Reaction of N-acylated isofebrifugine with acid

Article abstract of DOI:10.3987/COM-00-8991

The reaction of N-acylated isofebrifugine with hydrochloric acid is discussed. Although the corresponding deprotected compound was not isolated, three new heterocyclic compounds were obtained. Based on these findings, new furan and pyrrole derivatives wer

Full text of DOI:10.3987/COM-00-8991

HETEROCYCLES, Vol. 53, No.10, 2000, pp. 2247 - 2252, Received, 30th June, 2000
REACTION OF N-ACYLATED ISOFEBRIFUGINE WITH ACID
Yasuo Takeuchi,* Kumiko Azuma, Hitoshi Abe, and Takashi Harayama
Faculty of Pharmaceutical Sciences, Okayama University,
Okayama 700-8530, Japan
Abstract - The reaction of N-acylated isofebrifugine with hydrochloric acid is
discussed. Although the corresponding deprotected compound was not isolated,
three new heterocyclic compounds were obtained. Based on these findings, new
furan and pyrrole derivatives were prepared.
Febrifugine (d-1) is an antimalarial agent that was isolated from Dichroa febrifuga and Hydrangea umbellata
along with isofebrifugine (d-2).1a-c Although several methods for synthesizing d-12a, b and its racemate
(1)3a-d have been reported, there are few methods for d-22b and its racemate (2)3b (Figure 1). Recently, we
developed a new method of synthesizing 1 via 2.4 In this method, an isofebrifugine derivative (3) protected
by a benzyloxycarbonyl group (Z) afforded 2 in moderate yield by hydrogenolysis. On the other hand, it
was known that the alkoxycarbonyl group in the febrifugine derivative was successfully deprotected by acid
hydrolysis.2b, 3b We attempted reacting 3 with acid to improve the yield of the deprotection.
N
HO
O
N
HO O
N
N
N
H
N
H
O
O
Febrifugine (d-1)
Isofebrifugine (d-2)
Figure 1
Although we could not find 2 in the reaction mixture of 3 and 15% hydrochloric acid in acetonitrile under
reflux for 0.5 h, we were able to isolate the furan derivative (4) in 36% yield and the 1,4-diketone derivative
(5) in 4% yield (Scheme 1). Even when the reaction time was prolonged to 2 h, 2 was not detected, but a
new compound (6) was obtained in 6% yield along with 4 and 5. The structure of this compound was
determined from analytical data to include a condensed pyrrole ring. These results indicate that opening of
the piperidine ring occurred before deprotection of the acyl group in the reaction of Z-protected isofebrifugine
with hydrochloric acid. Using boron trifluoride etherate instead of hydrochloric acid in the reaction of 3
afforded 4 in 74% yield.

N
O
N
N
HN
Z
O
N
O
N
O
O
HO
15% HCl
N
O
N
4
N
N
N
Z
O
or BF •OEt
3
2
O
6
3
HN
Z
Z = —COOCH Ph
2
5
Scheme 1
We thought that 3 would successively produce 4, 5, and 6 in order and that new furan or pyrrole derivatives
could be prepared using this reaction. As a convenient model of 3, we selected 7, which is 3 without the
quinazoline ring (Scheme 2). Using molecular orbital calculations, Uesato et al. predicted that compound
(7) with a deprotecting Z group would exist in the hemi-ketal form (7) rather than the keto form (8).5 We
calculated that a stable structure (9) would form when the benzyl group of 7 or 8 with a methyl
group by the PM3 method.6 Our calculations supported Uesato’s prediction5 that the hemi-ketal forms (7a,
b) were significantly more stable than the keto form (8a) (Figure 2).
7a (hemi-ketal form)
7b (hemi-ketal form)
8a (keto form)
(H.f. = -187.64 kcal/mol)
(H.f. = -186.97kcal/mol)
(H.f. = -185.14 kcal/mol)
Figure 2
In contrast with the calculations, dehydrobromination of 94 with potassium tert-butoxide followed by
treatment with acid afforded 8, whose methyl proton was observed as a singlet peak at δ 2.07 ppm in
1
DMSO-d6 with H-NMR. However, an additional peak was observed at δ 1.50 ppm in CDCl3 with H-
1
13
NMR and two peaks were observed at δ 207.3 and d 102.7 ppm with C-NMR. From these results, we
concluded that 8 would rapidly afford a mixture of 7 and 8 in CDCl3. The reaction of a mixture of 7 and 8

with borontrifluoride etherate afforded the furan derivative (10) in 49% yield. The reaction of 10 with
hydrochloric acid gave the 1,4-diketone derivative (11) in 85% yield. Removal of the Z group of 11 by
hydrogenolysis followed with the condensation reaction afforded the pyrrole derivative (12), which was
identified by comparing the 1H-NMR data with reported 1H-NMR data (Scheme 2).7a, b
HO O
Me
N
Z
t-BuOK, dry THF
0°C, 0.5 h, then
O
BF •OEt , dry MeCN
O
3
2
7
Me
Br
HN
Z
N
Z
HO
O
poured into10% HCl
73%
rt, 30 min, 49%
10
Me
N
Z
9
8
O
10% HCl, MeCN
reflux, 45 min, 85%
H , 10% Pd/C
2
O
N
Me
Me
dry MeOH, 55%
HN
Z
11
12
Scheme 2
EXPERIMENTAL
General: Melting points were determined on a Yanagimoto micro melting point apparatus and are
uncorrected. IR spectra were recorded on a JASCO A-102 spectrophotometer. MS spectra were recorded on a
1
VG-70SE spectrometer. H-NMR spectra were run on a Hitachi R-1500 (60 MHz) spectrometer. Merck
silica gel 60 (230-400 mesh) was employed for column chromatography.
Reaction of 3 with Hydrochloric acid in MeCN.
A mixture of 3 (1.01 g, 2.32 mmol) and 5N-HCl (5 mL) in MeCN (15 mL) was heated at reflux for 0.5 h.
The mixture was made basic with 10% NaOH and extracted with AcOEt (100 mL x 2). AcOEt layer was
washed with brine (100 mL), dried over anhydrous MgSO , and the solvent was evaporated off. The
4
residue was chromatographed (SiO ). The first eluant (AcOEt:hexane = 2:1) gave benzyl N-[3-[5-[(4-oxo-
2
-1
3(4H)-quinazolinyl)methyl]-2-furyl]propyl]carbamate (4, 0.35 g, 36%) as a colorless oil. IR (neat) cm :
1
3340, 1710, 1680, 1260. H-NMR (CDCl3) δ: 1.68—1.92 (m, 2H), 2.63 (t, 2H, J = 7.5 Hz), 3.21 (q,
2H, J = 6.5 Hz), 4.71 (br s, 1H), 5.09 (s, 4H), 5.96 (d, 1H, J = 3.1 Hz), 6.34 (d, 1H, J = 3.1 Hz), 7.33
(s, 5H), 7.52—7.79 (m, 3H), 8.15 (s, 1H), 8.32 (dd, 1H, J = 7.6, 1.2 Hz). HRMS (FAB) Calcd for
+
C H N O (MH) : 418.1767. Found: 418.1780. The second eluant (AcOEt) gave benzyl N-[4,7-
24 24 3 4
dioxo-8-(4-oxo-3(4H)-quinazolinyl)octyl]carbamate (5, 0.038 g, 4%) as colorless needles, mp

-1
1
137—138°C (AcOEt and hexane). IR (KBr) cm : 3320, 1710, 1690, 1280. H-NMR (CDCl3) δ:
1.66—2.00 (m, 2H), 2.51 (t, 2H, J = 6.6 Hz), 2.79 (s, 4H), 3.19 (q, 2H, J = 6.5 Hz), 4.85 (s, 2H), 5.09
(s, 2H), 7.34 (s, 5H), 7.42—7.82 (m, 3H), 7.92 (s, 1H), 8.28 (dd, 1H, J = 7.3, 1.5 Hz). MS (FAB,
+
positive ion mode) m/z: 436 (MH) . Anal. Calcd for C H N O : C, 66.20; H, 5.79; N, 9.65. Found:
24 25 3 5
C, 66.11; H, 5.49; N, 9.62.
Reaction of 3 with Hydrochloric Acid.
A mixture of 3 (0.99 g, 2.27 mmol) and 5N-HCl (15 mL) was heated at reflux for 2 h. The mixture was
made basic with 10% NaOH and extracted with AcOEt (100 mL x 2). AcOEt layer was washed with brine
(200 mL), dried over anhydrous MgSO , and the solvent was evaporated off. The residue was
4
chromatographied (SiO ). The first eluant (AcOEt:hexane = 1:1) gave 3-[(2,3-dihydro-1H-6-pyrrolo[1,2-
2
a]pyrrolyl)methyl]-4(3H)-quinazolinone (6, 0.037 g, 6%) as colorless needles, mp 148—149°C (hexane).
-1
1
IR (CHCl ) cm : 1650. H-NMR (CDCl ) δ: 2.45—2.81 (m, 4H), 3.89 (t, 2H, J = 6.5 Hz), 5.15 (s,
3
2H), 5.77 (d, 1H, J = 3.4 Hz), 6.30 (d, 1H, J = 3.4 Hz), 7.49—7.76 (m, 3H), 8.09 (s, 1H), 8.33 (dd,
3
+
1H, J = 8.8, 1.2 Hz). HRMS (FAB) Calcd for C H N O (M) : 265.1215. Found: 265.1212. Anal.
16 15 3
Calcd for C H N O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.58; H, 5.80; N, 15.25. The second
16 15 3
eluent (AcOEt:hexane=2:1) gave 4 (0.023 mg, 2%) and The third eluent (AcOEt) gave 5 (0.023 mg, 2%).
Benzyl N-[3-[5-[(4-Oxo-3(4H)-quinazolinyl)methyl]-2-furyl]propyl]carbamate (4)
To a solution of 3 (1.53 g, 3.51 mmol) in MeCN (10 mL), BF •OEt (0.45 mL, 3.55 mmol) was added.
2
3
The mixture was heated at reflux for 0.5 h. The mixture was made basic with saturated KHCO and extracted
3
with AcOEt (100 mL). AcOEt layer was washed with brine (100 mL), dried over anhydrous MgSO , and the
4
solvent was evaporated off. The residue was chromatographed (SiO ; hexane:AcOEt = 2:1) to give 4 (1.08
2
g, 74%).
(2S*,3S*)-Benzyl 3-Hydroxy-2-(2-oxo)propyl-1-piperidinecarboxylate (7) and
(3aS*,7aS*)-Benzyl 2-hydroxy-2-methylhexahydrofuro[3,2-b]pyridine-4(2H)-
carboxylate (8)
To a solution of (3aS*,7aS*)-benzyl 2-(bromomethyl)hexahydrofuru[3,2-b]pyridine-4(2H)-carboxylate (9,
t
0.50 g, 1.41 mmol) in dry THF (5 mL), KOBu (0.32 g, 2.85 mmol) was added at 0°C and the mixture was
stirred at the same temperature for 0.5 h. The mixture was poured into water (100 mL), made acidic with 10%
HCl, and extracted with AcOEt (100 mL x 2). The AcOEt layer was washed with brine (100 mL), dried over
anhydrous MgSO , and the solvent was removed. The residue was chromatographed (SiO , AcOEt:hexane
4
2
= 1:1) to give a mixture of 7 and 8 (0.30 g, 73%) as a colorless oil. HRMS (FAB) Calcd for C H NO
+
4
16 22
(MH) : 292.1548. Found: 292.1532.
Benzyl N-[3-(5-methyl-2-furyl)propyl]carbamate (10)
To a solution of a mixture (0.74 g, 2.50 mmol) of 7 and 8 in dry MeCN (5 mL), BF •OEt (0.32 mL, 2.50
3
mmol) was added dropwise and the mixture was heated at reflux for 0.5 h. The mixture was poured into
2

saturated KHCO solution (50 mL) and extracted with AcOEt (50 mL x 2). The AcOEt layer was washed
3
with brine (100 mL), dried over anhydrous MgSO , and the solvent was removed. The residue was
4
-1
chromatographed (SiO , AcOEt:hexane = 1:4) to give 10 (0.34 g, 49%) as a colorless oil. IR (neat) cm :
1
2
3340, 2950, 1700, 1250. H-NMR (CDCl ) δ: 1.68—2.00 (m, 2H), 2.23 (s, 3H), 2.61 (t, 2H, J = 6.8
3
Hz), 3.23 (q, 2H, J = 6.5 Hz), 4.70 (br s, 1H), 5.10 (s, 2H), 5.85 (s, 2H), 7.34 (s, 5H). HRMS (FAB)
+
+
Calcd for C H NO (M) : 273.1365. Found: 273.1359. Calcd for C H NO (MH) : 274.1443.
3
16 19
Found: 274.1385.
16 20
3
Benzyl N-(4,7-Dioxooctyl)carbamate (11)
A mixture of 10 (0.80 g, 2.93 mmol) and 10% HCl (5 mL) in MeCN (10 mL) was heated at reflux for 45
min. The mixture was made basic with 10% NaOH solution and extracted with AcOEt (100 mL x 2). The
AcOEt layer was washed with brine (200 mL), dried over anhydrous MgSO , and the solvent was removed.
4
The residue was chromatographed (SiO , AcOEt:hexane = 1:1) to give 11 (0.73 g, 85%) as colorless plates,
2
-1
1
mp 32—33°C. IR (KBr) cm : 3330, 1700, 1270. H-NMR (CDCl ) δ: 1.66—2.00 (m, 2H), 2.16 (s, 3H),
3
2.52 (t, 2H, J = 6.5 Hz), 2.66 (s, 4H), 3.19 (q, 2H, J = 6.5 Hz), 4.90 (br s, 1H), 5.10 (s, 2H), 7.34 (s,
+
5H). HRMS (FAB) Calcd for C H NO (MH) : 292.1549. Found: 292.1521.
16 22
4
Dihydro-6-methyl-1H-pyrrolo[1,2-a]pyrrole (12)
A mixture of 11 (0.72 g, 2.46 mmol) and 10% Pd/C (0.12 g) in dry MeOH (10 mL) was stirred at the rt for
24 h under the atomosphare of H . The mixture was filtered off and the solvent was removed. The residure
2
1
was chromatographed (SiO , AcOEt:hexane = 1:30) to give 12 (0.16 g, 55%) as a colorless oil. H-NMR
2
7a,b 1
data of this compound were identified with those of reported data
: H-NMR (CDCl ) δ: 2.19 (s, 3H),
3
2.30—3.00 (m, 4H), 3.79 (t, 2H, J = 6.7 Hz), 5.67 (d, 1H, J = 3.2 Hz), 5.86 (d, 1H, J = 3.2 Hz).
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