A novel and concise synthesis of spirodienone alkaloids using hypervalent iodine(III) reagents

Article abstract of DOI:10.1248/cpb.52.1231

Intramolecular oxidative coupling reaction of N-protected benzyltetrahydroisoquinoline derivatives using hypervalent iodine(III) reagents was investigated. The use of remarkable combination of phenyliodine bis (trifluoroacetate) (PIFA) and heteropoly acid (HPA) in wet acetonitrile smoothly afforded morphinandienone alkaloids, while neospirinedienone alkaloids were obtained in high yield under anhydrous conditions.

Full text of DOI:10.1248/cpb.52.1231

October 2004
Chem. Pharm. Bull. 52(10) 1231—1234 (2004)
1231
A Novel and Concise Synthesis of Spirodienone Alkaloids Using
Hypervalent Iodine(III) Reagents
Hiromi HAMAMOTO, Yukiko SHIOZAKI, Kayoko HATA, Hirofumi TOHMA, and Yasuyuki KITA*
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan.
Received July 8, 2004; accepted July 29, 2004; published online July 30, 2004
Intramolecular oxidative coupling reaction of N-protected benzyltetrahydroisoquinoline derivatives using
hypervalent iodine(III) reagents was investigated. The use of remarkable combination of phenyliodine bis (triflu-
oroacetate) (PIFA) and heteropoly acid (HPA) in wet acetonitrile smoothly afforded morphinandienone alkaloids,
while neospirinedienone alkaloids were obtained in high yield under anhydrous conditions.
Key words hypervalent iodine reagent; heteropoly acid; spiro compound; C–C coupling; alkaloid
The oxidative coupling reaction of phenol derivatives com- combination of PIFA and HPA in the oxidation of benzylte-
prises a key step in the biosynthesis of various types of spiro- trahydroisoquinoline derivatives.36) In that research, the inhi-
dienone alkaloids.1,2) A great deal of effort to develop bio- bition of the oxidation owing to the influence of their tertiary
genetic-type syntheses using heavy metal oxidizing reagents amine was observed and the extra addition of strong acid
such as mercury(II), thallium(III), vanadium(V), or ruthe- (5 eq) such as, BF3·Et2O, TfOH, or FSO3H with PIFA/HPA
nium(IV) salts, has been devoted.3—8) However, the organic provided successful conversion into morphinandienones.
reaction with heavy metal reagents needs harsh acidic condi- During the research, we found that protection of the amine
tion because of their low solubility in organic solvent and the with trifluoroacetyl group can give another alternative to
yields and selectivity are not always satisfactory. Moreover, introduce the corresponding morphinandienone. It is note-
heavy metal reagents are highly toxic and must be handled worthy that the oxidation proceeds in the presence of
with great care. Over several years, hypervalent iodine(III) PIFA/HPA and the extra addition of strong acid is not neces-
reagents have received much attention due to low toxicity, sary, whereas most other approaches to morphinandienones
ready availability, easy handling, and their reactivities similar require the harsh acidic condition.
to those of heavy metal reagents.9—12) In continuation of our
As our continuing efforts to establish a concise and gen-
research on the use of hypervalent iodine(III) reagents in eral synthesis of morphinandienones, we have described
organic synthesis, the oxidative coupling reaction of phenol herein a full account of our studies on the intramolecular
ether derivatives involving aromatic cation-radical intermedi- oxidative coupling reaction of a variety of N-protected ben-
ates was originally reported by us.13) Recently, we have zyltetrahydroisoquinoline derivatives using hypervalent
developed a new oxidative route to spirodienones by non- iodine(III) reagents.
phenolic coupling reaction on treatment with a combination
of hypervalent iodine(III) reagent, phenyliodine bis (trifluo- Result and Discussion
roacetate) (PIFA) and heteropoly acids (HPAs) which are
readily available, inexpensive, easy to handle, noncorrosive, the N-protected benzyltetrahydroisoquinoline derivatives (1),
nonvolatile, and oldorless solid acids.14,15)
the reactions using PIFA/HPA together with an emphasis on
To explore the feasibility of the oxidative cyclization of
The oxidation of benzyltetrahydroisoquinoline derivatives nitrogen protection2) as illustrated in Table 1 were investi-
is the key reaction in the synthesis of several types of alka- gated. Although N-trifluoroacetyl or pentafluorobenzoyl pro-
loids and has received considerable attention since the first tection caused a favorable cyclization leading to morphinan-
indication of biosynthetic importance of this type of reaction dienones (2) upon treatment with a combination of PIFA and
by Barton and Cohen in 1957.1,2,16) Much of this attention has tungsto(VI) phosphoric acid (H3[PW12O40]) (entries 1, 2), no
been focused on the transformation into morphinandienone- coupling product was obtained from other substrates such as,
type alkaloids.17—25) Although electrochemical investigations N-carbamate, N-formate, or N-borane complex (entries 3—
demonstrated efficient conversion into morphinandienones 5). Unsuitable result exerted by 1c—e may be due to the
via non-phenolic coupling reaction,26—29) the approaches lower oxidation potential of the tertiary amine center of the
using chemical oxidation were unsuccessful in the main and substrates in comparison with the dimethoxydialkylbenzene
did not afford practical routes to morphinandienones.30—35)
Very recently, we examined potentiality of the use of novel
moiety.37)
In the reactions of 1a and 1b, neospirinedienones (3a, b),
Chart 1. Formation of Spirodienones on Treatment with PIFA/HPA
* To whom correspondence should be addressed. e-mail: kita@phsosaka-u.ac.jp
© 2004 Pharmaceutical Society of Japan

1232
Vol. 52, No. 10
Table 1. Oxidative Coupling Reaction of N-Protected Benzyltetrahy-
droisoquinoline Derivatives (1) with PIFA-HPA
Entry Substrate
NX
2 (%)b)
3 (%)b)
1
2
3
4
5
1a
1b
1c
1d
1e
NCOCF3
NCOC6F5
NCHO
NCO2Et
NCH3·BH3
63 (2a)
34 (2b)
NDc)
32 (3a)
28 (3b)
NDc)
NDc)
NDc)
Chart 2. Possible Reaction Formation Mechanism for Neospirinedienones
NDc)
NDc)
a) HPA: ca. 30 mol%. b) Yield of isolated products. c) ND: not detected.
Table 3. Synthesis of Morphinandienones (2) and Neospirinedienones (3)
Table 2. Oxidative Coupling Reaction of Trifluoroacetylnorlaudanosine (1a)
Temp.
(°C)
Time
(h)
2a
3a
Entry Additive
H2O
(%)a) (%)a)
Ent- Sub-
Condi-
tion
2
3
OR1
OR2
X
OR
ORꢀ
ry
1
2
3
4
5
6
7
8
strate
(%)b)
(%)b)
1
2
3
4
5
6
7
8
H3[PW12O40]b)
H3[PW12O40]b)
H3[PW12O40]b)
H3[PW12O40]b)
H3[PMo12O40]b)
H4[SiW12O40]b)
H4[SiMo12O40]b)
H3[PW12O40]b)/
(CF3CO)2Oc)
None
0.5%
2.5%
5%
2.5%
2.5%
2.5%
None
ꢁ20—0
ꢁ20—0
ꢁ20—0
ꢁ20—rt
ꢁ20—0
ꢁ20—0
ꢁ20—0
ꢁ20—0
0.5
0.5
1
2
1
1
1
0.5
63
70
84
57
72
87
54
0
32
24
9
3
5
8
5
90
1a
OMe OMe
OMe OMe
OBn OMe
OMe OBn
OMe OMe
OMe OMe
OBn OMe
OMe OBn
COCF3
COC6F5
COCF3
COCF3
COCF3
COC6F5
COCF3
COCF3
A
A
A
A
B
B
B
B
84 OMe
9
OMe
(3a)
(2a)
1b
1f
67 OMe Trace OMe
(2b)
OBn
(2f)
(3b)
10 OMe
(3a)
62
1g
72 OMe Trace OBn
(2a)
—
(3g)
90 OMe
(3a)
53 OMe
(3b)
73 OMe
(3a)
98
BF3·Et2Od)
None
0.5%
2.5%
ꢁ40—0
ꢁ20—0
0—rt
0.5
1
3
0
39
43
90
51
13
1a
NDc)
NDc)
NDc)
NDc)
9
10 BF3·Et2Od)
11 BF3·Et2Od)
1b
1f
—
—
—
a) Yield of isolated products. b) ca. 30 mol%. c) 4 eq. d) 2 eq.
1g
OBn
(3g)
which would be Erythtrina alkaloid precursors, were
obtained as a side-product.30) In order to achieve the selective
synthesis of 2, cyclization was carried out under various con-
ditions (Table 2). Dominant formation of 2a occurred in the
presence of wet acetonitrile and the better results were
observed in entries 3 and 6. It is noteworthy that the reaction
proceeds under such mild conditions with simple experimen-
tal protocol. On the contrary, exclusive formation of 3a in
high yield was also observed under anhydrous conditions
(entries 8, 9). These results therefore suggest that the pres-
ence of water in the reaction medium plays an important role
in its selectivity.14,15) We also carried out the reaction with
PIFA/BF3·Et2O in wet acetonitrile, but the yield and selectiv-
ity of 2a were decreased relative to the reaction with
PIFA/HPA (entries 10, 11).
a) 25 mg/ml. b) Yield of isolated products. c) ND: not detected.
as shown in Chart 2: route 1, via the proerthrinadienone
intermediate [B] requires loss of the 7-alkyl group and route
2, via the morphinandienone intermediate [A] requires loss
of the 6-alkyl group.31) Giving results in Table 3, isolation of
the spirodienone-type products (2), which should be intro-
duced through nucleophilic addition of H2O to intermediate
[A] demonstrated the justification of route 2 (entries 1—4;
wet condition). Additionally, formation of 3 with the present
substituent (Rꢀ) will also follow this opinion (entries 5—8).
Conclusion
We have shown oxidative coupling reaction of the N-pro-
tected benzyltetrahydroisoquinoline derivatives using hyper-
valent iodine(III) reagents. A concise and efficient synthesis
of morphinandienones has been achieved by the novel use of
remarkable combination of PIFA and HPA. Alternatively,
neospirinedienones have been smoothly synthesized by using
PIFA/BF3·Et2O or PIFA/HPA/TFAA. The simplicity of the
Next, we investigated the oxidative cyclization of some
other substrates (1) (Table 3). Similarly, treatment with
PIFA/HPA in wet acetonitrile afforded morphinandienone-
type products (2), while PIFA/BF3·Et2O in dry acetonitrile
produced neospirinedienone-type products (3).
As for formation of 3, two plausible routes are envisaged

October 2004
1233
123.2, 126.7, 128.6, 148.7, 149.0, 151.9 156.6, 180.1. (minor) d: 37.0, 38.7,
41.0, 42.1, 52.0, 55.3, 55.9, 56.3, 108.7, 110.5, 117.6, 122.7, 126.4, 128.6,
148.7, 149.0, 151.8 156.3, 180.1. EI-HR-MS m/z: 423.1292 (Calcd for
C21H20F3NO5: 423.1293). EI-MS m/z (%): 423.2 (100) [Mꢃ].
reaction protocol and the high yielding conversion in mild re-
action systems may find much advantage for the application
to the synthesis of other spirodienone alkaloids derivatives.
Further studies along these lines are now in progress.
6-Pentafruorobenzoylnorsebiferine (2b) Colorless solid; mp 125—
1
126 °C. IR (KBr) cmꢁ1: 1651, 1624. H-NMR (CDCl3) d: 1.80—2.04 (2H,
Experimental
m), 2.83—3.35 (3H, m), 3.80, 3.82 (total 3H, each s), 3.86, 3.88 (total 3H,
each s), 3.89, 3.91 (total 3H, each s), 3.47, 4.67 (total 1H, each dd, Jꢂ18.0,
5.1, 14.1, 5.7 Hz), 4.48, 5.81 (total 1H, each d, Jꢂ5.1, 5.7 Hz), 6.16, 6.34
(total 1H, each s), 6.39, 6.47 (total 1H, each s), 6.61, 6.66 (total 1H, each s),
6.83, 6.86 (total 1H, each s). 13C-NMR (CDCl3) (major) d: 36.3, 38.5, 41.1,
42.3, 51.2, 55.2, 55.9, 56.3, 108.7, 110.8, 117.4, 123.0, 127.0, 128.5, 148.6,
148.9, 151.9 157.1, 180.2. (minor) d: 36.6, 38.8, 41.4, 42.5, 51.2, 55.2, 55.9,
56.3, 108.6, 110.5, 117.7, 122.1, 126.2, 128.5, 148.6, 148.9, 151.7 156.8,
180.1. EI-HR-MS m/z: 521.1261 (Calcd for C26H20F5NO5: 521.1261). EI-
MS m/z (%): 521.0 (100) [Mꢃ].
All melting points are uncorrected. 1H- and 13C-NMR spectra were
recorded at 300 and 75 MHz, respectively. All NMR spectra were recorded
in CDCl3 with either TMS or residual CHCl3 as the internal standard. In-
frared (IR) absorption spectra (cmꢁ1) were recorded as KBr pellets. Alu-
minium oxide 60 (basic, Merck) and silica gel 60N (Kanto Chemical Com-
pany) were used for column chromatography. The organic layer was dried
with anhydrous MgSO4 or Na2SO4. PIFA is commercially available.
H3[PW12O40] and H3[PMo12O40] were a Kanto Chemical Company product.
H4[SiW12O40] were purchased from Aldrich. H4[SiMo12O40] was purchased
from Wako Pure Chemical Industries. 1a—g were prepared by known meth-
ods.27)
3-Benzyloxy-6,7-dimethoxy-11-trifluoroacetyl-9,10-dihydro-4a,10-
propanephenanthren-2-one (2f) Colorless solid; mp 214—215 °C. IR
1
(KBr) cmꢁ1: 1682, 1651. H-NMR (CDCl3) d: 1.71—2.03 (2H, m), 2.84—
N-Trifluoroacetyl-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-6,7-
dimethoxyisoquinoline (1a)28) Colorless solid; mp 136—137 °C; IR
3.24 (3H, m), 3.27, 4.41 (total 1H, each dd, Jꢂ18.3, 5.4, 14.1, 4.8 Hz), 3.66,
3.67 (total 3H, each s), 3.83, 3.84 (total 3H, each s), 4.97, 4.98, 5.23 (total
2H, each d, s, d, Jꢂ13.2, 13.2 Hz), 4.96, 5.56 (total 1H, each d, Jꢂ4.8,
5.4 Hz), 6.37 (1H, s), 6.40 (1H, s), 6.45 (1H, s), 6.58 (1H, s), 7.28—7.40
(5H, m). 13C-NMR (CDCl3) (major) d: 37.8, 39.4, 41.5, 42.3, 51.9, 55.9
(2C), 70.1, 108.3, 110.5, 120.4, 123.3, 126.5, 126.7 (2C), 126.7, 128.1,
128.8 (2C), 135.9, 148.5, 148.7, 150.5 156.3, 180.2. (minor) d: 36.8, 38.6,
40.9, 42.2, 51.9, 56.2 (2C), 70.1, 108.2, 110.2, 120.6, 122.9, 126.2, 126.7
(2C), 128.1, 128.4, 128.8 (2C), 135.9, 148.6, 148.8, 150.5 155.9, 180.2; EI-
HR-MS m/z: 499.1619 (Calcd for C27H24F3NO5: 499.1606). EI-MS m/z (%):
499.1 (100) [Mꢃ].
1
(KBr) cmꢁ1: 1688. H-NMR (CDCl3) d: 2.61—2.67 (1 H, m), 2.82—3.24
(4H, m), 3.32—3.48 (1H, m), 3.69 (3H, s), 3.78 (3H, s), 3.85, 3.86 (total 6H,
each s), 5.57 (1H, t, Jꢂ6.3 Hz), 5.94, 6.31 (total 1H, each s), 6.54—6.61
(3H, m), 6.74, 6.79 (total 1H, each d, Jꢂ8.1 Hz). 13C-NMR (CDCl3) d: 28.5,
40.5, 41.3, 55.4, 55.7, 55.8, 55.8, 55.9, 110.2, 110.9 (2C), 112.6, 116.5
(Jꢂ287 Hz), 121.9, 125.0, 126.5, 129.3, 147.4, 147.9, 148.0, 148.7, 155.8
(Jꢂ35 Hz). Anal. Calcd for C22H24F3NO5: C, 60.13; H, 5.51; N, 3.19. Found:
C, 60.21; H, 5.54; N, 3.23.
N-Pentafluorobenzoyl-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-6,7-
dimethoxyisoquinoline (1b) Colorless solid; mp 182—183 °C. IR (KBr)
cmꢁ1: 1651. 1H-NMR (CDCl3) d: 2.44—2.52 (1H, m), 2.70—3.30 (4H, m),
3.34—3.42 (1H, m), 3.73 (3H, s), 3.75 (3H, s), 3.84 (3H, s), 3.85 (3H, s),
5.82 (1H, t, Jꢂ6.3 Hz), 6.27, 6.48 (total 1H, each s), 6.59—6.64 (3H, m),
6.74 (1H, d, Jꢂ8.7 Hz). 13C-NMR (CDCl3) d: 28.6, 41.5, 42.3, 54.5, 55.6,
55.8 (2C), 60.3, 110.2, 110.8, 110.9, 111.4, 112.7, 122.0, 125.2, 126.8,
129.4, 137.7 (Jꢂ252 Hz, 2C), 141.8 (Jꢂ239 Hz), 142.8 (Jꢂ243 Hz, 2C),
147.5, 147.9, 148.0, 148.6, 157.3. Anal. Calcd for C27H24F5NO5: C, 60.34;
H, 4.50; N, 2.61. Found: C, 60.39; H, 4.53; N, 2.65.
N-Trifluoroacetyl-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-6–ben-
zyloxy-7-methoxyisoquinoline (1f)38) Colorless solid; mp 142—143°C.
IR (KBr) cmꢁ1: 1682. 1H-NMR (CDCl3) d: 2.54—2.61 (1H, m), 2.76—3.19
(4H, m), 3.35—3.45 (1H, m), 3.71 (3H, s), 3.78 (3H, s), 3.86 (3H, s), 5.11
(2H, s), 5.56 (1H, t, Jꢂ6.3 Hz), 5.98, 6.35 (total 1H, each s), 6.52—6.73
(3H, m), 6.74, 6.80 (total 1H, each d, Jꢂ8.1 Hz), 7.26—7.44 (5H, m). 13C-
NMR (CDCl3) d: 28.4, 40.5, 41.3, 55.4, 55.7, 55.8, 55.9, 71.0, 110.8, 110.9,
112.6, 113.6, 121.9, 125.0, 127.1, 127.2 (2C), 127.9, 128.6 (2C), 129.3,
136.8, 147.2, 147.9, 148.1, 148.7, 155.8 (Jꢂ36 Hz). Anal. Calcd for
C28H28F3NO5: C, 65.23; H, 5.47; N, 2.72. Found: C, 64.86; H, 5.58; N, 2.69.
N-Trifluoroacetyl-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-7-ben-
zyloxy-6-methoxyisoquinoline (1g)8) Colorless solid; mp 164—165 °C
(lit.8) 159.5—160 °C). IR (KBr) cmꢁ1: 1688. 1H-NMR (CDCl3) d: 2.46—
2.67 (1H, m), 2.78—3.17 (4H, m), 3.26—3.34 (1H, m), 3.75 (3H, s), 3.84
(3H, s), 3.86 (3H, s), 4.92 (1H, d, Jꢂ12.3 Hz), 5.00 (1H, d, Jꢂ12.3 Hz), 5.47
(1H, t, Jꢂ5.9 Hz), 6.04, 6.36 (total 1H, each s), 6.47—6.63 (3H, m), 6.72,
6.78 (total 1H, each d, Jꢂ8.1 Hz), 7.29—7.36 (5H, m). 13C-NMR (CDCl3)
d: 28.4, 40.5, 40.5, 55.2, 55.6, 55.7, 55.9, 70.9, 110.9, 111.4, 112.6, 113.1,
121.8, 125.6, 126.3, 127.0 (2C), 127.8, 128.4 (2C), 129.2, 136.7, 146.4,
147.9, 148.7 (2C), 155.7 (Jꢂ35 Hz). Anal. Calcd for C28H28F3NO5: C,
65.23; H, 5.47; N, 2.72. Found: C, 65.21; H, 5.43; N, 2.71.
General Coupling Procedure Leading to Neospirinedienone Deriva-
tives (3) by Treatment with PIFA/BF3·Et2O (Condition B) To a stirred
solution of 1 (0.10 mmol) in CH3CN (4.0 ml) was added PIFA (43.0 mg,
0.10 mmol) and BF3·Et2O (25 ml, 0.2 mmol) at ꢁ20 °C. Stirring was contin-
ued for 30 min at ꢁ20 to 0 °C. The solution was diluted with AcOEt and
then quenched with aq. NaHCO3 (sat.). The mixture was extracted with
AcOEt and washed with brine. The organic extract was concentrated and
the residue was purified by column chromatography on silica gel
(hexane/EtOAc/Et3N, 10 : 15 : 0.5) to afford the neospirinedienone deriva-
tives (3).
Coupling Procedure Leading to N-Trifluoroacetyl Neospirinedioenone
(3a) by Treatment with PIFA/HPA/(CF3CO)2O To a stirred solution of
1a (43.9 mg, 0.10 mmol) in 1.0% -(CF3CO)2O/CH3CN (4.0 ml) was added
HPA (100 mg) and PIFA (43.0 mg, 0.10 mmol) at ꢁ20°C. Stirring was con-
tinued for 30 min at ꢁ20 to 0 °C. The solution was diluted with AcOEt and
then quenched with aq. NaHCO3 (sat.). The mixture was extracted with
AcOEt and washed with brine. The organic extract was concentrated and the
residue was purified by column chromatography on silica gel (hexane/
EtOAc/Et3N, 10 : 15 : 0.5) to afford the N-trifluoroacetyl neospirinedioenone
(3a, 38.2 mg, 90%).
N-Trifluoroacetyl Neospirinedioenone (3a)28,39) Colorless solid; mp
250—251 °C (lit.39) 247—248 °C). IR (KBr) cmꢁ1: 1693, 1639. 1H-NMR
(CDCl3) d: 1.94—2.34 (4H, m), 2.87, 3.10 (total 1H, each dd, Jꢂ18.3, 6.3,
17.4, 3.0 Hz), 3.21, 3.47 (total 1H, each dd, Jꢂ17.4, 7.2, 18.3, 9.3 Hz), 3.68,
3.73 (total 3H, each s), 3.91 (6H, s), 4.49, 4.64 (total 1H, each dd, Jꢂ9.3,
6.3, 7.2, 3.0 Hz), 5.69, 5.83 (total 1H, each s), 6.60 (1H, s), 6.65, 6.76 (total
1H, each s), 6.98, 7.07 (total 1H, each s). 13C-NMR (CDCl3) (major)
d: 31.7, 41.2, 45.1, 47.4, 55.2, 56.1 (2C), 60.6, 108.0, 111.1, 116.4, 116.2
(Jꢂ287 Hz), 123.7, 125.2, 127.4, 148.7, 151.3, 151.8, 155.9 (Jꢂ37 Hz),
General Coupling Procedure Leading to Morphinandienone Deriva- 156.8, 180.8. (minor) d: 33.3, 36.2, 45.0, 48.1, 55.2, 56.0 (2C), 60.7, 107.4,
tives (2) by Treatment with PIFA/HPA (Condition A) To a stirred solu-
tion of 1 (0.10 mmol) in 2.5%-H2O/CH3CN (4.0 ml) was added HPA
(100 mg) and PIFA (43.0 mg, 0.10 mmol) at ꢁ20 °C. Stirring was continued
for 60 min at ꢁ20 to 0 °C. The solution was dilute with AcOEt and filtered
through a pad of alumina. The filtrate was concentrated and the residue was
110.5, 114.4, 116.1 (Jꢂ287 Hz), 122.6, 123.9, 127.0, 148.7, 151.8, 152.1,
154.4, 155.7 (Jꢂ37 Hz), 180.7. EI-HR-MS m/z: 423.1294 (Calcd for
C21H20F3NO5: 423.1293). EI-MS m/z (%): 423.2 (100) [Mꢃ]. Anal. Calcd for
C21H20F3NO5: C, 59.57; H, 4.76; N, 3.31. Found: C, 59.34; H, 4.79; N, 3.32.
3,10,11-Trimethoxy-7-pentafluorobenzoyl-6,7,7a,8-tetrahydro-5H-
purified by column chromatography on silica gel (hexane/EtOAc/Et3N, bibenzo-[d,f]indol-2-one (3b) Colorless solid; mp 290—292 °C. IR (KBr)
10 : 15 : 0.5) to morphinandienone derivatives (2).
cmꢁ1: 1633, 1589. 1H-NMR (CDCl3) d: 2.08—2.39 (4H, m), 2.88, 2.99
(total 1H, each dd, Jꢂ18.1, 6.5, 17.6, 3.2 Hz), 3.22, 3.48 (total 1H, each dd,
6-Trifluoroacetylnorsebiferine (2a)5,25,28) Colorless solid; mp 182—
183 °C (lit.25) 203—204 °C; lit.5) 179.4—181.5 °C). IR (KBr) cmꢁ1: 1678, Jꢂ17.6, 7.6, 18.1, 9.5 Hz), 3.69, 3.74 (total 3H, each s), 3.96 (6H, s), 4.49,
1
1649. H-NMR (CDCl3) d: 1.79—2.09 (2H, m), 2.89—3.29 (3H, m), 3.44,
4.64 (total 1H, each dd, Jꢂ9.5, 6.5, 7.6, 3.2 Hz), 5.68, 5.82 (total 1H, each s),
4.45 (total 1H, each dd, Jꢂ18.3, 5.7, 14.1, 5.4 Hz), 3.81 (3H, s), 3.86 (3H, 6.60 (1H, s), 6.66, 6.77 (total 1H, each s), 6.98, 7.07 (total 1H, each s). 13C-
s), 3.90 (3H, s), 4.99, 5.60 (total 1H, each d, Jꢂ5.4, 5.7 Hz), 6.36, 6.37 (total
NMR (CDCl3) (major) d: 32.0, 40.6, 46.2, 48.6, 55.3, 56.1 (2C), 59.5,
1H, each s), 6.41 (1H, s), 6.62 (1H, s), 6.84 (1H, s). 13C-NMR (CDCl3) 107.7, 111.1, 116.8, 123.4, 125.3, 127.9, 148.6, 151.3, 151.7, 157.0 180.9.
(major) d: 37.9, 39.5, 41.6, 42.2, 52.0, 55.2, 55.9, 56.4, 108.7, 110.8, 117.4, (minor) d: 33.0, 37.5, 45.6, 47.5, 55.1, 56.0 (2C), 61.8, 107.4, 110.5, 114.7,

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Vol. 52, No. 10
122.8, 123.9, 126.5, 148.7, 151.7, 152.1, 154.6 180.7. EI-HR-MS m/z: 14) Hamamoto H., Anilkmar G., Tohma H., Kita Y., Chem. Eur. J., 8,
521.1259 (Calcd for C26H20F5NO5: 521.1261).
5377—5383 (2002).
3-Benzyloxy-10,11-dimethoxy-7-trifluoroacetyl-6,7,7a,8-tetrahydro-
5H-bibenzo[d,f]indol-2-one (3g) Colorless solid; mp 190—191 °C. IR
15) For recent review on heteropoly acids, see: Kozhevnikov I. V., Chem.
Rev., 98, 171—198 (1998).
(KBr) cmꢁ1: 1692, 1659. 1H-NMR (CDCl3) d: 1.78—2.30 (4H, m), 2.82, 16) Kametani T., Fukumoto K., Synthesis, 1972, 657—674 (1972).
2.90 (total 1H, each dd, Jꢂ18.3, 6.6, 17.7, 3.6 Hz), 3.26, 3.42 (total 1H, each
dd, Jꢂ17.7, 7.8, 18.3, 8.7 Hz), 3.89 (3H, s), 3.90 (3H, s), 4.37, 4.53 (total
17) Stuart K. L., Chem. Rev., 71, 47—72 (1971).
18) Kametani T., Fukumoto K., J. Heterocycl. Chem., 8, 341—357 (1971).
1H, each dd, Jꢂ8.7, 6.6, 7.8, 3.6 Hz), 4.96, 4.97, 5.10 (total 2H, each d, s, 19) Kametani T., Fukumoto K., Acc. Chem. Res., 5, 212—219 (1972).
d, Jꢂ12.6, 12.6 Hz), 5.73, 5.83 (total 1H, each s), 6.58, 6.64 (total 1H, each 20) Kametani T., Fukumoto K., Synthesis, 1972, 657—674 (1972).
s), 6.62, 6.77 (total 1H, each s), 6.99, 7.07 (total 1H, each s), 7.27—7.41 21) Blaskó G., Cordell G. A., Heterocycles, 27, 1269—1300 (1988).
(5H, m). 13C-NMR (CDCl3) (major) d: 31.5, 40.8, 44.7, 47.0, 55.9, 56.0,
60.2, 70.0, 107.7, 110.8, 119.3, 123.7, 124.5, 127.2, 127.3 (2C), 128.1,
128.6 (2C), 135.7, 148.5, 149.7, 151.7, 155.8, 180.7. (minor) d: 33.1, 36.1,
44.6, 47.9, 55.8, 55.9, 60.3, 70.1, 107.2, 110.4, 117.5, 122.3, 123.8, 126.9,
22) Kametani T., Fukumoto K., Satoh F., Bioorg. Chem., 3, 430—497
(1974).
23) Franck B., Dunkelman G., Lubs H. J., Angew. Chem., Int. Ed., 6,
1075—1076 (1967).
127.2 (2C), 127.3, 128.7 (2C), 135.7, 148.6, 150.3, 152.0, 153.8, 180.7. EI- 24) Blaskó G., Dörnyel G., Bárczai-Bake M., Péchy P., Szántay C., J. Org.
HR-MS m/z: 499.1610 (Calcd for C27H24F3NO5: 499.1606). EI-MS m/z (%):
Chem., 49, 1439—1441 (1984).
25) Hara H., Komoriya S., Miyashita T., Hoshino O., Tetrahedron Asym-
metry, 6, 1683—1692 (1995).
499.3 (77.0) [Mꢃ], 91.1 (100).
Acknowledgement This work was supported by a Grant-in-Aid for Sci-
entific Research (S) (No.7690) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
26) Miller L. L., Stermitz F. R., Falck J. R., J. Am. Chem. Soc., 93, 5941—
5942 (1971).
27) Miller L. L., Stermitz F. R., Falck J. R., J. Am. Chem. Soc., 95, 2651—
2656 (1973).
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