Synthesis of Amaryllidaceae alkaloids, siculine, oxocrinine, epicrinine, and buflavine

Article abstract of DOI:10.1016/j.tet.2004.03.087

Three crinane type of alkaloids isolated from Amaryllidaceae family were synthesized by taking advantage of the PIFA-mediated intramolecular p-p′ diphenol coupling reaction of norbelladine derivatives. Furthermore, buflavine was also prepared by using the p-p′ diphenol coupling followed by dienone-phenol rearrangement as a key step.

Full text of DOI:10.1016/j.tet.2004.03.087

Tetrahedron 60 (2004) 4901–4907
Synthesis of Amaryllidaceae alkaloids, siculine, oxocrinine,
epicrinine, and buflavine
*
Sumiaki Kodama, Hirofumi Takita, Tetsuya Kajimoto, Kiyoharu Nishide and Manabu Node
Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku,
Kyoto 607-8412, Japan
Received 5 February 2004; accepted 26 March 2004
Abstract—Three crinane type of alkaloids isolated from Amaryllidaceae family were synthesized by taking advantage of the PIFA-mediated
intramolecular p-p0 diphenol coupling reaction of norbelladine derivatives. Furthermore, buflavine was also prepared by using the p-p0
diphenol coupling followed by dienone–phenol rearrangement as a key step.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
compounds for pharmaceutical research since crinane,12 the
common structure of the crinine alkaloids, exhibited
antivirus, antitumor, and anticholinergic activities.13
Furthermore, it is also an acceptable hypothesis that
buflavine (7) isolated from Boophane flava14 might be
also generated by the p-p0 coupling followed by dienone–
phenol rearrangement. In this paper, we would like to report
Amaryllidaceae family is an attractive source of alkaloids,1
which are valuable as targets for total synthesis because of
their unique structures, limited supply, and promising
bioactivities such as cholinesterase inhibition which has
being found in galanthamine.2,3 The alkaloids are, in the
metabolic pathways, synthesized at least by three different
types of intramolecular phenol coupling, that is, the
coupling between the positions of p-o0, p-p0, and o-p0
(phenol–O-methylcathecol) in O-methylnorbelladine (1).
Galanth-amine, for example, is one of the p-o0 coupling
products while lycoline is generated via the o-p0 coupling.4
By mimicking the biosynthetic phenol coupling, we have
recently attained the total syntheses of galanthamine and
narwedine, in which O-methylcathecol ring of 1 was
replaced with 2-O-methylpyrogarrole in order0 to avoid the
mixture of two products resulting from the p-o and the p-p0
coupling.5 The p-p0 phenol coupling of 1 would generate
maritidine (2), which was synthesized by several groups
taking advantage of effective carbon–carbon bond for-
mation such as oxidative phenol coupling6 and Heck
reaction7 as key steps. Demethylation, epimerization, and/
or formal oxidation of methoxy groups of maritidine (2)
would provide crinine (3)8 and its derivatives, for example,
siculine (4) from Sternbergia sicula,9 oxocrinine (5)
isolated from Crinum americanum,10 and epicrinine (6)
from Nerine bowdenii11 (Fig. 1).
These could be promising candidates as excellent lead
Keywords: Phenol coupling; Phenyliodine(III) bis(trifluoroacete) (PIFA);
Siculine; Oxocrinine; Epicrinine; Buflavine.
*
Corresponding author. Tel.: þ81-75-595-4639; fax: þ81-75-595-4775;
e-mail address: node@mb.kyoto-phu.ac.jp
Figure 1. Structures of Amaryllidaceae alkaloids.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.087

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S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
(PIFA)5,6c,d,15 proceeded the phenol coupling to afford
dienone (11). Deprotection of the benzyl group of 11 with
boron trichloride and successive hydrolysis of trifluoro-
acetylamide group with 10% potassium hydroxide in
methanol gave the intramolecular Michael adduct (12).
Reduction of 12 with L-Selectride afforded siculine (4)
(Scheme 1).
This strategy is also applicable to the synthesis of
oxocrinine (5)6i,16 and its related alkaloids. Reductive
amination of piperonal (13) and tyramine was followed by
N-acylation with either trifluoroacetic anhydride or ethyl
formate to give 14a, 14b. The obtained 14a, 14b were,
respectively, allowed to the oxidative coupling with PIFA
giving the desired coupled products 15a, 15b in excellent
yields. Respective hydrolysis of the protecting groups of
15a and 15b with 10% potassium hydroxide in methanol
followed by spontaneous intramolecular Michael addition
afforded oxocrinine (5), and successive reduction with
L-Selectride gave epicrinine (6)16a,17 that can be converted
to crinine (3) by the known method (Scheme 2).18
Scheme 1. Synthetic route of siculine (4).
Next, we tried to synthesize buflavine (7), which was
prepared by Kobayashi 25 years prior to its isolation and
characterization.19 Since it has been isolated in 1995,
buflavine (7) was synthesized by three groups using the
biaryl coupling, that is, Meyers’ coupling20 and Suzuki–
Miyaura coupling reactions.21 However, tedious procedures
were required to prepare arylborate or polymethoxybenzene
derivatives before employing the coupling reactions. Being
encouraged by the usefulness of the p-p0 phenol coupling
with PIFA for the synthesis of Amallylidaceae alkaloids as
mentioned above, in addition to the previous reports,5 we
confirmed that applying the phenol coupling could effec-
tively revise the synthetic route of 7. Reductive amination of
3,4-dimethoxybenzaldehyde (16) with tyramine in the
presence of sodium borohydride was first conducted to
give the amine, and successive protection of the amino
group with ethyl formate gave 17. Unfortunately,
oxidative coupling reactions that are reported to accompany
the facile synthesis of the alkaloids generated via the p-p0
oxidative phenol coupling as a part of our synthetic studies
of Amaryllidaceae alkaloids.
2. Result and discussion
We started our synthetic study of these alkaloids with the
synthesis of siculine (4), of which synthetic studies have not
been reported so far. After the protection of phenolic group
of isovanillin (8) with benzyl group, obtained 3-O-
benzylisovanillin (9) was exposed by reductive amination
with tyramine in the presence of sodium borohydride to
afford phenethylbenzylamine (10). Protection of the amino
group of 10 with trifluoroacetyl group, followed by the
oxidation with phenyliodine(III) bis(trifluoroacetate)
Scheme 2. Synthetic route of oxocrinine (5) and epicrinine (6).

S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
4903
Scheme 3. Synthetic route of buflavine (7).
eight-membered ring formation, for example, PIFA-
mediated reaction with boron trifluoride etherate,22 did not
give any satisfactory results in this case. Therefore, the
seven-membered product 18 of the p-p0 oxidative coupling
of 17 with PIFA18 was treated with methanesulfonic acid to
convert it to 19 by dienone–phenol rearrangement.6h In
order to deoxygenate the phenolic hydroxyl group, 19 was
converted to triflate (20) followed by palladium-catalyzed
reduction to afford 21. Reduction of formamide group of 21
with lithium aluminum hydride gave buflavine (7)
(Scheme 3). As expected, the overall yield of this synthetic
route (64%) is much higher than those reported so far in the
literatures.20,21
INOVA-400 spectrometer with tetramethylsilane as an
internal standard. Mass spectra (MS) were determined on
a JEOL JMS-SX 102A QQ or a JEOL JMS-GC-mate mass
spectrometer. Combustion analysis was done on a Perkin–
Elmer Series II CHNS/O Analyzer 2400. Specific rotations
were recorded on a Horiba SEPA-200 automatic digital
polarimeter. Their data were recorded with Shimadzu
C-R6A Chromatopac. Acetate buffer was adjusted with a
Horiba pH meter F-13. Wakogel C-200 (silica gel) (100–
200 mesh, Wako) was used for open column chromato-
graphy. Flash column chromatography was performed with
Silica Gel 60N (Kanto Chemical Co., Inc.). Silica gel 60
F-254 plates (Merck) were used for thin layer chromato-
graphy (TLC). Preparative TLC (PTLC) was done with
Silica gel 60 F-254 plate (0.25 mm, Merck) or Silica gel 60
F-254 plate (0.5 mm, Merck). When necessary, compounds
were further purified by a recycle HPLC (JAI LC-908) on
GPC column (JAIGEL 1H and 2H) after purification on
silica gel.
3. Conclusion
As mentioned above, we have succeeded in the first
synthesis of siculine (4), the synthesis of buflavine (7)
with the highest overall yield reported so far, and the short
step synthesis of oxocrinine (5) 0 and epicrinine (6), by
applying the PIFA-mediated p-p diphenol coupling of
norbelladine derivatives. The coupling reaction is
applicable even on the industrial scale since it generates
only volatile iodobenzene and trifluoroacetic acid. Further
study on the synthesis of chiral compounds of 3–6 is now in
progress.
4.2. Materials
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium benzophenone ketyl, and dichloromethane was
distilled from CaH2, after washing with water 10 times, to
remove methanol contaminants. Most of the reagents were
obtained from Wako Pure Chemical Industries, Ltd.,
Nakalai Tesque, Inc., Aldrich Chemical Inc.
4. Experimental
4.1. General
4.2.1. N-30-Benzyloxy-40-methoxyphenylmethyl-[2-(4-
hydroxyphenyl)]ethylamine (10). Potassium carbonate
(4.4 g, 32.0 mmol) and benzyl chloride (2.3 mL,
19.6 mmol) were successively added to a solution of
isovanillin (8) (2.5 g, 16.3 mmol) in N,N-dimethylforma-
mide (16 mL), and the reaction mixture was stirred for 3 h at
90 8C. After the reaction, the mixture was concentrated in
vacuo and extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous Na2SO4, and
Melting points were taken on a micro hot-stage apparatus
(Yanagimoto) and were uncorrected. Infrared (IR) spectra
were recorded on a Shimadzu FTIR-8300 diffraction grating
1
infrared spectrophotometer and H- and 13C NMR spectra
were obtained on a JEOL JNM-AL300, a Varian Unity

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S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
concentrated in vacuo. Purification of the residue by column
chromatography (silica gel, n-hexane/ethyl acetate, 3/1)
afforded 30-O-benzylisovanillin (9). Tyramine (2.9 g,
21.0 mmol) was added to a solution of 9 in methanol
(40 mL), and the reaction mixture was stood to stir for 1 day.
Sodium borohydride (728.2 mg, 19.2 mmol) was added to
the reaction mixture at 0 8C and the mixture was stirred for
another 3 h at room temperature. Crystal needles (10) (4.8 g,
82%) appearing in the reaction vessel were collected by
filtration. Mp 135–136 8C (methanol); 1H NMR (400 MHz,
CDCl3): d 7.38–7.23 (m, 5H), 6.96 (d, J¼8.6 Hz, 2H), 6.86
(s, 1H), 6.78 (s, 2H), 6.65 (d, J¼8.6 Hz, 2H), 4.98 (s, 2H),
3.83 (s, 3H), 3.68 (s, 2H), 2.81 (t, J¼6.8 Hz, 2H), 2.71 (t,
J¼6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 155.23,
148.80, 148.12, 137.02, 131.50, 130.22, 129.71, 128.42,
127.73 127.38 121.13, 115.71, 114.17, 111.62, 70.69, 56.00,
Na2SO4 and concentrated in vacuo. Purification of the
residue by column chromatography (silica gel, n-hexane/
ethyl acetate, 2/3) afforded a debenzylated compound
1
(150.9 mg, 79%) as a colorless oil; H NMR (400 MHz,
CDCl3): d 7.06 (d, J¼10.3 Hz, 1H), 6.95 (d, J¼10.3 Hz,
1H), 6.90 and 6.74 (s, 1H), 6.51 (s, 1H), 6.33 (d, J¼6.2 Hz,
1H), 6.31 (d, J¼6.2 Hz, 1H), 5.76 (brs, 1H, OH), 4.77 and
4.74 (s, 2H), 3.86 (dd, J¼12.5, 8.1 Hz, 2H), 3.76 and 3.75 (s,
3H), 2.44–2.34 (m, 2H); 13C NMR (100 MHz, CDCl3): d
185.39, 185.26, 153.15, 152.76, 146.33, 144.92, 144.90,
128.63, 128.50, 127.15, 127.01, 117.61, 117.53, 116.31,
112.02, 111.94, 55.97, 55.91, 48.51, 48.22 48.13, 45.34,
45.30, 44.23, 35.83, 33.89; IR (CHCl3): 3541, 1690, 1665,
1626, 1591, 1516 cm21; HRMS calcd for C18H16NO4F3
(Mþ): 367.1031, found: 367.1034. To a solution of the
debenzylated compound (25 mg, 0.07 mmol) in methanol
(0.5 mL), was added 10% aqueous solution of potassium
hydroxide (0.5 mL) and stirred for 30 min at room
temperature. The reaction mixture was concentrated in
vacuo and extracted with chloroform. The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification of the residue by column chromatography
(silica gel, chloroform/methanol, 10/1) afforded 12
(16.1 mg, 87%) as colorless crystals; mp 252–255 8C
(decomp.) (n-hexane) (lit.,6a,c mp 250–252 8C, decomp.);
1H NMR (400 MHz, CDCl3): d 7.70 (d, J¼10.3 Hz, 1H),
6.88 (s, 1H), 6.61 (s, 1H), 6.11 (d, J¼10.3 Hz, 1H), 4.40 (d,
J¼16.8 Hz, 1H), 3.92 (s, 3H), 3.81 (d, J¼16.8 Hz, 1H), 3.67
(dd, J¼12.9, 5.6 Hz, 1H), 3.56 (ddd, J¼13.3, 10.1, 3.5 Hz,
1H), 3.03 (ddd, J¼14.2, 7.9, 5.3 Hz, 1H), 2.71 (dd, J¼16.8,
5.7 Hz, 1H), 2.49 (dd, J¼16.8, 13.0 Hz, 1H), 2.40 (ddd,
J¼12.4, 9.0, 3.7 Hz, 1H), 2.19 (ddd, J¼12.1, 10.5, 6.3 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 198.17, 149.56,
145.29, 144.59, 134.17, 128.74, 125.78, 113.26, 104.53,
68.94, 61.32, 56.10, 54.05, 44.77, 44.46, 40.12; IR (CHCl3):
3543, 1680, 1506 cm21; HRMS calcd for C16H17NO3 (Mþ):
271.1208, found: 271.1205.
53.25, 49.92, 34.60; IR (CHCl3): 1612, 1593, 1514 cm21
;
HRMS calcd for C23H25NO3 (Mþ): 363.1834, found:
363.1838. Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93;
N, 3.85. Found: C, 76.02; H, 6.94; N, 3.82.
4.2.2. Preparation of dienone (11). Trifluoroacetic
anhydride (0.93 mL, 6.6 mmol) was added to a solution of
10 (1.0 g, 2.8 mmol) in pyridine (10 mL) at 0 8C. The
reaction mixture was stirred for 1 day at 0 8C, and then the
methanol was added to quench the reaction. The mixture
was concentrated in vacuo and extracted with ethyl acetate.
The organic layer was successively washed with 1 M HCl,
saturated NaHCO3, brine, and then dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification of the
residue by column chromatography (silica gel, n-hexane/
ethyl acetate, 1/1) afforded trifluoroacetamide (1.3 g, 100%)
1
as a colorless oil. H NMR spectral and HRMS data were
completely coincided with those in the literature;6g 13C
NMR (100 MHz, CDCl3): d 154.89, 154.69, 149.59, 149.46,
148.15, 148.13, 136.58, 136.52, 129.75, 129.70, 129.63,
128.88, 128.55, 128.46, 127.95, 127.84, 127.63, 127.27,
127.21, 126.70, 121.24, 120.65, 115.60, 115.44, 113.96,
113.41, 111.74, 111.66, 71.01, 70.84, 55.96, 55.93, 51.13,
49.40, 48.22, 48.19, 48.11, 34.14, 31.73; IR (CHCl3): 1686,
1516 cm21. To a solution of the trifluoroacetamide (1.2 g,
2.5 mmol) in CF3CH2OH (12 mL), was added a solution of
phenyliodine(III) bis(trifluoroacetate) (1.2 g, 2.8 mmol) in
CF3CH2OH (12 mL) at 225 8C. The reaction mixture was
stirred for 30 min, and then concentrated in vacuo.
Purification of the residue by column chromatography
(silica gel, ethyl acetate) afforded 11 (0.9 g, 78%) as an
4.2.4. Siculine (4). Lithium tri-sec-buthylborohydride
(L-Selectridew) (0.22 mL, 1.0 M solution in THF,
0.22 mmol) was added to a solution of 12 (24.4 mg,
0.09 mmol) in THF (5 mL) at 278 8C, and the reaction
mixture was stirred for 1 day at 278 8C. After quenching the
reaction with aqueous solution of Na2SO4, the mixture was
extracted with chloroform. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification
of the residue by column chromatography (silica gel,
chloroform/methanol, 5/1) afforded siculine (4) (13.1 mg,
1
amorphous powder. H NMR, IR spectral and HRMS data
were completely coincided with those in the literature;6g 13C
NMR (100 MHz, CDCl3): d 185.23, 185.09, 152.88, 152.46,
149.34, 149.20, 147.40, 147.14, 136.43, 136.37, 128.58,
128.53, 128.42, 128.33, 128.01, 127.98, 127.91, 127.67,
127.38, 127.26, 127.16, 127.10, 116.48, 115.91, 113.32,
113.26, 71.12, 70.94, 56.10, 55.97, 48.63, 48.42, 48.28,
48.14, 45.30, 45.27, 44.17, 35.81, 33.83.
53%) as colorless crystals. H NMR spectral and EI-MS
1
data were completely coincided with those in the literature;9
mp 235–239 8C (decomp.) (chloroform); 13C NMR
(100 MHz, CD3OD): d 148.32, 146.79, 135.70, 133.08,
129.11, 128.07, 122.28, 114.75, 107.36, 68.23, 67.45, 60.99,
56.61, 53.56, 44.38, 33.93; IR (CHCl3): 3331, 2963, 2934,
1506, 1466, 1447, 1315, 1275, 1240, 1198, 1128, 1094,
1026, 868 cm21; HRMS calcd for C16H19NO3 (Mþ):
273.1365, found: 273.1370.
4.2.3. 8-Demethyl-3-oxomaritidine (12). Boron trichloride
(0.78 mL, 1.0 M solution in dichloromethane, 0.78 mmol)
was added to a solution of 11 (238 mg, 0.52 mmol) in
dichloromethane (3 mL) at 278 8C. The reaction mixture
was stirred for 3 days at 278 8C, and then water was added
to quench the reaction. The mixture was extracted with
chloroform. The organic layer was dried over anhydrous
4.2.5. N-Trifluoroacetyl-N-30, 40-methylenedioxyphenyl-
methyl-[2-(4-hydroxyphenyl)]ethylamine (14a). Tyra-
mine (1.1 g, 8.0 mmol) was added to a solution of
piperonal (13) (1.0 g, 6.7 mmol) in methanol (8 mL), and
the reaction mixture was stirred for 6 h at room temperature.

S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
4905
Sodium borohydride (277.3 mg, 7.3 mmol) was added to the
mixture and stirred for 1 day. The reaction mixture was
concentrated in vacuo, and extracted with chloroform. The
organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo and treated for further reaction
without purification. Trifluoroacetic anhydride (2.4 mL,
16.8 mmol) was added to a solution of the residue in
pyridine (18 mL) and the mixture was stirred for 2 h at 0 8C.
After quenching the reaction with methanol, the mixture
was concentrated in vacuo and extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the residue by column
chromatography (silica gel, n-hexane/ethyl acetate, 2/1)
afforded 14a (3.0 g, 100%) as colorless crystals. All the
spectral data was coincided with those in the literature.23
(400 MHz, CDCl3): d 8.23 and 8.18 (s, 1H), 7.03 (d,
J¼10.3 Hz, 1H), 6.95 (d, J¼10.3 Hz, 1H), 6.80 and 6.65 (s,
1H), 6.56 and 6.54 (s, 1H), 6.32–6.27 (m, 2H), 5.95 and
5.92 (s, 2H), 4.56 and 4.60 (s, 2H), 3.79 and 3.74 (t,
J¼6.1 Hz, 2H), 2.36–2.33 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 185.30, 185.18, 162.60, 161.56, 153.05, 152.46,
147.61, 147.41, 147.06, 147.02, 130.85, 130.75, 129.52,
129.45, 127.24, 127.03, 110.87, 110.18, 109.58, 109.26,
101.73, 101.60, 49.93, 48.50, 48.40, 45.62, 45.30, 40.33,
36.06, 34.23; IR (CHCl3): 1666, 1626, 1506 cm21; HRMS
calcd for C17H15NO4 (Mþ): 297.1001, found: 297.1006.
Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71.
Found: C, 68.41; H, 5.07; N, 4.63.
4.2.7. Oxocrinine (5) from 15a. 10% aqueous solution of
potassium hydroxide (1.5 mL) was added to a solution of
15a (110 mg, 0.30 mmol) in methanol (1.5 mL) at room
temperature. The reaction mixture was stirred for 9 h at
room temperature, and then concentrated in vacuo. The
residue was extracted with chloroform and the organic layer
was dried over anhydrous Na2SO4 and concentrated in
vacuo. Purification of the residue by column chromato-
graphy (silica gel, chloroform/methanol, 10/1) afforded 5
(70.6 mg, 87%) as colorless crystals, accompanied with the
starting material 15a (7.0 mg, 6%). Mp 171–173 8C (ethyl
acetate) (lit.,16a mp 175–178 8C; lit.,16b 170–172 8C). All
the spectral data of 5 was completely coincided with those
in the literature.10,16
4.2.6. N-Formyl-N-30,40-methylenedioxyphenylmethyl-
[2-(4-hydroxyphenyl)]ethylamine
(14b).
Tyramine
(2.2 g, 16.0 mmol) was added to a solution of piperonal
(13) (2.0 g, 13.3 mmol) in methanol (32 mL) and the
mixture was stirred at room temperature for 3 h. Sodium
borohydride (553.4 mg, 14.6 mmol) was added and stirred
for 1 h at room temperature. After the reaction, the mixture
was concentrated in vacuo, and extracted with chloroform.
The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo and treated for further reaction
without purification. The residue was dissolved in ethyl
formate (40 mL) and refluxed for 2 days, and the mixture
was concentrated in vacuo. Purification of the residue by
column chromatography (silica gel, chloroform/methanol,
30/1) afforded 14b (4.3 g, 100%) as colorless crystals; mp
4.2.8. Preparation of oxocrine (5) from 15b. 10% aqueous
solution of potassium hydroxide (1.0 mL) was added to a
solution of 15b (45.5 mg, 0.15 mmol) in methanol (1.5 mL)
at room temperature. The reaction mixture was stirred for
9 h at 60 8C, and then concentrated in vacuo. The residue
was extracted with chloroform and the organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification of the residue by column chromatography
(silica gel, chloroform/methanol, 10/1) afforded 5 (25.3 mg,
61%) as colorless crystals. All the spectral data of 5 was
completely coincided with those in the literature.10,16
1
113–115 8C (n-hexane); H NMR (400 MHz, CDCl3): d
8.21 and 7.80 (s, 1H), 7.01 (d, J¼8.4 Hz, 1H), 6.92 (d,
J¼8.4 Hz, 1H), 6.78–6.71 (m, 4H), 6.63 and 6.61 (s, 2H),
4.46 (s, 1H), 4.15 (s, 1H), 3.43 (t, J¼7.4 Hz, 1H), 3.33 (t,
J¼6.5 Hz, 1H), 2.72 (t, J¼7.0 Hz, 1H), 2.70 (t, J¼6.4 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 163.35, 162.91,
155.34, 154.89, 148.24, 148.05, 147.57, 147.21, 129.90,
129.85, 129.35, 128.80, 121.81, 121.18, 115.73, 115.43,
108.77, 108.41, 108.24, 107.86, 101.28, 101.12, 51.68,
48.58, 45.34, 43.58, 33.71, 32.33; IR (CHCl3): 1665, 1516,
1504 cm21; HRMS calcd for C17H17NO4 (Mþ): 299.1157,
found: 299.1153. Anal. Calcd for C17H17NO4: C, 68.21; H,
5.72; N, 4.68. Found: C, 68.30; H, 5.77; N, 4.71.
4.2.9. Epicrinine (6). Lithium tri-sec-buthylborohydride
(L-Selectridew) (0.37 mL, 1.0 M solution in THF,
0.37 mmol) was added to a solution of 5 (42 mg,
0.16 mmol) in THF (1 mL) at 278 8C, and the reaction
mixture was stirred for 1 day at 278 8C. The reaction was
quenched with saturated aqueous Na2SO4, and the mixture
was extracted with chloroform. The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo.
Purification of the residue by column chromatography
(silica gel, chloroform/methanol, 5/1) afforded epicrinine
(6) (34.6 mg, 82%) as colorless crystals. Mp 232–235 8C
(decomp.) (ethyl acetate) (lit.,16a mp 235–239 8C; lit.,18
234–235 8C). All the spectral data was coincided with those
in the literature.11,17
PIFA oxidation of 14a. Phenyliodine(III) bis(trifluoro-
acetate) (64 mg, 0.15 mmol) in CF3CH2OH (2 mL) was
added to a solution of 14a (50 mg, 0.14 mmol) in CF3CH2-
OH (3 mL) at 240 8C. The reaction mixture was stirred for
20 min at 240 8C, and then concentrated in vacuo.
Purification of the residue by column chromatography
(silica gel, n-hexane/ethyl acetate, 1/1) afforded 15a
(36.9 mg, 74%) as a colorless crystals. All the spectral
data was coincided with those in the literature.6g
PIFA oxidation of 14b. Phenyliodine(III) bis(trifluoro-
acetate) (790.2 mg, 1.8 mmol) in CF3CH2OH (10 mL) was
added to a solution of 14b (0.5 g, 1.7 mmol) in CF3CH2OH
(20 mL) at 0 8C. The reaction mixture was stirred for 30 min
and then concentrated in vacuo. Purification of the residue
by column chromatography (silica gel, chloroform/
methanol, 20/1) afforded 15b (0.45 g, 91%) as colorless
crystals; mp 195–198 8C (ethyl acetate); 1H NMR
4.2.10. N-Formyl-N-30,40-dimethoxyphenylmethyl-[2-(4-
hydroxyphenyl)]ethylamine (17). Tyramine (990.6 mg,
7.22 mmol) was added to a solution of 3,4-dimethoxy-
benzaldehyde (16) (1.0 g, 6.02 mmol) in methanol (12 mL),
and the reaction was stirred for 6 h at room temperature.
Sodium borohydride (250.5 mg, 6.62 mmol) was added to
the mixture, and it was stirred for 4 h at room temperature

4906
S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
and concentrated in vacuo. The residue was extracted with
chloroform and the organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo, and treated for further
reaction without purification. The residue was dissolved in
ethyl formate (30 mL) and refluxed for 1 day, and then
concentrated in vacuo. Crystallization of the residue from
diethyl ether afforded 17 (1.82 g, 96%) as colorless crystals;
mp 95–97 8C (ethyl acetate); 1H NMR (400 MHz, CDCl3):
d 8.23 and 7.81 (s, 1H), 6.99 (d, J¼8.6 Hz, 1H), 6.89 (d,
J¼8.6 Hz, 1H), 6.84–6.61 (m, 5H), 4.50 and 4.20 (s, 2H),
3.869 and 3.866 (s, 3H), 3.84 and 3.83 (s, 3H), 3.45 and 3.34
(t, J¼6.9 Hz, 2H), 2.71 and 2.70 (t, J¼7.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 163.39, 163.01, 155.51, 155.13,
149.29, 149.21, 148.90, 149.61, 129.78, 129.69, 129.55,
128.59, 127.86, 120.82, 120.15, 115.68, 115.41, 111.46,
111.18, 110.93, 110.41, 55.88, 55.83, 51.70, 48.69, 45.45,
111.81, 111.42, 60.49, 55.94, 55.92, 50.18, 49.85, 44.55,
43.17, 34.32, 32.41; IR (CHCl3): 1659, 1607, 1578,
1518 cm21, HRMS calcd for C18H19NO4 (Mþ): 313.1314,
found: 313.1318. Anal. Calcd for C18H19NO4: C, 68.99; H,
6.11; N, 4.47. Found: C, 68.71; H, 6.12; N, 4.42.
4.2.12. N-Formyl-2,3-dimethoxy-10-trifluoromethane-
sulfonyloxy-5,6,7,8-tetrahydrodibenz[c,e]azocine (20).
Trifluoromethanesulfonic
anhydride
(0.065 mL,
0.38 mmol) was added to a solution of 19 (50 mg,
0.16 mmol) in pyridine (1 mL) at 0 8C. The reaction mixture
was stirred for 5 h at 0 8C and then continued to stir for
another 3 h at room temperature. The reaction was quenched
with water and the mixture was extracted with ethyl acetate.
The organic layer was washed with 1 M HCl, saturated
NaHCO3, brine, and dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the residue by column
chromatography (silica gel, chloroform/methanol, 10/1)
afforded 20 (44.9 mg, 63%) as colorless crystals,
accompanied with the starting material 19 (17 mg, 34%);
mp 124–125 8C (n-hexane); 1H NMR (400 MHz, CDCl3): d
8.34 and 8.13 (s, 1H), 7.41–7.25 (m, 4H), 6.76 and 6.73 (s,
1H), 5.16 and 5.13 (s, 1H), 3.95 (s, 3H), 3.93 (m, 1H), 3.92
and 3.91 (s, 3H), 3.25 and 3.22 (d, J¼10.8 Hz, 1H), 3.11 and
3.08 (s, 1H), 3.03 and 3.00 (d, J¼6.6 Hz, 1H), 2.45 and 2.41
(dd, J¼11.1, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
162.23, 161.75, 149.56, 149.34, 148.99, 148.41, 147.83,
147.75, 142.61, 142.10, 140.48, 139.73, 131.38, 131.27,
130.87, 130.48, 128.44, 128.29, 122.46, 122.09, 120.90,
120.73, 120.32, 117.13, 113.94, 112.23, 111.64, 111.57,
56.11, 56.07, 56.01, 50.03, 48.88, 44.39, 42.30, 34.83,
32.96; IR (CHCl3): 1665, 1607, 1574, 1518 cm21; HRMS
calcd for C19H18NO4SF3 (Mþ): 445.0807, found: 445.0804.
Anal. Calcd for C19H18NO4SF3: C, 51.23; H, 4.07; N, 3.14.
Found: C, 51.49; H, 4.25; N, 3.12.
43.65, 33.68, 32.33; IR (CHCl3): 1663, 1614, 1595 cm21
;
HRMS calcd for C18H21NO4 (Mþ): 315.1470, found:
315.1465. Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71;
N, 4.44. Found: C, 68.70; H, 6.70; N, 4.59.
PIFA oxidation of 17. Phenyliodine(III) bis(trifluoroacetate)
(1.5 g, 3.49 mmol) in CF3CH2OH (10 mL) was added to a
solution of 17 (1.0 g, 3.17 mmol) in CF3CH2OH (20 mL).
The reaction mixture was stirred for 30 min at room
temperature, and then concentrated in vacuo. Purification
of the residue by column chromatography (silica gel,
chloroform/methanol, 50/1) afforded 18 (912.8 mg, 92%)
1
as colorless crystals; mp 187–189 8C (ethyl acetate); H
NMR (400 MHz, CDCl3): d 8.26 and 8.20 (s, 1H), 7.09 and
6.99 (d, J¼10.2 Hz, 2H), 6.82 and 6.66 (s, 1H), 6.54 and
6.53 (s, 1H), 6.32 and 6.31 (d, J¼10.2 Hz, 2H), 4.12 and
4.65 (s, 2H), 3.891 and 3.885 (s, 3H), 3.82 and 3.77 (t,
J¼6.2 Hz, 2H), 3.734 and 3.731 (s, 3H), 2.38–2.34 (m, 2H);
13C NMR (100 MHz, CDCl3): d 185.40, 185.28, 162.57,
161.53, 153.25, 152.66, 148.30, 148.05, 147.99, 147.97,
129.62, 129.51, 128.10, 127.97, 127.11, 126.89, 113.64,
113.01, 112.62, 112.25, 55.93, 55.91, 55.87, 49.83, 48.39,
48.26, 45.65, 45.15, 40.31, 36.24, 34.38; IR (CHCl3): 1666,
1624, 1609, 1522 cm21; HRMS calcd for C18H19NO4
(Mþ): 313.1314, found: 313.1317. Anal. Calcd for
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 68.71;
H, 6.12; N, 4.60.
4.2.13. N-Formyl-2,3-dimethoxy-5,6,7,8-tetrahydro-
dibenz-[c,e]azocine (21). Palladium acetate (4.3 mg,
0.019 mmol), triphenylphosphine (10.1 mg, 0.039 mmol),
formic acid (0.007 mL, 0.193 mmol) and triethylamine
(0.041 mL, 0.291 mmol) were added to a solution of 20
(43.0 mg, 0.097 mmol) in N,N-dimethylformamide (1 mL),
and then the reaction mixture was stirred for 2 days at 60 8C.
The mixture was concentrated in vacuo and the residue was
extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4 and concentrated
in vacuo. Purification of the residue by column chromato-
graphy (silica gel, chloroform/methanol, 5/1) afforded 21
(25.0 mg, 87%) as colorless crystals; mp 185–187 8C
4.2.11. Dienone–phenol rearrangement of 18. Methane-
sulfonic acid (1.5 mL) was added to 18 (50 mg, 0.16 mmol)
at room temperature, and stirred for 1 day. The mixture was
neutralized with saturated aqueous NaHCO3, and extracted
with ethyl acetate. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification
of the residue by column chromatography (silica gel, ethyl
acetate) afforded 19 (45.9 mg, 92%) as colorless crystals;
mp 229–231 8C (methanol); 1H NMR (400 MHz, CDCl3): d
8.36 and 8.12 (s, 1H), 7.33 (s, 1H), 7.14 and 7.11 (d,
J¼8.2 Hz, 1H), 6.91 and 6.88 (d, J¼2.6 Hz, 1H), 6.83 and
6.80 (d, J¼2.7 Hz, 1H), 6.82 and 6.77 (s, 1H), 6.47 and 6.45
(brs, 1H, OH), 5.11 and 5.07 (s, 1H), 3.93 and 3.89 (s, 3H),
3.88 and 3.86 (s, 3H), 3.84–3.81 (m, 1H), 3.22 and 3.19 (d,
J¼10.9, 1H), 3.22 and 3.18 (s, 1H), 2.91 and 2.88 (d,
J¼6.4 Hz, 1H), 2.35 and 2.32 (d, J¼11.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 162.57, 162.07, 154.73, 148.62,
148.13, 141.36, 140.91, 132.54, 131.11, 130.66, 128.03,
127.87, 116.50, 116.06, 115.47, 115.29, 113.62, 112.38,
1
(methanol); H NMR (400 MHz, CDCl3): d 8.38 and 8.13
(s, 1H), 7.40–7.26 (m, 5H), 6.79 (s, 1H), 5.13 and 5.10 (s,
1H), 3.95 (s, 3H), 3.91–3.86 (m, 1H), 3.90 and 3.89 (s, 3H),
3.26 and 3.22 (d, J¼11.1 Hz, 1) 3.16 and 3.12 (s, 1H), 2.98
and 2.95 (d, J¼6.6 Hz, 1H), 2.44 and 2.40 (dd, J¼11.0,
1.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 162.25,
161.76, 148.81, 148.68, 148.56, 148.08, 140.13, 139.98,
139.68, 139.18, 132.98, 132.54, 129.82, 129.49, 129.40,
128.35, 128.33, 128.18, 128.13, 126.74, 126.60, 113.64,
112.44, 111.87, 111.41, 56.02, 55.95, 55.88, 49.99, 49.29,
44.39, 42.66, 35.25, 33.37; IR (CHCl3): 1661, 1607,
1518 cm21; HRMS calcd for C18H19NO3 (Mþ): 297.1365,
found: 297.1361. Anal. Calcd for C18H19NO3: C, 72.71; H,
6.44; N, 4.71. Found: C, 72.70; H, 6.35; N, 4.74.

S. Kodama et al. / Tetrahedron 60 (2004) 4901–4907
4907
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1
viscous oil; H NMR (400 MHz, CDCl3): d 7.37–7.22 (m,
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