugine (D-2).1a,b After the first proposal
of the plane structure of D-1 and D-2 in 1952,2a the
relative2b and absolute2c structure were proposed on the
basis of the Baker’s synthetic work.3a-c However, relative
configuration was corrected in 19722d and then Kobayashi
et al. corrected the absolute structures of D-1 and D-2 by
achieving the asymmetrical synthesis of all stereoisomers
in 19992e (Figure 1). The overall synthetic yield of the
racemate (1) of D-1 in the reported methods3a-d is low and
the synthetic method of the racemate (2) of D-2 is not
Figure 1
The key intermediate 8 was successfully prepared with
complete stereoselectivity (Scheme 1). The O-allylation
and reduction4 of the pyridinium chloride 4, which was
prepared from 3-hydroxypyridine (3) and benzyl chloride
in 94% yield, afforded 3-allyl-N-benzyl derivative 5 in
60% yield. The benzyl group was replaced5 to a benzyl-
oxycarbonyl (Z) group by treating 5 with benzyl chloro-
formate in tetrahydrofuran (THF) to give 6 in 93% yield.
Scheme 1
Synthesis 1999, No. 10, 1814–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of D/L-Febrifugine and D/L-Isofebrifugine
1815
The Claisen rearrangement of 6 at 130 °C in cymene
smoothly proceeded to give 4-allylpiperidin-3 one deriva-
tive 7 in 69% yield. On the other hand, in the presence of
boron trifluoride-diethyl ether complex (BF3·OEt2) at
room temperature, the unusual Claisen rearrangement of
6 afforded the piperidin-3-one derivative 8 with the allyl
group at the 2 position in 74% yield. This convenient re-
sult shows that the isomerization6 of the double bond on
the piperidine ring of 6 proceeds before the migration7 of
the allyl group in the presence of a Lewis acid. The proof
of the isomerization of the double bond was suppported
by the result that D3,4 piperidine derivatives 14 prepared
from N-benzyl derivative 13 gave D2,3 piperidine deriva-
tives 15 in 60% yield under the same conditions as in the
reaction of 6 (Scheme 2).
ClCOOCH2Ph
THF, rt, 1 h
PhCH2O
PhCH2O
N
N
91%
CH2Ph
COOCH2Ph
13
14
BF3•OEt2, MeCN
rt, 1 h
PhCH2O
Figure 2
60%
N
COOCH2Ph
15
hydrogenolysis of 12 gave D/L-isofebrifugine (2) in 56%,
which isomerized9 to give D/L-febrifugine (1) in 70%
yield. The 1H and 13C NMR data for 1 and 2 agreed with
reported values10 of D-1 and D-2, respectively (Table).
Scheme 2
Reduction of 8 with sodium borohydride (NaBH4) at room
temperature gave 9 in 97% yield as the sole product with-
out involving the diastereomeric isomer. The PM3
calculation8a,b of 8 indicated two stable conformers (8a,b)
based on the anti and gauche conformations between the
Z and allyl groups (Figure 2). One is minimized conform-
er 8a having the allyl group at the axial position and the
other is optimized conformer 8b having the allyl group at
the equatorial position. The unexpected energy difference
(about 4 kcal/mol) of heat of formation of 8a and 8b
showed that 8 almost exists in the form of 8a and that hy-
dride attack toward carbonyl group of 8a would occur
from the axial direction under the control of the torsional
strain to give 9.
We were able to prepare febrifugine derivatives in the
highest overall yield (5.2% from 3) without using the very
expensive, toxic, or dangerous reagents used in other re-
ports.2a-d We think that our method is widely applicable to
the synthesis of the derivatives needed to study the struc-
ture-activity relationship of febrifugine.
Melting points were determined on a Yanagimoto micro melting
point apparatus and are uncorrected. IR spectra were recorded on a
JASCO A-102 spectrometer. Mass spectra (MS) were recorded on
a VG-70SE spectrometer. 1H and 13C NMR spectra were run on a
Hitachi R-1500 or a Varian VXR-500 spectrometer. Analytical
HPLC was performed on Chemcosorb 5Si-U (Chemco). Merck sil-
ica gel 60 (230–400 mesh) was employed for column chromatogra-
phy. Extracts were dried using anhyd MgSO4.
D/L-Febrifugine (1) and D/L-isofebrifugine (2) were suc-
cessfully prepared from 9 via the cyclic intermediate 10.
The bromoetherfication of 8 using N-bromosuccinimide
(NBS) afforded benzyl 2-(bromomethyl)hexahydrofu-
ro[3,2-b]pyridine-4(2H)-carboxylate (10) in 85% yield, of
which HPLC data indicated was a 3:1 mixture of the dias-
tereomeric isomers, although we could not determine the
configuration of products. The reaction of 3 successive
steps, which is dehydrobromination using potassium tert-
butoxide, bromohydration using NBS and water, and cou-
pling reaction with quinazolinone (11), afforded Z-pro-
tected D/L-isofebrifugine (12) in 40% yield from 10. The
1-Benzyl-3-hydroxypyridinium Chloride
To a suspended solution of 1 (25.5 g, 26.8 mmol) in toluene (200
mL) (chloromethyl)benzene (31 mL, 26.9 mmol) was added. The
mixture was heated at reflux for 1 h. The precipitates were filtered
off and washed with EtOAc and Et2O. Recrystallization of the resi-
due from CHCl3 gave 4 (55.6 g, 94%) as colorless needles, mp 159–
160 °C.
IR (KBr): n = 3380, 3020, 1580, 1500, 1320, 740 cm-1.
1H NMR (60 MHz, CD3OD): d = 5.79 (2 H, s), 7.49 (5 H, s), 7.80–
8.10 (2 H, m), 8.40–8.70 (1 H, m), 8.57 (1 H, s).
Synthesis 1999, No. 10, 1814–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

1816
Y. Takeuchi et al.
PAPER
Table 13C- and 1H NMR of Febrifugine (D-1, DL-1) and Isofebrifugine (D-2, DL-2)
Posi-
tiona
Febrifugine
Isofebrifugine
13C NMR
DL-1c
1H NMR
13C NMR
DL-2f
1H NMR
D-1b
D-1d
DL-1e
D-2b
D-2d
DL-2g
2
146.7
161.3
122.1
127.8
127.7
134.8
127.0
148.5
55.0
148.0
160.0
121.4
127.3
127.2
134.5
126.1
148.1
54.7
7.93 (s)
8.20 (s)
148.5
161.8
122.1
127.7
127.3
134.6
127.1
148.3
50.0
148.1
161.4
121.8
128.3
127.4
134.2
126.8
148.0
49.8
8.31 (s)
8.29 (s)
4
4a
5
8.26 (dd)
8.14 (br d)
8.35 (ddd)
7.50 (ddd)
7.76 (ddd)
7.71 (ddd)
8.28 (br d)
7.47 (br t)
7.73 (br t)
7.68 (br d)
6
7.50 (ddd)
7.77 (ddd)
7.72 (ddd)
7.57 (br t)
7.86 (br t)
7.71 (br d)
7
8
8a
1’
4.84 (d),
4.92 (d)
4.99 (d),
5.03 (d)
4.15 (d),
4.45 (d)
4.13 (d),
4.30 (d)
2’
3’
203.1
46.0
203.9
45.6
105.6
44.6
105.4
43.2
2.63 (dd),
3.12 (dd)
2.75 (dt),
3.07 (br t)
1.88 (d),
2.08 (d)
1.86 (d),
2.03–2.12
2''
3''
4''
60.2
72.3
44.0
60.1
70.8
34.3
2.86 (ddd)
3.28 (ddd)
2.85 (br d)
55.8
77.0
43.4
55.6
77.3
26.7
3.30 (dd)
3.27 (br t)
3.86 (br d)
–
3.89 (ddd)
1.36 (ddt),
2.06 (ddd)
1.25–1.42,
1.91 (br d)
1.57 (ddd),
2.12 (ddd)
1.50–1.55,
2.03–2.12
5''
6''
25.6
34.5
25.8
43.8
1.51 (dt),
1.72 (dt)
1.36-1.44,
1.61 (br t)
20.1
26.8
20.0
44.5
1.50 (m),
1.78 (m)
1.50–1.55,
1.78–1.82
2.55 (dt),
2.95 (dd)
2.45 (dt),
3.02 (dd)
2.54 (dt),
3.00 (dd)
2.53 (br t),
2.97 (br d)
a See Figure 1
b CDCl3, 75.5 MHz (Lit. 10)
c CDCl3, 125 MHz
d CDCl3, 300 MHz (Lit. 10)
e CDCl3, 500 MHz
f DMSO-d6, 125 MHz
g DMSO-d6, 500 MHz
Anal. calcd for C12H12ClNO: C, 65.02; H, 5.46; N, 6.32. Found: C,
64.94; H, 5.51, N, 6.36.
1H NMR (60 MHz, CDCl3): d = 2.00–2.30 (2 H, m), 2.40–2.70 (2
H, m), 2.95 (2 H, br d, J = 1.4 Hz), 3.59 (2 H, s), 4.20 (2 H, br d,
J = 5.0 Hz), 4.66 (1 H, br, J = 3.5 Hz), 5.00–5.50 (2 H, m), 5.60–
6.40 (1 H, m), 7.31 (5 H, s).
5-(Allyloxy)-1-benzyl-1,2,3,6-tetrahydropyridine (5)
HRMS (FAB): m/z calcd for C15H20NO(MH+)230.1545; found
230.1573.
To a solution of 4 (22.17 g, 0.10 mol) and allyl bromide (9.6 mL,
0.11 mol) in anhyd MeOH (50 mL) NaH (4.40 g, 0.11 mol as 60%
dispersion in mineral oil) was added portionwise. After reflux for 4
h, the mixture was cooled and NaBH4 (3.78 g, 0.10 mol) was added
portionwise at 0 °C. The mixture was stirred at r.t. for 0.5 h, acidi-
fied with 10% HCl and basified with sat. KHCO3. The mixture was
poured into H2O (200 mL) and extracted with EtOAc (2 x 200 mL).
The combined organic layers were washed with brine (200 mL) and
the solvent was removed. The residue purified by column chroma-
tography (silica gel, hexane: EtOAc = 15:1) to give 5 (13.86 g,
60%) as colorless oil.
Benzyl 5-(Allyloxy)-3,6-dihydro-1(2H)-pyridinecarboxylate (6)
To a solution of 1 (0.46 g, 2.0 mmol) in anhyd THF (2 mL) benzyl
chloroformate (benzyl chloridocarbonate) (0.86 mL, 6.0 mmol) was
added dropwise at 0 °C. The mixture was stirred at r.t. for 1 h,
poured into sat. KHCO3 (50 mL), and extracted with EtOAc (2 x 30
mL). The combined organic layers were washed with brine (50
mL), dried, filtered and concentrated. The residue was purified by
column chromatography (silica gel, EtOAc:hexane = 1:15) to give
6 (0.51 g, 93%) as colorless oil.
IR (CHCl3): n = 2900, 1670, 1180, 1020, 920 cm-1.
Synthesis 1999, No. 10, 1814–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of D/L-Febrifugine and D/L-Isofebrifugine
1817
IR (CHCl3): n = 2900, 1680, 1430, 1220, 1110, 1000 cm-1.
IR (neat): n = 2950, 1700, 1420, 1260 cm-1.
1H NMR (60 MHz, CDCl3, rotomers): d = 1.30–2.50 (6 H, m),
2.60–3.30 (1 H, m), 3.30–3.50 (2 H, m), 3.60–5.00 (4 H, m), 5.15 (2
H, s), 7.35 (5 H, s).
HRMS (FAB): m/z calcd for C16H21BrNO3 (MH+) 354.0705, found
354.0733.
1H NMR (60 MHz, CDCl3): d = 2.00–2.40 (2 H, m), 3.53 (2 H, br t,
J = 5.7 Hz), 3.93 (2 H, br d, J = 1.4 Hz), 4.23 (2 H, br d, J = 5.0 Hz),
4.60–4.90 (1 H, m), 5.10–5.50 (2 H, m), 5.15 (2 H, s), 5.60–6.20 (1
H, m), 7.35 (5 H, s).
HRMS (FAB): m/z calcd for C16H20NO3(MH+) 274.1443; found
274.1444.
(3aS*, 7aS*)-Benzyl 2-Hydroxy-2-[(4-oxo-3(4H)-quinazoli-
nyl)methyl]hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate
(12)
Benzyl 4-Allyl-3-oxo-1-piperidinecarboxylate (7)
A solution of 6 (0.55 g, 2.0 mmol) in p-cymene (3 mL) was heated
at 130 °C for 1 h. The residue was purified by column chromatog-
raphy (silica gel, EtOAc:hexane = 1:3) to give 7 (0.38 g, 69%) as
colorless oil.
IR (neat): n = 3400, 2930, 1700, 1420 cm-1.
1H NMR (60 MHz, CDCl3, rotomers): d = 1.00–3.00 (5 H, m),
3.20–4.00 (2 H, m), 4.07 (2 H, br, J = 1.7 Hz), 4.30–6.20 (3 H, m)
5.14 (2 H, s), 7.34 (5 H, s).
To a solution of 10 (1.78 g, 5.0 mmol) in anhyd THF (5 mL) potas-
sium tert-butoxide (0.74 g, 6.0 mmol) was added. The mixture was
heated at reflux for 1 h. After cooling, the mixture was added to a
solution of NBS (1.07 g, 6.0 mmol) in MeCN (5 mL) and H2O
(5 mL). The mixture was stirred at r.t. for 0.5 h, poured into 10%
Na2S2O3 (100 mL) and extracted with EtOAc (2 x 50 mL). The com-
bined organic layers were washed with sat. KHCO3 (100 mL) and
brine (100 mL), dried, filtered and concentrated. A mixture of the
residue, 4(3H)-quinazolinone (11, 0.88 g, 6.0 mmol), anhyd K2CO3
(0.83 g, 6.0 mmol) in anhyd DMF (10 mL) was stirred at r.t. for 1 h.
The mixture was poured into brine (100 mL) and extracted with
EtOAc (2 x 50 mL). The combined organic layers were washed with
brine (50 mL), dried, filtered and concentrated. The residue was
subjected to column chromatography (Al2O3; EtOAc:i-PrOH = 2:1)
to give 12 (0.87 g, 40%) as amorphous solid.
HRMS (FAB): m/z calcd for C16H19NO3 273.1365; found 273.1326.
Benzyl 2-allyl-3-oxo-1-piperidinecarboxylate (8)
To a solution of 6 (10.93 g, 40.0 mmol) in anhyd MeCN (40 mL)
BF3·OEt2 (5.1 mL, 40.2 mmol) was added dropwise. The mixture
was stirred at r.t. for 1.5 h under Ar, poured into sat. KHCO3 (100
mL) and extracted with EtOAc (2 x 100 mL). The combined organic
layers were washed with brine (100 mL), dried, filtered and concen-
trated. The residue was subjected to column chromatography (silica
gel; hexane: EtOAc = 3:1) to give 8 (8.09 g, 74%) as colorless oil.
IR (CHCl3): n = 2950, 1680, 1420, 1310, 1220 cm-1.
1H NMR (60 MHz, CDCl3, rotomers): d = 1.60–2.20 (2 H, m),
2.20–2.80 (4 H, m), 2.80–3.50 (1 H, m), 3.90–4.40 (1 H, m), 4.50–
6.20 (4 H, m), 5.14 (2 H, s), 7.35 (5 H, s).
IR (neat): n = 3380, 1680, 1430, 1260 cm-1.
1H NMR (500 MHz, CDCl3, rotomers): d = 1.34–1.44 (4/3 H, m),
1.53–1.58 (2/3 H, m), 1.70–1.73 (1/3 H, m), 1.77–1.85 (4/3 H, m),
1.89–1.93 (1/3 H, m), 2.10 (2/3 H, dd, J = 13.0, 10.0 Hz), 2.24 (1/
3 H, dd, J = 13.5, 10.0 Hz), 2.30 (2/3 H, dd, J = 13.5, 8.0 Hz), 2.45
(1/3 H, dd, J = 13.5, 8.0 Hz), 2.86–2.90 (2/3 H, m), 2.97 (1/3 H, td,
J = 12.5, 3.0 Hz), 3.76 (2/3 H, br d, J = 12.5 Hz), 3.88 (1/3 H, dt,
J = 13.0, 4.0 Hz), 4.02–4.08 (2/3 H, m), 4.25–4.40 (7/3 H, m), 4.58
(1/3 H, br q, J = 8.0 Hz), 4.95 (2/3 H, br q, J = 7.5 Hz), 5.06–5.13
(2 H, m), 7.26–7.37 (5 H, m), 7.50 (1 H, br t, J = 7.0 Hz), 7.69–7.78
(2 H, m), 8.10 (1/3 H, s), 8.18 (2/3 H, s), 8.28 (1 H, br, J = 8.0 Hz).
HRMS (FAB): m/z calcd for C16H20NO3 (MH+) 274.1443; found
274.1463.
(2S*, 3S*)-Benzyl 2-Allyl-3-hydroxy-1-piperidinecarboxylate
(9)
HRMS (FAB): m/z calcd for C24H26N3O5 (MH+) 436.1872, found
436.1928. m/z calcd for C24H24N3O4 (MH-H2O) 418.1769; found
418.1779.
To a solution of 8 (7.42 g, 27.1 mmol) in MeOH (30 mL) NaBH4
(0.51 g, 13.5 mmol) was added portionwise at 0 °C. The mixture
was stirred at 0 °C for 1 h, poured into 10% HCl (100 mL) and ex-
tracted with EtOAc (3 x 50 mL). The combined organic layers were
washed with brine (100 mL), dried, filtered and concentrated to give
9 (7.26 g, 97%) as colorless oil.
IR (CHCl3): n = 3400, 2950, 1670, 1420, 1240 cm-1.
1H NMR (60 MHz, CDCl3, rotomers): d = 1.40–1.90 (4 H, m), 2.07
(1 H, s), 2.20–3.00 (3 H, m), 3.10–5.30 (5 H, m), 5.11 (2 H, s), 5.30–
6.20 (1 H, m), 7.33 (5 H, s).
D/L-Isofebrifugine (2)
A mixture of 11 (0.44 g, 1.0 mmol), 20% Pd(OH)2/C (0.05 g) in an-
hyd MeOH (5 mL) was stirred at r.t. for 7 h under H2. After filtra-
tion, the solvent was removed. The residure was recrystallized from
EtOAc to give 2 (0.17 g, 56%) as colorless needles, mp 134–
135 °C; dihydrochloride: mp 171–175 °C (dec.).
IR (CHCl3): n = 3300, 1660 cm-1.
1
The H and 13C NMR data are included in the Table.
HRMS (FAB): m/z calcd for C16H22NO3 (MH+) 276.1600; found
276.1571.
Anal. calcd for C16H19N3O3: C, 63.77; H, 6.35; N, 13.94. Found: C,
63.67; H, 6.41; N, 13.72.
(3aS*, 7aS*)-Benzyl 2-(Bromomethyl)hexahydrofuro[3,2-b]py-
ridine-4(2H)-carboxylate (10)
D/L-Febrifugine (1)
A solution of 2 (108.5 mg, 0.36 mmol) in EtOH (0.5 mL) was heat-
ed at reflux for 2 h. The precipitate was filtered off and recrystal-
lized from EtOAc to give 1 (79.3 mg, 73%) as colorless needles, mp
188–190 °C (lit.3b 133–134 °C); dihydrochloride mp 202–204 °C
(dec.) (lit.3a 204 °C (dec.))
IR (CHCl3): n = 3320, 3030, 1730, 1670 cm-1.
The 1H and 13C NMR data are included in the Table.
To a solution of 9 (7.26 g, 26.4 mmol) in MeCN (50 mL) NBS (5.16
g, 29.0 mmol) was added. The mixture was stirred at r.t. for 0.5 h,
poured into 10% Na2S2O3 (200 mL) and extracted with EtOAc
(2 x 100 mL). The combined organic layers were washed with sat.
KHCO3 (100 mL) and brine (100 mL), dried, filtered and concen-
trated. The residue was subjected to column chromatography (silica
gel; hexane: EtOAc = 3:1) to give 10 (7.98 g, 85%) as light yellow
oil.
Anal. calcd for C16H19N3O3: C, 63.77; H, 6.35; N, 13.94. Found: C,
63.58; H, 6.49; N, 13.95.
HPLC: column, Chemcosorb 5Si-U; column temperature, r.t.; elu-
ent, hexane: EtOAc = 3:1; flow rate = 1.0 mL/min; wavelength,
254 nm; tR = 10.0 and 11.0 min (75:25).
Synthesis 1999, No. 10, 1814–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

1818
Y. Takeuchi et al.
PAPER
Benzyl 3-(Benzyloxy)-1-piperidinecarboxylate (14)
References
To a solution of 134 (1.40 g, 5.0 mmol) in anhyd THF (5 mL) benzyl
chloridocarbonate (2.2 mL, 15.4 mmol) was added dropwise at
0 °C. The mixture was stirred at r.t. for 1 h, and the solvent was re-
moved. The residue was purified by column chromatography (silica
gel, EtOAc:hexane = 1:15) to give 14 (1.48 g, 91%) as colorless oil.
(1) (a) Koepeli J. B.; Mead J. F.; Brockman, Jr. J. Am. Chem. Soc.
1947, 69, 1836.
(b) Koepeli J. B.; Mead J. F.; Brockman, Jr. J. Am. Chem. Soc.
1949, 69, 1048,
(2) (a) Brockman J. A.; Moffat J. J. Am. Chem. Soc. 1950, 72,
3323.
IR (neat): n = 2900, 1700, 1670, 1440, 1230, 1100 cm-1.
1H NMR (60 MHz, CDCl3): d = 2.00–2.40 (2 H, m), 3.53 (2 H, t,
J = 5.5 Hz), 3.97 (2 H, br d, J = 1.7 Hz), 4.74, (2 H, s), 4.60–5.00 (1
H, m), 5.14 (2 H, s), 7.33 (10 H, s).
HRMS (FAB): m/z calcd for C20H22NO3 (MH+) 324.1600,
found:324.1646.
(b) Baker B. R.; McEvoy F. J.; Schaub R. E.; Joseph J. P.;
Williams J. H. J. Org. Chem. 1953, 18, 178.
(c) Hill R. K.; Edwards A. G. Chem. Ind. 1962, 12, 858.
(d) Barringer D. F.; Berkelhammer G.; Wayne R. S. J. Org.
Chem. 1973, 38, 1937.
(e) Kobayashi S.; Ueno M.; Suzuki R.; Ishitani H.
Tetrahedron Lett. 1999, 40, 2175.
Benzyl 5-(Benzyloxy)-3,4-dihydro-1(2H)-pyridinecarboxylate
(15)
(3) (a) Baker B. R.; Schaub R. E.; McEvoy F. J.; Williams J. H. J.
Org. Chem. 1952, 17, 132.
To a solution of 14 (0.65 g, 2.0 mmol) in anhyd MeCN (3 mL)
BF3·OEt2 (0.25 mL, 2.0 mmol) was added dropwise. The mixture
was stirred at r.t. for 1 h under Ar, poured into H2O (30 mL) and ex-
tracted with EtOAc (2 x 30 mL). The combined organic layers were
washed with sat. KHCO3 (50 mL) and brine (100 mL), dried, fil-
tered and concentrated. The residue was subjected to column chro-
matographiy (silica gel; hexane:EtOAc = 15:1) to give 15 (0.39 g,
60%) as colorless oil.
(b) Baker B. R.; McEvoy F. J.; Schaub R. E.; Joseph J. P.;
Williams J. H. J. Org. Chem. 1953, 18, 153.
(c) Baker B. R.; McEvoy F. J. J. Org. Chem. 1955, 20, 136.
(d) Burgess L. E.; Gross E. K. M.; Jurka J. Tetrahedron Lett.
1996, 37, 3255.
(4) Krogsgaard-Larsen P.; Hjeds H. Acta Chem. Scand. 1976, 30,
884.
(5) Campbell A. L.; Pilipauskas D. R.; Khanna K. I.; Rhodes R.
A. Tetrahedron Lett. 1987, 28, 2331.
IR (CHCl3): n = 2950, 1700, 1410 cm-1.
(6) Wanner K. T.; Kärtner A. Heterocycles 1987, 26, 917.
(7) Lutz R. P. Chem. Rev. 1984, 84, 205.
(8) (a) Stewart J. J. P. J. Comp. Chem. 1989, 10, 209.
(b) Stewart J. J. P. J. Comp. Chem. 1989, 10, 221.
(9) Uesato S.; Kuroda Y.; Kato M.; Fujiwara Y.; Hase Y.; Fujita
T.; Chem. Pharm. Bull. 1998, 46, 1.
1H NMR (60 MHz, CDCl3, rotomers): d = 1.60–2.40 (4 H, m),
3.40–3.70 (2 H, m), 4.74 (2 H, s), 5.18 (2 H, s), 6.30–6.60 (1 H, m),
7.35 (10 H, s).
MS (FAB): m/z = 324 (MH+), 323 (M+).
(10) Murata K.; Takano F.; Fushiya S.; Oshima Y. J. Nat. Prod.
1998, 61, 729.
Acknowledgement
The present work was supported by a Grant-Aid for Scientific Re-
search on Priority Areas (No. 08281105) from the Ministry of Edu-
cation, Science, Sports and Culture of Japan. We are grateful to the
SC-NMR Laboratory of Okayama University for the use of the fa-
cilities.
Article Identifier:
1437-210X,E;1999,0,10,1814,1818,ftx,en;F03099SS.pdf
Synthesis 1999, No. 10, 1814–1818 ISSN 0039-7881 © Thieme Stuttgart · New York