An oxidative intramolecular phenolic coupling reaction for the synthesis of amaryllidaceae alkaloids using a hypervalent iodine(III) reagent

Article abstract of DOI:10.1021/jo9606766

The oxidative intramolecular phenolic coupling reaction of norbelladine derivatives (1) was investigated with the aim of preparing amaryllidaceae alkaloids. Spirodienone compounds (2), which are intermediates for the synthesis of an amaryllidaceae alkaloid, (+)-maritidine, or phenol ether derivatives containing the 5,6,7,8-tetrahydrobenzazocine systems (9), were selectively obtained by the reaction of 1 and the hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA). Both p-p′ coupling (11) and p-o′ coupling spirodienone compounds (12) were obtained by the reaction of phenol derivatives having an alkoxy group at the C-3′ position (10) with PIFA.

Full text of DOI:10.1021/jo9606766

J . Org. Chem. 1996, 61, 5857-5864
5857
An Oxid a tive In tr a m olecu la r P h en olic Cou p lin g Rea ction for th e
Syn th esis of Am a r yllid a cea e Alk a loid s Usin g a Hyp er va len t
Iod in e(III) Rea gen t
Yasuyuki Kita,*,† Takeshi Takada,† Michiyo Gyoten,† Hirofumi Tohma,†
Meinhart H. Zenk,*,‡ and J o¨rg Eichhorn‡
Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565, J apan, and
Lehrstuhl fu¨r Pharmazeutische Biologie, Universita¨t Mu¨nchen, Karlstrasse 29 80333 Mu¨nchen, Germany
Received April 12, 1996X
The oxidative intramolecular phenolic coupling reaction of norbelladine derivatives (1) was
investigated with the aim of preparing amaryllidaceae alkaloids. Spirodienone compounds (2),
which are intermediates for the synthesis of an amaryllidaceae alkaloid, (+)-maritidine, or phenol
ether derivatives containing the 5,6,7,8-tetrahydrobenzazocine systems (9), were selectively obtained
by the reaction of 1 and the hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate)
(PIFA). Both p-p′ coupling (11) and p-o′ coupling spirodienone compounds (12) were obtained by
the reaction of phenol derivatives having an alkoxy group at the C-3′ position (10) with PIFA.
In tr od u ction
(CF3CH2OH) and 1,1,1,3,3,3-hexafluoro-2-propanol ((CF3)2-
CHOH), and found efficient phenolic oxidative reactions,7
which lead to the convenient synthesis of azacarbocyclic
spirodienones from phenol derivatives7a including to the
total synthesis7b of the antitumor marine natural product,
discorhabdin C (Scheme 1).8
The oxidative phenolic coupling reaction comprises a
key step in the biosynthesis of a wide variety of natural
products such as morphine or Amaryllidaceae alkaloids.1
In 1957, Barton and Cohen suggested that the phenolic
oxidation of diphenolic benzyltetrahydroisoquinoline pre-
cursors may generate the bond between the aporphine
rings A and D, and this proposal has been amply
supported by the results of numerous subsequent bio-
synthetic and synthetic studies.2 Since that time, a
number of biogenetic-type phenolic coupling reactions for
the synthesis of Amaryllidaceae alkaloids using heavy
metal oxidizing reagents (such as Tl(III)3 or V(V)4 salts)
have been investigated. However, lack of regiocontrol
during the cyclization and low yields of the coupling
products have remained problematic. Moreover, Tl(III)
or V(V) salts are highly toxic and must be handled very
carefully. To solve these problems, oxidative phenolic
coupling reactions using hypervalent iodine(III) reagents,
which are safe and useful synthetic reagents,5 were
examined. Several phenolic coupling reactions using
iodine(III) reagents have been reported,6 but most of
these reactions were only applicable to a limited sub-
strate, and the obtained yields were generally low.
For the last decade, we have examined the oxidative
reactions of phenol derivatives using hypervalent iodine
reagents, phenyliodine(III) diacetate (PIDA) and phen-
yliodine(III) bis(trifluoroacetate) (PIFA), in poorly nu-
cleophilic polar solvents such as 2,2,2-trifluoroethanol
We now report a novel and useful oxidative phenolic
coupling reaction using the hypervalent iodine(III) re-
agent, PIFA. Treatment of norbelladine derivatives (1)
and PIFA in (CF3)2CHOH or CF3CH2OH caused a phe-
nolic coupling reaction to give the spirodienone compound
(2), which is the intermediate for the synthesis of
Amaryllidaceae alkaloids (Scheme 2).9
Resu lts a n d Discu ssion
Norbelladine derivatives 1 were readily prepared by a
modification of the reported methods.4a Treatment of
(5) For reviews, see: (a) Banks, D. F. Chem. Rev. 1966, 66, 243. (b)
Varvoglis, A. Chem. Soc. Rev. 1981, 10, 377. (c) Koser, G. F. Hyper-
valent Halogen Compounds. In The Chemistry of Functional Groups;
Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, U.K., 1983; Supple-
ment D, Chapter 18, p 721. (d) Varvoglis, A. Synthesis 1984, 709. (e)
Moriarty, R. M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244. (f) Ochiai,
M.; Nagao, Y. Yuki Gosei Kagaku Kyokaishi 1986, 44, 660. (g) Moriarty,
R. M.; Valid, R. K.; Koser, G. F. Synlett 1990, 365. (h) Varvoglis, A.
The Organic Chemistry of Polycoordinated Iodine; VCH Publishers,
Inc.: New York, 1992. (i) Kita, Y.; Tohma, H.; Yakura, T. Trends Org.
Chem. 1992, 3, 113. (j) Kita, Y.; Tohma, H. Farumasia 1992, 28, 984.
(k) Stang, P. J . Angew. Chem., Int. Ed. Engl. 1992, 31, 274.
(6) (a) Sza´ntay, C.; Blasko´, G.; Ba´rczai-Beke, M.; Pe´chy, P.; Do¨rnyei,
G. Tetrahedron Lett. 1980, 21, 3509. (b) White, J . D.; Chong, W. K.
M.; Thirring, K. J . Org. Chem. 1983, 48, 2302. (c) White, J . D.;
Caravatti, G.; Kline, T. B.; Edstrom, E. Tetrahedron 1983, 39, 2393.
(d) Krihna, K. V. R.; Sujatha, K.; Kapil, R. S. Tetrahedron Lett. 1990,
31, 1351. (e) Pelter, A.; Ward, R. S.; Abd-El-Ghani, A. J . Chem. Soc.,
Perkin Trans. 1 1992, 2249. (f) Ward, R. S.; Pelter, A.; Abd-El-Ghani,
A. Tetrahedron 1996, 52, 1303.
† Osaka University.
‡ Universita¨t Mu¨nchen.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Dhingra, O. P. In Oxidation in Organic Chemistry; Trahanovsky,
W. S., Ed.; Academic Press: New York, 1982; Part D, p 207.
(2) (a) Barton, D. H. R.; Cohen, T. Festschrift A. Stoll; Birkhauser:
Basel, 1957. (b) Wildman, W. C.; Fales, H. M.; Battersby, A. R. J . Am.
Chem. Soc. 1962, 84, 681. (c) Barton, D. H. R.; Kinby, G. W.; Taylor,
J . B.; Thomas, T. S. J . Chem. Soc. C 1963, 4545. (d) Paton, J . M.;
Pauson, P. L.; Stevens, T. S. J . Chem. Soc. C 1969, 1309.
(3) (a) Schwartz, M. A.; Rose B. F.; Vishnuvajjala, B. J . Am. Chem.
Soc. 1973, 95, 612. (b) Tomioka, K.; Koga, K.; Yamada, S. Chem.
Pharm. Bull. 1977, 25, 2681. (c) Shimizu, K.; Tomioka, K.; Yamada,
S.; Koga, K. Chem. Pharm. Bull. 1978, 26, 3765.
(7) (a) Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y.
Tetrahedron Lett. 1989, 30, 1119. (b) Kita, Y.; Tohma, H.; Inagaki, M.;
Hatanaka, K.; Kikuchi, K.; Yakura, T. Ibid. 1991, 32, 2035. (c) Kita,
Y.; Okunaka, R.; Kondo, M.; Tohma, H.; Inagaki, M.; Hatanaka, K. J .
Chem. Soc., Chem. Commun. 1992, 429. (d) Kita, Y.; Tohma, H.;
Inagaki, M.; Hatanaka, K.; Yakura, T. J . Am. Chem. Soc. 1992, 114,
2175. (e) Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.;
Fujita, S.; Tohma, H. J . Org. Chem. 1996, 61, 223.
(8) (a) Perry, N. B.; Blunt, J . W.; McCombs, J . D.; Munro, M. H. G.
J . Org. Chem. 1986, 51, 5476. (b) Blunt, J . W.; Calder, V. L.; Fenwick,
G. D.; Lake, R. J .; McCombs, J . D.; Munro, M. H. G.; Perry, N. B. J .
Nat. Prod. 1987, 59, 290. (c) Perry, N. B.; Blunt, J . W.; Munro, M. H.
G.; Higa, T.; Sakai, R. J . Org. Chem. 1988, 53, 4127. (d) Perry, N. B.;
Blunt, J . W.; Munro, M. G. H. Tetrahedron 1988, 44, 1727.
(4) (a) Schwartz, M. A.; Holton, R. A. J . Am. Chem. Soc. 1970, 92,
1090. (b) Schwartz, M. A.; Rose, B. F.; Holton, R. A.; Scott, S. W.;
Vishnuvajjala, B. J . Am. Chem. Soc. 1977, 99, 2571. (c) Kupchan, S.
M.; Dhingra, O. P.; Kim, C.-K. J . Org. Chem. 1978, 43, 4976.
(9) Martin, S. F. In Alkaloids; Brossi, A., Ed.; Academic Press, Inc.:
New York, 1987; Vol. 30, p 251.
S0022-3263(96)00676-7 CCC: $12.00 © 1996 American Chemical Society

5858 J . Org. Chem., Vol. 61, No. 17, 1996
Kita et al.
Ta ble 2. P h en olic Cou p lin g Rea ction of 1 P r otected a s
a n Am id e or a Ca r ba m a te
Sch em e 1
entry
R
product
yield (%)
1
2
3
4
5
6
7
COCF3
CO2tBu
TEOC
CO2Et
COC6F5
CH3
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
61
49
54
48
50
H
1g
2g
Sch em e 2
Sch em e 3
Ta ble 1. P h en olic Cou p lin g Rea ction of 1a in Va r iou s
Solven ts
Sch em e 4
3′,4′-dimethyl-N-(trifluoroacetyl)norbelladine (1a ) and
PIFA in CF3CH2OH at -40 °C gave an aryl-aryl
coupling product 2a in 61% yield. The reaction of 1a and
PIFA at 25 °C gave 2a in a slightly lower yield (50%).
The reaction proceeds in poorly nucleophilic polar protic
solvents such as (CF3)2CHOH and CF3CH2OH. A reac-
tion in polar nucleophilic solvents such as acetonitrile
(CH3CN) gave a mixture of 2a (50%) and acetamido
derivatives (3). In other solvents, an unsatisfactory
result was obtained (Table 1).
We next investigated the reactivity of the N-protected
norbelladine compounds. Although N-amide or N-car-
bamate protection caused a favorable aryl-aryl coupling
reaction upon treatment with PIFA, no coupling products
were obtained from the N-methylated or unprotected
norbelladine compound (Table 2).
or aqueous hydrogen chloride to give (()-oxomaritidine
(4) and 5, respectively (Scheme 3). In the case of the
norbelladine derivative (6) prepared from the L-tyrosine
methyl ester and isovanilin,3b the intramolecular coupling
reaction proceeded smoothly to give the coupling product
(7), which is known as a key intermediate for (+)-
maritidine (Scheme 4).3b
Furthermore, we investigated the reactivity of norbel-
ladine derivatives having hydroxy groups protected as
an ether or an ester at the C-3′ and C-4′ positions. The
results are summarized in Table 3. The reaction of the
O-silylated derivatives with PIFA afforded the corre-
sponding coupling products in slightly lower yields than
that of the methylated derivatives. Acetylated deriva-
tives also reacted with PIFA to give the coupling prod-
ucts, although the yields were quite low. The reaction
of the substrate having free hydroxy groups, however,
gave no phenolic coupling product.
The amide group of 2a and the carbamate group of 2b
could be cleaved by treatment with potassium carbonate10
(10) Newman, H. J . Org. Chem. 1965, 30, 1287.

Synthesis of Amaryllidaceae Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 5859
Ta ble 3. P h en olic Cou p lin g Rea ction of Nor bella d in e
Der iva tives
Con clu sion s
A novel oxidative phenolic coupling method has been
developed using a hypervalent iodine(III) reagent instead
of a heavy metal oxidizing reagent (Tl(III) or V(V) salt).
This method can be applied to the intramolecular cy-
clization of norbelladine derivatives having various pro-
tecting groups. The nature of the substituents on the
aromatic rings has an important effect on the outcome
of the reaction. In addition, poorly nucleophilic polar
protic solvents such as (CF3)2CHOH or CF3CH2OH are
very suitable for these phenolic coupling reactions.
Further application of the reaction to the synthesis of
other alkaloids is currently in progress.
entry
substrate
R1
Me
R2
Me
product
yield (%)
1
2
3
4
5
6
7
8
9
1a
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
2a
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
61
56
42
42
35
49
32
37
trace
19
trace
trace
-CH2-
TBDMS
TBDMS
Me
PhCH2
Me
Me
CH3CO
H
Me
TBDMS
TBDMS
Me
tBuCO
CH3CO
Me
Exp er im en ta l Section
All melting points are uncorrected. Infrared (IR) absorption
spectra (cm-1) were recorded as a KBr pellet. 1H NMR (and
13C NMR) spectra were recorded in CDCl3, unless otherwise
noted, at 200, 250, 270, or 500 MHz with TMS as an internal
standard. Most of the 1H NMR spectra of amido compounds
exhibited the presence of two rotamers. E. Merck silica gel
60 for column chromatography and E. Merck precoated TLC
plates, silica gel F254, for preparative thin layer chromatogra-
phy were used. Organic layers were dried with anhydrous
MgSO4 or Na2SO4. PIFA is commercially available. CF3CH2-
OH and (CF3)2CHOH were obtained from commercial suppliers
and were used without further purification. Compounds
(1a ,g,h ,p , and 6) were prepared by known methods.
10
11
12
Me
H
H
Me
H
The oxidative cyclization of substrates having a hy-
droxy group protected as an ether at the C-4 position was
also investigated. The reaction of the silyloxy derivatives
with PIFA gave 2a in good yield. Treatment of benzyloxy
(8d ) or methoxy derivatives (8e) with PIFA in CF3CH2-
OH, on the other hand, selectively afforded the coupling
product (9d or 9e) containing the 5,6,7,8-tetrahydrobenz-
azocine system. These results are summarized in Table
4.
ter t-Bu tyl 1-(3,4-Dim eth oxyp h en yl)-4-(4-h yd r oxyp h en -
yl)-2-a za bu ta n e-2-ca r boxyla te (1b). Di-tert-butyl dicarbon-
ate (1.53 g, 7.00 mmol) was added to a suspension of 1g (1.83
g, 6.36 mmol) and sodium carbonate (674 mg, 6.36 mmol) in
H2O (15 mL)-dioxane (15 mL) at 0 °C. After the mixture was
stirred for 1 h, water was added to the reaction mixture. The
mixture was extracted with AcOEt, and the organic layer was
washed with water and brine and concentrated in vacuo. The
residue was purified by chromatography on silica gel (n-
hexane-AcOEt ) 2:1) to give 1b (2.42 g, 98%) as a colorless
Finally, we investigated the oxidative cyclization of the
substrates having a methoxy or silyloxy group at the C-3′
position (10). Treatment of 10a (R ) Me) with PIFA in
CF3CH2OH afforded both p-p′ coupling (11a ) and p-o′
coupling products (12a ). In the reaction of 10a in CH3-
CN, the formation ratio of 12a /11a had increased al-
though the overall yield of the coupling products had
decreased (Table 5). 10b (R ) TBDMS) was also con-
verted to the coupling products (11b, 12b), which could
not be separated by chromatography. Treatment of the
mixture (11b, 12b) with n-tetrabutylammonium fluoride
in THF gave 11c (R ) H) and a narwedine11 derivative
(13), respectively, in good yield (95%) (Scheme 5).
1
oil: IR 3350, 1690, 1670; H NMR (500 MHz, CDCl3) δ 1.48
(s, 9H), 2.67, 2.72 (brs, 2H), 2.28, 3.37 (brs, 2H), 3.84 (s, 3H),
3.86 (s, 3H), 4.30 (brs, 2H), 4.98 (s, 1H), 6.73-6.80 (m, 5H),
6.97 (brs, 2H); HRMS calcd for C22H29NO5 (M+) 387.2046,
found 387.2070.
2-(Tr im eth ylsilyl)eth yl 1-(3,4-Dim eth oxyp h en yl)-4-(4-
h yd r oxyp h en yl)-2-a za bu ta n e-2-ca r boxyla te (1c). 2-(Tri-
methylsilyl)ethyl 4-nitrophenyl carbonate (242 mg, 0.857
mmol) was added to a solution of 1g (223.8 mg, 0.779 mmol)
and sodium bicarbonate (72.0 mg, 0.857 mmol) in H2O (2 mL)-
dioxane (5 mL) at rt. After the reaction mixture was stirred
for 12 h, water was added. The mixture was extracted with
AcOEt, and the extracts were washed with saturated NaHCO3
solution, water, and brine and then concentrated in vacuo. The
residue was purified by chromatography on silica gel (n-
hexane-Et2O ) 1:1) to give 1c (263.7 mg, 78%) as a colorless
solid: mp 95-96 °C (from Et2O-n-hexane): IR 3350, 2836,
1671; 1H NMR (270 MHz, CDCl3) δ 0.04 (s, 9H), 1.02 (t, 2H, J
) 8.6 Hz), 2.69 (brs, 2H), 3.34 (brs, 2H), 3.84 (s, 3H), 3.86 (s,
3H), 4.22 (brs, 2H), 4.32 (s, 2H), 5.59 (s, 1H), 6.73-6.82 (m,
5H), 6.98 (d, 2H, J ) 7.6 Hz). Anal. Calcd for C23H33NO5Si:
C, 64.01; H, 7.71; N, 3.25. Found: C, 63.89; H, 7.54; N, 3.29.
Eth yl 1-(3,4-Dim eth oxyp h en yl)-4-(4-h yd r oxyp h en yl)-
2-azabu tan e-2-car boxylate (1d). Ethyl chloroformate (0.499
mL, 5.21 mmol) was added to a suspension of 1g (374 mg, 1.30
mmol) and potassium carbonate (1.08 g, 7.81 mmol) in acetone
(12 mL) at rt. After being stirred for 1.5 h, the reaction
mixture was refluxed for 12 h. Then the mixture was cooled
and evaporated in vacuo. After general workup, the residue
was purified by chromatography on silica gel (n-hexane-
AcOEt ) 2:1) to give N,O-diprotected compounds. A solution
of the compound and NaOH (201 mg, 5.03 mmol) in EtOH (6.4
mL)-H2O (0.5 mL) was stirred at 70 °C for 30 min. After
cooling, the mixture was quenched with saturated NH4Cl
The phenolic intramolecular coupling reaction using
PIFA seems to proceed by either an ionic mechanism7a
(A) or a radical mechanism12 (B), which we reported very
recently for the hypervalent iodine-induced nucleophilic
substitution of para-substituted phenol ethers (Scheme
6). Although details of the mechanism remain unknown,
the reaction of the substrate having a free hydroxy group
(R ) H) with PIFA is explained as follows: The reaction
provides intermediates (A), which may induce a nucleo-
philic intramolecular cyclization. On the other hand, the
reaction of substrates having no free hydroxy group or
highly electron-donating methoxy groups in the aromatic
ring with PIFA gave a cation radical intermediate (B),
which may cause a nucleophilic intramolecular cycliza-
tion. In the case of the 4-methoxy and 4-(benzyloxy)
compounds 8d and 8e, in which the carbon-oxygen ether
bond at the 4-position is stable to cleavage, the reaction
follows pathway b in poorly nucleophilic solvents.
(11) Bazhenova, E. D.; Aliev, Kh. U.; Zakirov, U. B. Farmakol.
Alkaloidov Ikh. Proizvod. 1972, 74; Chem. Abstr. 1974, 80, 103864r.
(12) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh,
S.; Sakurai, H.; Oka, S. J . Am. Chem. Soc. 1994, 116, 3684.

5860 J . Org. Chem., Vol. 61, No. 17, 1996
Kita et al.
Ta ble 4. Rea ction of th e Su bstr a tes w ith a Hyd r oxy Gr ou p P r otected a s a n Eth er a t th e C-4 P osition
entry
substrate
R
solvent
reaction time
2a (%)
9 (%)
1
2
3
4
5
6
7
8
9
1a
8a
8b
8c
8d
8e
8e
8e
8e
H
TMS
TBDMS
TBDPS
PhCH2
Me
CF3CH2OH
5 min
30 min
4.5 h
4 h
24 h
30 min
1 h
61
57
66
23
12
48
47
42
23
(CF3)2CHOH
CH3CN
CH2Cl2
3.5 h
24 h
33
22
(d, 1H, J ) 8.5 Hz); HRMS calcd for C24H20NO4F5 (M+)
481.1311, found 481.1311.
Ta ble 5. Rea ction of Su bstr a tes Bea r in g a Meth oxy or
Silyloxy Gr ou p a t th e C-3′ P osition
N -(3,4-Dim e t h oxyb e n zyl)-4-(h yd r oxyp h e n e t h yl)-N -
-m eth yla m in e (1f). Formaldehyde (37% solution in H2O, 6.3
mL) was added to a solution of 1g (442,0 mg, 1.54 mmol) in
MeOH (20 mL) at rt. After being stirred for 1.5 h, the mixture
was cooled, NaBH4 (1.05 g, 27.7 mmol) was added slowly under
ice bath cooling, and the suspension was stirred at rt for 30
min. Evaporation of the solvent gave a residue, which was
mixed with AcOEt and water. The resulting mixture was
neutralized by addition of concd HCl and extracted with
AcOEt. The extracts were washed with water and brine and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel (AcOEt) to give 1f (422.7 mg, 91%) as a
colorless solid: IR 3400; 1H NMR (200 MHz, CDCl3) δ 2.28 (s,
3H), 2.58-2.64 (m, 2H), 2.71-2.77 (m, 2H), 3.50 (s, 2H), 3.83
(s, 3H), 3.87 (s, 3H), 6.72 (d, 2H, J ) 8.1 Hz), 6.80 (s, 2H),
entry
R
solvent
yield (%) ratio of 11/12
1
2
3
CH3 (10a )
TBDMS (10b) CF3CH2OH
TBDMS (10b) CH3CN
CF3CH2OH
60
40
12
2.5
3.6
2.0
Sch em e 5. Dep r otection of th e Silyl Eth er
6.86 (s, 1H), 7.03 (d, 2H, J ) 8.4 Hz); HRMS calcd for C18H23
-
NO3 (M+) 301.1678, found 301.1668.
Gen er a l P r oced u r e of P r ep a r in g N-Tr iflu or oa cety-
la ted Com p ou n d s 1h -o. (CF3CO)2O (2.0-3.0 mmol) was
added to a solution of O-protected norbelladine derivative (1.0
mmol) in pyridine (5 mL) at 0 °C under nitrogen. Then the
reaction mixture was stirred for 30 min, and water and AcOEt
were added. The organic layer was separated, washed with
10% HCl, water, and brine, and concentrated in vacuo. The
residue was purified with chromatography on silica gel (AcOEt-
n-hexane) to give the corresponding N-trifluoroacetylated
compounds in good yields.
solution and concentrated in vacuo. The residue was extracted
with AcOEt, and the extracts were washed with water and
brine and then concentrated in vacuo. The residue was
purified by chromatography on silica gel (n-hexane-AcOEt )
3:2) to give 1d (396.7 mg, 85%) as a colorless oil: IR 3350,
1695, 1671; 1H NMR (270 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.3
Hz), 2.70 (brs, 2H), 3.35 (brs, 2H), 3.85 (s, 3H), 3.86 (s, 3H),
4.18 (brs, 2H), 4.32 (s, 2H), 5.31 (s, 1H), 6.73-6.82 (m, 5H),
6.99 (brs, 2H); HRMS calcd for C20H25NO5 (M+) 359.1733,
found 359.1745.
N-(3,4-Dim eth oxyben zyl)-N-(4-h yd r oxyp h en eth yl)p en -
ta flu or oben za m id e (1e). Pentafluorobenzoyl chloride (0.21
mL, 1.46 mmol) was added to a solution of 1g (142 mg, 0.495
mmol) in pyridine (2 mL) at 0 °C. After being stirred for 45
min, the mixture was quenched with water and then extracted
with CH2Cl2. The organic layer was washed with water and
brine and then concentrated in vacuo. After general workup,
the residue was purified by chromatography on silica gel (n-
hexane-AcOEt ) 3:1) to give N,O-diprotected compounds. A
suspension of the compound (57.6 mg, 0.0852 mmol) in MeOH
(6 mL)-H2O (3 mL)-CH2Cl2 (2 mL) was stirred at rt for 1 h,
and then the reaction mixture was concentrated in vacuo. The
residue was purified by chromatography on silica gel (n-
hexane-AcOEt ) 3:2) to give 1e (18.2 mg, 44%) as a colorless
solid: IR 3350, 1653; 1H NMR (250 MHz, CDCl3) δ 2.66, 2.89
(t, 2H, J ) 7.3 Hz), 3.28, 3.63 (t, 2H, J ) 7.3 Hz), 3.84, 3.86,
3.87, 3.89 (s, 6H), 4.08, 4.69 (s, 2H), 4.84, 4.88 (s, 1H), 6.54 (s,
0.5H), 6.58 (dd, 0.5H, J ) 8.8, 1.8 Hz), 6.70-6.88 (m, 5H), 7.09
N-[3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-m eth oxyben zyl]-
N-(4-h yd r oxyp h en et h yl)t r iflu or oa cet a m id e (1i). Reac-
tants: NH-compound (704 mg, 1.82 mmol) in pyridine (5 mL);
(CF3CO)2O (0.51 mL, 3.64 mmol). 1i (722 mg, 82%): colorless
1
oil; IR 3400, 1670; H NMR (500 MHz, CDCl3) δ 0.14 (s, 6H),
0.98, 0.99 (s, 9H), 2.68-2.82 (m, 2H), 3.41-3.46 (m, 2H), 3.79,
3.80 (s, 3H), 4.29, 4.55 (s, 2H), 5.31 (s, 1H), 6.65 (d, 0.5H, J )
2.0 Hz), 6.70 (dd, 0.5H, J ) 8.2, 2.0 Hz), 6.74-6.83 (m, 4H),
6.97 (d, 2H, J ) 8.3 Hz). Anal. Calcd for C24H32NO4F3Si: C,
59.61; H, 6.67; N, 2.90. Found: C, 59.30; H, 6.64; N, 2.84.
N-[3,4-Bis[(ter t-b u t yld im et h ylsilyl)oxy]b en zyl]-N-(4-
h yd r oxyp h en eth yl)tr iflu or oa ceta m id e (1j). Reactants:
NH-compound (2.26 g, 4.63 mmol) in pyridine (15 mL); (CF3-
CO)2O (1.31 mL, 9.26 mmol). 1j (2.31 g, 85%): colorless solid;
mp 107-108 °C (from Et2O-n-hexane); IR 3400, 2955, 1678;
1H NMR (500 MHz, CDCl3) δ 0.17, 0.19 (s, 12H), 0.96, 0.97,
0.98 (s, 18H), 2.69-2.80 (m, 2H), 3.41-3.46 (m, 2H), 4.26, 4.52
(s, 2H), 4.76, 4.79 (s, 1H), 6.60, 6.67 (dd, 1H, J ) 8.6, 7.7, 2.6,
1.7 Hz), 6.64 (d, 0.5H, J ) 2.6 Hz), 6.72-6.81 (m, 3.5H), 6.98
(d, 2H, J ) 8.6 Hz); HRMS calcd for C29H44NO4F3Si2 (M+)
583.2761, found 583.2775. Anal. Calcd for C29H44NO4F3Si2:
C, 59.66; H, 7.60; N, 2.40. Found: C, 59.65; H, 7.39; N, 2.46.
N-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-m eth oxyben zyl]-
N-(4-h yd r oxyp h en eth yl)tr iflu or oa ceta m id e (1k ). Reac-
tants: NH-compound (270.7 mg, 0.698 mmol) in pyridine (2

Synthesis of Amaryllidaceae Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 5861
Sch em e 6
mL); (CF3CO)2O (0.20 mL, 1.40 mmol). 1k (200.4 mg, 63%):
colorless oil; IR 3400, 1640, 1630; 1H NMR (500 MHz, CDCl3)
δ 0.15 (s, 6H), 0.99 (s, 9H), 2.69-2.80 (m, 2H), 3.44-3.48 (m,
2H), 3.77, 3.78 (s, 3H), 4.34, 4.58 (s, 2H), 5.12, 5.14 (s, 1H),
6.62-6.83 (m, 5H), 6.97 (d, 2H, J ) 8.6 Hz). Anal. Calcd for
C24H32NO4F3Si: C, 59.61; H, 6.67; N, 2.90. Found: C, 59.44;
H, 6.70; N, 3.01.
N-[3-(Ben zyloxy)-4-m eth oxyben zyl]-N-(4-h ydr oxyph en -
eth yl)tr iflu or oa ceta m id e (1l). Reactants: NH-compound
(327.8 mg, 0.902 mmol) in pyridine (1.5 mL); (CF3CO)2O (0.25
mL, 1.80 mmol). 1l (408.9 mg, 99%): colorless oil; IR 3400,
1686; 1H NMR (500 MHz, CDCl3) δ 2.62-2.71 (m, 2H), 3.30-
3.37 (m, 2H), 3.88, 3.89 (s, 3H), 4.24, 4.51 (s, 2H), 4.94, 4.97
(s, 1H), 5.13 (s, 2H), 6.61, 6.76 (d, 1H, J ) 1.7 Hz), 6.68, 6.78
(dd, 1H, J ) 7.7, 1.7 Hz), 6.74, 6.76 (d, 2H, J ) 8.6 Hz), 6.84,
6.85 (d, 1H, J ) 7.7 Hz), 6.93 (d, 2H, J ) 8.6 Hz), 7.27-7.41
(m, 5H); HRMS calcd for C25H24NO4F3 (M+) 459.1658, found
459.1666.
N-(4-Hyd r oxyp h en eth yl)-N-(3-m eth oxyben zyl)tr iflu o-
r oa cet a m id e (10a ). Reactants: NH-compound (199.2 mg,
0.774 mmol) in pyridine (1.5 mL); (CF3CO)2O (0.33 mL, 2.32
mmol). 10a (246.5 mg, 90%): crystals; IR 3400, 1688, 1682;
1H NMR (500 MHz, CDCl3) δ 2.75-2.83 (m, 2H), 3.45-3.51
(m, 2H), 3.79 (s, 3H), 4.36, 4.62 (s, 2H), 5.09, 5.12 (s, 1H), 6.66
(s, 0.5H), 6.72, 6.80 (d, 1H, J ) 7.7, 6.8 Hz), 6.75-6.78 (m,
2.5H), 6.83-6.87 (m, 1H), 6.99 (d, 2H, J ) 8.6 Hz), 7.25-7.28
(d, 1H, J ) 7.7, 6.8 Hz); HRMS calcd for C18H18NO3F3 (M+)
353.1238, found 353.1256.
N-[3-[(ter t-Bu tyldim eth ylsilyl)oxy]ben zyl]-N-(4-h ydr ox-
yp h en eth yl)tr iflu or oa ceta m id e (10b). Reactants: NH-
compound (1.32 g, 3.68 mmol) in pyridine (5 mL); (CF3CO)2O
(1.04 mL, 7.36 mmol). 10b (1.59 g, 96%): colorless oil; IR 3400,
1
1682; H NMR (250 MHz, CDCl3) δ 0.18 (s, 6H), 0.97 (s, 9H),
2.72-2.84 (m, 2H), 3.43-3.51 (m, 2H), 4.33, 4.60 (s, 2H), 4.76,
4.79 (s, 1H), 6.61 (d, 0.5H, J ) 1.8 Hz), 6.69-6.82 (m, 2.5H),
6.76 (d, 2H, J ) 8.8, 8.5 Hz), 6.99, 7.00 (d, 2H, J ) 8.8, 8.5
Hz), 7.21 (ddd, 1H, J ) 8.0, 7.3, 2.6 Hz). Anal. Calcd for
C23H30NO3F3Si: C, 60.90; H, 6.67; N, 3.09. Found: C, 60.71;
H, 6.63; N, 3.07.
4-[[N-(4-Hydr oxyph en eth yl)-N-(tr iflu or oacetyl)am in o]-
m eth yl]-2-m eth oxyp h en yl P iva la te (1m ). Reactants: NH-
compound (170.0 mg, 0.476 mmol) in pyridine (1.5 mL);
(CF3CO)2O (0.20 mL, 1.43 mmol). 1m (203.1 mg, 94%):
colorless solid; mp 72-73 °C (from Et2O-n-hexane); IR 3450,
4-[[N-(4-Hydr oxyph en eth yl)-N-(tr iflu or oacetyl)am in o]-
m eth yl]-2-m eth oxyp h en yl Aceta te (1n ). An NH-compound
prepared from [(tert-butyldimethylsilyl)oxy]tyramine and van-
illin was trifluoroacetylated by the general method to give an
N-COCF3 compound (1.33 g, 97%). The N-COCF3 compound
(1.31 g, 2.71 mmol) was acetylated by a known method to give
an O-acetylated compound (1.28 g, 90%). To both the N- and
O-diprotected compounds (41.3 mg, 0.0786 mmol) was added
tetra-n-butylammonium fluoride (1.0 M solution in THF, 0.086
mL) in THF (0.5 mL) containing AcOH (14.2 mg, 0.236 mmol)
and the resulting mixture stirred for 5 min. The mixture was
evaporated, and the residue was purified by chromatography
on silica gel (CH2Cl2-MeOH ) 50:1) to give 1n (30.5 mg, 94%)
1
1755, 1690; H NMR (250 MHz, CDCl3) δ 1.36 (s, 9H), 2.73-
2.84 (m, 2H), 3.44-3.51 (m, 2H), 3.76 (s, 3H), 4.33, 4.59 (s,
2H), 4.99 (brs, 1H), 6.65-6.79 (m, 4H), 6.95 (d, 2H, J ) 8.5
Hz), 6.97, 6.98 (d, 1H, J ) 7.8 Hz); HRMS calcd for C23H26
-
NO5F3 (M+) 453.1763, found 453.1741.
N-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en eth yl]-N-(3,4-
dim eth oxyben zyl)tr iflu or oacetam ide (8b). Reactants: NH-
compound (167.9 mg, 0.418 mmol) in pyridine (1.0 mL);
(CF3CO)2O (0.088 mL, 0.627 mmol). 8b (200.3 mg, 96%):
colorless oil; IR 2950, 1692; 1H NMR (250 MHz, CDCl3) δ 0.17
(s, 6H), 0.97 (s, 9H), 2.72-2.84 (m, 2H), 3.43-3.51 (m, 2H),
3.85, 3.87, (s, 6H), 4.28, 4.57 (s, 2H), 6.61, 6.76 (d, 1H, J ) 1.8
Hz), 6.65-6.85 (m, 2H), 6.77 (d, 2H, J ) 8.5 Hz), 6.98 (d, 2H,
J ) 8.5 Hz). Anal. Calcd for C25H34NO4F3Si: C, 60.34; H,
6.89; N, 2.81. Found: C, 60.12; H, 6.78; N, 2.81.
1
as a colorless oil: IR 3400, 1767, 1685; H NMR (250 MHz,
CDCl3) δ 2.31, 2.32 (s, 3H), 2.74-2.85 (m, 2H), 3.45-3.54 (m,
2H), 3.79 (s, 3H), 4.34, 4.59 (s, 2H), 5.48, 5.50 (s, 1H), 6.67,
6.74 (s, 1H), 6.73, 6.75 (d, 2H, J ) 8.5 Hz), 6.81 (dd, 1H, J )
7.5, 2.0 Hz), 6.97 (d, 2H, J ) 8.5 Hz), 7.00, 7.02 (d, 1H, J )
8.0 Hz); HRMS calcd for C20H20NO5F3 (M+) 411.1290, found
411.1284. Anal. Calcd for C20H20NO5F3: C, 58.39; H, 4.90;
N, 3.40. Found: C, 58.05; H, 4.95; N, 3.67.
N-[4-[(ter t-Bu t yld ip h en ylsilyl)oxy]p h en et h yl]-N-(3,4-
d im eth oxyben zyl)tr iflu or oa cetoa m id e (8c). tert-Butyl-
diphenylsilyl chloride (1.60 mL, 0.622 mmol) was added to a
solution of 1a (159 mg, 0.415 mmol) and imidazole (57.0 mg,
0.830 mmol) in DMF (1.5 mL) at rt under nitrogen. After the
mixture was stirred for 1 h, water and Et2O were added. The
N-(3,4-Dim eth oxyben zyl)-N-(4-m eth oxyp h en eth yl)tr i-
flu or oa ceta m id e (8e). Reactants: NH-compound (469.9 mg,
1.56 mmol) in pyridine (1.5 mL); (CF3CO)2O (0.66 mL, 4.68
mmol). 8e (635.2 mg, quant): colorless oil; IR 1690; 1H NMR
(200 MHz, CDCl3) δ 2.72-2.87 (m, 2H), 3.43-3.52 (m, 2H),
3.79 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.33, 4.59 (s, 2H), 6.62-
6.86 (m, 5H), 7.05 (d, 2H, J ) 8.4 Hz); HRMS calcd for C20H22
-
-
NO4F3 (M+) 397.1501, found 397.1503. Anal. Calcd for C20H22
NO4F3: C, 60.45; H, 5.58; N, 3.52. Found: C, 60.24; H, 5.47;
N, 3.53.

5862 J . Org. Chem., Vol. 61, No. 17, 1996
Kita et al.
organic layer was separated, washed with water and brine,
and concentrated in vacuo. The residue was purified by
chromatography on silica gel (n-hexane-AcOEt ) 10:1) to give
Eth yl 7,8-Dim eth oxy-4′-oxo-2,3,4,5-tetr a h yd r o-1H-[2]-
ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien e-2-ca r boxy-
la te (2d ). Reactants: 1d (203.5 mg, 0.566 mmol) in CF3CH2-
OH (4 mL); PIFA (267.8 mg, 0.623 mmol). 2d (97.8 mg, 49%):
colorless solid; mp 92-94 °C (from Et2O); IR 1700, 1667, 1624;
1H NMR (270 MHz, CDCl3) δ 1.17-1.30 (m, 3H), 2.28 (brs,
2H), 3.72 (s, 3H), 3.76-3.83 (m, 2H), 3.88 (s, 3H), 4.09-4.19
(m, 2H), 4.58, 4.66 (s, 2H), 6.29 (d, 2H, J ) 10.2 Hz), 6.52,
6.53 (s, 1H), 6.66, 6.76 (s, 1H), 7.02, 7.03 (d, 2H, J ) 9.9, 10.2
Hz); HRMS calcd for C20H23NO5 (M+) 357.1576, found 357.1603.
2-(P en ta flu or oben zoyl)-7,8-d im eth oxy-2,3,4,5-tetr a h y-
d r o-1H-[2]ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien -4′-
on e (2e). Reactants: 1e (32.1 mg, 0.0667 mmol) in CF3CH2-
OH (2 mL); PIFA (31.5 mg, 0.0733 mmol). 2e (17.8 mg, 56%):
colorless solid; mp 188-190 °C (from Et2O); IR 1667, 1652;
1H NMR (500 MHz, CDCl3) δ 2.32-2.45 (m, 2H), 3.67 (s, 3H),
3.74, 3.75 (s, 3H), 3.92 (s, 1H), 4.08 (t, 1H, J ) 6.0 Hz), 4.49,
4.94 (s, 2H), 5.97, 6.52, 6.55, 6.86 (s, 2H), 6.29, 6.34 (d, 2H, J
) 10.3, 9.4 Hz), 7.01 (d, 2H, J ) 10.3 Hz). Anal. Calcd for
C24H18NO4F5: C, 60.13; H, 3.78; N, 2.92. Found: C, 59.92; H,
3.74; N, 2.93.
2-(Tr iflu or oa cet yl)-7,8-(m et h ylen ed ioxy)-2,3,4,5-t et -
r ah ydr o-1H-[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien -
4′-on e (2h ). Reactants: 1h (30.8 mg, 0.0839 mmol) in
CF3CH2OH (1 mL); PIFA (39.7 mg, 0.0923 mmol) in CF3CH2-
OH (1 mL). 2h (17.3 mg, 56%): colorless solid; mp 143-145
°C (from Et2O); IR 1690, 1667, 1626; 1H NMR (200 MHz,
CDCl3) δ 2.34-2.43 (m, 2H), 3.89-3.98 (m, 2H), 4.74, 4.76 (s,
2H), 5.94, 5.96 (s, 2H), 6.30, 6.31 (d, 2H, J ) 10.2, 10.4 Hz)
6.55 (s, 1H), 6.63, 6.81 (s, 1H), 6.90, 7.00 (d, 2H, J ) 10.2,
10.4 Hz); 13C NMR (67.8 MHz, CDCl3) δ 33.7, 35.7, 44.2, 45.2,
45.3, 48.2, 48.3, 48.5, 48.6, 48.7, 101.7, 101.8, 109.7, 109.9,
110.0, 111.3, 117.3 (m), 127.1, 127.4, 129.0, 129.1, 129.3, 129.4,
147.2, 147.9, 148.0, 152.3, 152.7, 157.0 (m), 184.9, 185.1;
HRMS calcd for C18H14NO4F3 (M+) 365.0875, found 365.0880.
8-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-(tr iflu or oa cetyl)-7-
m et h oxy-2,3,4,5-t et r a h yd r o-1H -[2]b en za zep in e-5-sp ir o-
1′-cycloh exa -2′,5′-d ien -4′-on e (2i). Reactants: 1i (54.4 mg,
0.119 mmol) in CF3CH2OH (1 mL); PIFA (56.5 mg, 0.131
mmol) in CF3CH2OH (5 mL). 2i (22.5 mg, 42%): colorless
solid; mp 154-155 °C (from Et2O); IR 1692, 1671; 1H NMR
(270 MHz, CDCl3) δ 0.13, 0.14 (s, 6H), 0.97, 0.98 (s, 9H), 2.33-
2.41 (m, 2H), 3.65 (s, 3H), 3.90-3.94 (m, 2H), 4.71, 4.74 (s,
2H), 6.29, 6.32 (d, 2H, J ) 10.2 Hz), 6.48, 6.49 (s, 1H), 6.62,
6.79 (s, 1H), 6.95, 7.06 (d, 2H, J ) 9.9, 10.2 Hz). Anal. Calcd
for C24H30NO4F3Si: C, 59.86; H, 6.28; N, 2.91. Found: C,
59.69; H, 6.24; N, 2.93.
1
8c (236 mg, 91%) as a colorless oil: IR 1690; H NMR (500
MHz, CDCl3) δ 1.09 (s, 9H), 2.67-2.76 (m, 2H), 3.36-3.43 (m,
2H), 3.79, 3.81, 3.86 (s, 6H), 4.13, 4.48 (s, 2H), 6.54 (d, 0.5H,
J ) 1.7 Hz), 6.57 (d, 0.5H, J ) 7.7 Hz), 6.69-6.71 (m, 3H),
6.78, 6.79 (d, 1H, J ) 7.7 Hz), 6.85 (d, 2H, J ) 8.6 Hz), 7.33-
7.42 (m, 6H), 7.68-7.71 (m, 4H); HRMS calcd for C35H38NO4F3-
Si (M+) 621.2522, found 621.2522. Anal. Calcd for C35H38
-
NO4F3Si: C, 67.61; H, 6.16; N, 2.25. Found: C, 67.45; H, 6.14;
N, 2.34.
N-[4-(Ben zyloxy)p h en eth yl]-N-(3,4-d im eth oxyben zyl)-
tr iflu or oa ceta m id e (8d ). Benzyl bromide (0.057 mL, 0.472
mmol) was added to a suspension of 1a (164.4 mg, 0.429 mmol)
and potassium carbonate (65.2 mg, 0.472 mmol) in EtOH (3
mL). After being stirred for 30 min, the reaction mixture was
filtered and concentrated in vacuo. The residue was purified
by chromatography on silica gel (n-hexane-AcOEt ) 3:1) to
1
give 8d (197 mg, 97%) as a colorless oil: IR 1690; H NMR
(200 MHz, CDCl3) δ 2.72-2.86 (m, 2H), 3.43-3.53 (m, 2H),
3.85 (s, 3H), 3.88 (s, 3H), 4.32, 4.59 (s, 2H), 5.05 (s, 2H), 6.65-
6.93 (m, 5H), 7.05 (d, 2H, J ) 8.4 Hz), 7.29-7.44 (m, 5H). Anal.
Calcd for C26H26NO4F3: C, 65.95; H, 5.53; N, 2.96. Found: C,
65.74; H, 5.45; N, 2.93.
Gen er a l P r oced u r e for th e Oxid a tive Cycliza tion of
Nor bella d in e Der iva tives Usin g P IF A. To a stirred solu-
tion of a norbelladine derivative (0.1 mmol) in CF3CH2OH (1
mL) was added a solution of PIFA (0.11 mmol) in CF3CH2OH
(4 mL) at -40 °C under nitrogen, and the solution was stirred
for 10 min. Then the solution was evaporated, and the residue
was purified by column chromatography or preparative TLC
to give a phenolic coupling compound in moderate yield.
2-(Tr iflu or oa cetyl)-7,8-d im eth yl-2,3,4,5-tetr a h yd r o-1H-
[2]ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien -4′-on e (2a ).
Reactants: 1a (22.2 mg, 0.0579 mmol) in CF3CH2OH (1 mL);
PIFA (27.4 mg, 0.0637 mmol) in CF3CH2OH (1.5 mL). 2a (13.4
mg, 61%): colorless solid; mp 162-163 °C (from Et2O-n-
1
hexane); IR 1690, 1667, 1626; H NMR (270 MHz, CDCl3) δ
2.35-2.43 (m, 2H), 3.72, 3.87, 3.88 (s, 6H), 3.91-3.98 (m, 2H),
4.77, 4.81 (s, 2H), 6.31, 6.32 (d, 2H, J ) 10.2 Hz), 6.52 (s, 1H),
6.61, 6.80 (s, 1H), 6.94, 7.05 (d, 2H, J ) 10.2 Hz); 13C NMR
(67.8 MHz, CDCl3) δ 33,8, 35.8, 42.6, 45.2, 45.3, 48.1, 48.3,
48.4, 48.6, 48.7, 112.6, 112.7, 113.1, 114.1, 116.2 (q, J ) 288
Hz), 127.1, 127.2, 127.8, 127.9, 128.0, 148.1, 148.6, 148.7,
152.5, 152.9, 156.3 (m, J ) 35 Hz), 185.0, 185.2; HRMS calcd
for C19H18NO4F3 (M+) 381.1185, found 381.1168.
7,8-Bis[(ter t-bu tyld im eth ylsilyl)oxy]-2-tr iflu or oa cetyl-
2,3,4,5-tetr ah ydr o-1H-[2]ben zazepin e-5-spir o-1′-cycloh exa-
2′,5′-d ien -4′-on e (2j). Reactants: 1j (146 mg, 0.250 mmol)
in CF3CH2OH (3 mL); PIFA (108 mg, 0.250 mmol). 2j (60.5
mg, 42%): colorless solid; mp 174-175 °C (from Et2O); IR
ter t-Bu tyl 7,8-Dim eth oxy-4′-oxo-2,3,4,5-tetr a h yd r o-1H-
[2]ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien e-2-ca r box-
yla te (2b). Reactants: 1b (50.2 mg, 0.130 mmol) in CF3CH2-
OH (1 mL); PIFA (61.3 mg, 0.143 mmol) in CF3CH2OH (4 mL).
2b (24.4 mg, 49%): colorless solid; mp 148-149 °C (from Et2O);
1
1
1692, 1671; H NMR (500 MHz, CDCl3) δ 0.10, 0.18, 0.19 (s,
IR 1694, 1665, 1625; H NMR (500 MHz, CDCl3) δ 1.36, 1.47
12H), 0.90, 0.91 (s, 18H), 2.33-2.40 (m, 2H), 3.92-3.95 (m,
2H), 4.69, 4.73 (s, 2H), 6.29, 6.30 (d, 2H, J ) 10.3 Hz), 6.53,
6.54, 6.60, 6.76 (s, 2H), 6.92, 7.02 (d, 2H, J ) 10.3, 9.4 Hz);
HRMS calcd for C29H42NO4F3Si2 (M+) 581.2604, found 581.2620.
Anal. Calcd for C29H42NO4F3Si2: C, 59.87; H, 7.28; N, 2.41.
Found: C, 59.71; H, 7.04; N, 2.35.
(s, 9H), 2.26-2.29 (m, 2H), 3.73 (s, 3H), 3.76-3.78 (m, 2H)
3.87 (s, 3H), 4.50, 4.62 (s, 2H), 6.29 (d, 2H, J ) 10.3 Hz), 6.52,
6.82 (s, 1H), 6.64, 6.75 (s, 1H), 7.00, 7.03 (d, 2H, J ) 10.3 Hz);
13C NMR (62.9 MHz, CDCl3) δ 28.2, 35.6, 43.5, 44.3, 47.6, 48.4,
48.6, 55.7, 79.9, 80.1, 112.7, 112.8, 113.2, 126.5, 127.7, 131.4,
147.4, 147.7, 153.7, 154.4, 154.8, 185.4. Anal. Calcd for
C22H27NO5 C, 68.55; H, 7.06; N, 3.63. Found: C, 68.48, H,
7.03; N, 3.62.
2-(Tr im et h ylsilyl)et h yl 7,8-Dim et h oxy-4′-oxo-2,3,4,5-
tetr a h yd r o-1H-[2]ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-
d ien e-2-ca r boxyla te (2c). Reactants: 1c (53.7 mg, 0.124
mmol) in CF3CH2OH (1 mL); PIFA (58.9 mg, 0.137 mmol) in
CF3CH2OH (4 mL). 2c (28.9 mg, 54%): colorless solid; mp
167-169 °C (from Et2O-CH2Cl2); IR 1694, 1666, 1626; 1H
NMR (250 MHz, CDCl3) δ 0.01, 0.02 (s, 9H), 0.89-1.03 (m,
2H), 2.26 (brs, 2H), 3.70 (s, 3H), 3.75-3.82 (m, 2H), 3.86 (s,
3H), 4.09-4.22 (m, 2H), 4.57, 4.64 (s, 2H), 6.27 (d, 2H, J )
10.3 Hz), 6.48, 6.50 (s, 1H), 6.64, 6.74 (s, 1H), 6.99, 7.01 (d,
2H, J ) 9.8, 10.3 Hz); 13C NMR (62.9 MHz, CDCl3) δ -1.5,
17.8, 35.6, 35.8, 44.1, 48.1, 48.7, 55.9, 63.9, 112.9, 113.3, 126.7,
130.9, 147.7, 148.0, 153.7, 155.7, 185.5. Anal. Calcd for
C23H31NO5Si: C, 64.31; H, 7.27; N, 3.26. Found: C, 64.13; H,
7.06; N, 3.27.
7-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-(tr iflu or oa cetyl)-8-
m et h oxy-2,3,4,5-t et r a h yd r o-1H -[2]b en za zep in e-5-sp ir o-
1′-cycloh exa -2′,5′-d ien -4′-on e (2k ). Reactants: 1k (89.9 mg,
0.186 mmol) in CF3CH2OH (3 mL); PIFA (87.9 mg, 0.204
mmol). 2k (31.6 mg, 35%): colorless solid; mp 140-141 °C
(from Et2O-n-hexane); IR 1692, 1669; 1H NMR (270 MHz,
CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 2.32-2.40 (m, 2H), 3.80,
3.81 (s, 3H), 3.90-3.97 (m, 2H), 4.76, 4,79 (s, 2H), 6.29, 6.30
(d, 2H, J ) 9.9 Hz), 6.52 (s, 1H), 6.59, 6.77 (s, 1H), 6.91, 7.02
(d, 2H, J ) 9.9, 10.2 Hz); HRMS calcd for C24H30NO4F3Si (M+)
481.1896, found 481.1900. Anal. Calcd for C24H30NO4F3Si:
C, 59.86; H, 6.28; N, 2.91. Found: C, 59.97; H, 6.21; N, 2.87.
8-(Ben zyloxy)-2-(tr iflu or oa cetyl)-7-m eth oxy-2,3,4,5-tet-
r ah ydr o-1H-[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien -
4′-on e (2l). Reactants: 1l (61.6 mg, 0.134 mmol) in CF3CH2-
OH (1 mL); PIFA (63.4 mg, 0.147 mmol) in CF3CH2OH (4 mL).
2l (29.9 mg, 49%): colorless solid; mp 172-174 °C (from CH2-

Synthesis of Amaryllidaceae Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 5863
1
1
Cl2-n-hexane); IR 1692, 1667; H NMR (270 MHz, CDCl3) δ
IR 1690; H NMR (500 MHz, CDCl3) δ 1.11 (s, 9H), 2.31 (dd,
1H, J ) 14.5, 10.3 Hz), 2.89 (dd, 1H, J ) 14.5, 6.8 Hz), 3.14
(dd, 1H, J ) 14.5, 10.3 Hz), 3.22 (d, 1H, J ) 13.7 Hz), 3.75 (s,
3H), 3.90 (s, 3H), 4.20 (dd, 1H, J ) 14.5, 6.8 Hz), 5.12 (d, 1H,
J ) 13.7 Hz), 6.41 (s, 1H), 6.66 (d, 1H, J ) 2.6 Hz), 6.81 (dd,
1H, J ) 8.6, 2.6 Hz), 6.98 (d, 1H, J ) 7.7 Hz), 7.33-7.42 (m,
7H), 7.70-7.74 (m, 4H); HRMS calcd for C35H36NO4F3Si (M+)
619.2366, found 619.2340.
2.33-2.40 (m, 2H), 3.73, 3.74 (s, 3H), 3.88-3.94 (m, 2H), 4.69,
4.76 (s, 2H), 5.13 (s, 2H), 6.31, 6.32 (d, 2H, J ) 9.6, 10.2 Hz),
6.54, 6.56 (s, 1H), 6.65, 6.88 (1H, s), 6.93, 7.05 (d, 2H, J ) 9.9
Hz), 7.31-7.40 (m, 5H); HRMS calcd for C25H22NO4F3 (M+)
457.1501, found 457.1520.
2-(Tr iflu or oacetyl)-8-m eth oxy-4′-oxo-2,3,4,5-tetr ah ydr o-
1H-[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien yl 7-P iv-
a la te (2m ). Reactants: 1m (22.1 mg, 0.0487 mmol) in
CF3CH2OH (0.5 mL); PIFA (23.1 mg, 0.0536 mmol) in CF3-
CH2OH (2 mL). 2m (7.0 mg, 32%): colorless solid; mp 188-
190 °C (from Et2O); IR 2975, 1755, 1694, 1667, 1625; 1H NMR
(500 MHz, CDCl3) δ 1.32 (s, 9H), 2.35-2.42 (m, 2H), 3.81, 3.82
(s, 3H), 3.93-3.98 (m, 2H), 4.81, 4.84 (s, 2H), 6.30, 6.32 (d,
2H, J ) 9.4, 10.3 Hz), 6.68, 6.70, 6.89 (s, 2H), 6.92, 7.04 (d,
2H, J ) 10.3 Hz); HRMS calcd for C23H24NO5F3 (M+) 451.1606,
found 451.1607. Anal. Calcd for C23H24NO5F3: C, 61.19; H,
5.36; N, 3.10. Found: C, 61.11; H, 5.33; N, 3.26.
11-(Ben zyloxy)-6-(tr iflu or oacetyl)-2,3-dim eth oxy-5,6,7,8-
tetr a h yd r od iben z[c,e]a zocin e (9d ). Reactants: 8d (79.7
mg, 0.168 mmol) in CF3CH2OH (2 mL); PIFA (79.6 mg, 0.185
mmol) at rt. 9d (38.1 mg, 48%): colorless solid; mp 134-136
1
°C (from Et2O); IR 1686; H NMR (270 MHz, CDCl3) δ 2.40
(dd, 1H, J ) 14.9, 10.6 Hz), 2.98 (dd, 1H, J ) 14.9, 6.9 Hz),
3.19 (dd, 1H, J ) 14.2, 10.6 Hz), 3.31 (d, 1H, J ) 13.9 Hz),
3.87 (s, 3H), 3.94 (s, 3H), 4.26 (dd, 1H, J ) 13.9, 7.3 Hz), 5.11
(s, 2H), 5.18 (d, 1H, J ) 13.5 Hz), 6.76 (s, 1H), 6.94 (d, 1H, J
) 2.6 Hz), 7.00 (dd, 1H, J ) 8.6, 2.6 Hz), 7.18 (d, 1H, J ) 8.3
2-(Tr iflu or oacetyl)-8-m eth oxy-4′-oxo-2,3,4,5-tetr ah ydr o-
1H-[2]ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien yl 7-Ac-
eta te (2n ). Reactants: 1n (31.0 mg, 0.754 mmol) in CF3CH2-
OH (3.5 mL); PIFA (356 mg, 0.829 mmol). 2n (114 mg, 37%):
colorless solid; mp 153-155 °C (from Et2O); IR 1767, 1694,
Hz), 7.31-7.47 (m, 6H). Anal. Calcd for C26H24NO4F3: C,
66.24; H, 5.13; N, 2.97. Found: C, 66.24; H, 5.17; N, 2.99.
6-(Tr iflu or oa cet yl)-2,3,11-t r im et h oxy-5,6,7,8-t et r a h y-
d r od iben z[c,e]a zocin e (9e). Reactants: 8e (27.8 mg, 0.0700
mmol) in CF3CH2OH (1 mL); PIFA (33.1 mg, 0.0770 mmol) at
rt. 9e (13.1 mg, 47%): colorless solid; mp 134-136 °C (from
AcOEt-n-hexane); IR 1686; 1H NMR (270 MHz, CDCl3) δ 2.41
(dd, 1H, J ) 14.7, 9.7 Hz), 2.99 (dd, 1H, J ) 14.7, 7.1 Hz),
3.19 (dd, 1H, J ) 14.2, 10.6 Hz), 3.31 (d, 1H, J ) 13.9 Hz),
3.85 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.26 (dd, 1H, J ) 12.7,
6.4 Hz), 5.19 (d, 1H, J ) 13.9 Hz), 6.82 (s, 1H), 6.86 (d, 1H, J
) 2.6 Hz), 6.93 (dd, 1H, J ) 8.6, 2.6 Hz), 7.18 (d, 1H, J ) 8.6
Hz), 7.40 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 34.0, 48.4,
48.8, 55.4, 56.0, 112.0, 113.8, 114.0, 115.2, 118.9 (m), 127.1,
130.5, 131.2, 133.0, 140.9, 148.6, 148.8, 156.5 (m), 158.3;
HRMS calcd for C20H20NO4F3 (M+) 395.1341, found 395.1338.
Anal. Calcd for C20H20NO4F3: C, 60.76; H, 5.10; N, 3.54.
Found: C, 60.56; H, 5.07; N, 3.55.
1
1667, 1625; H NMR (200 MHz, CDCl3) δ 2.27 (s, 3H), 2.33-
2.43 (m, 2H), 3.84, 3.85 (s, 3H), 3.92-4.01 (m, 2H), 4.82, 4.85
(s, 2H), 6.15, 6.31 (d, 2H, J ) 10.4, 10.3 Hz), 6.72, 6.74, 6.92
(s, 2H), 6.92, 7.03 (d, 2H, J ) 10.3 Hz); HRMS calcd for C20H18
-
-
NO5F3 (M+) 409.1137, found 409.1137. Anal. Calcd for C20H18
NO5F3: C, 58.68; H, 4.43; N, 3.42. Found: C, 58.64; H, 4.48;
N, 3.43.
2-(Tr iflu or oa cet yl)-8-h yd r oxy-7-m et h oxy-2,3,4,5-t et -
r ah ydr o-1H-[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien -
4′-on e (2o). Reactants: 1o (22.1 mg, 0.0598 mmol) in
CF3CH2OH (0.75 mL); PIFA (28.3 mg, 0.0658 mmol) in CF3-
CH2OH (0.5 mL). 2o (4.1 mg, 19%): off-white amorphous
powder; IR 1690, 1665, 1620; 1H NMR (270 MHz, CDCl3) δ
2.35-2.43 (m, 2H), 3.75, 3.76 (s, 3H), 3.89-3.97 (m, 2H), 4.74,
4.77 (s, 2H), 5.58, 5.60 (s, 1H), 6.31, 6.32 (d, 2H, J ) 10.2 Hz),
6.51 (s, 1H), 6.74, 6.91 (s, 1H), 6.94, 7.05 (d, 2H, J ) 10.2 Hz);
HRMS calcd for C18H16NO4F3 (M+) 367.1032, found 367.1007.
N-[2-[1-(Acetylam in o)-4-oxo-2,5-cycloh exadien yl]eth yl]-
N-(3,4-d im eth oxyben zyl)tr iflu or oa cetoa m id e (3a ). Reac-
tants: 1a (22.7 mg, 0.0592 mmol) in CH3CN (1 mL); PIFA (28.0
mg, 0.0651 mmol). 3a (6.8 mg, 27%): colorless amorphous
powder; IR 3350, 1690, 1673, 1628; 1H NMR (270 MHz, CDCl3)
δ 1.84-1.90, 2.04-2.38 (m, 2H), 1.98, 2.00 (s, 3H), 3.20-3.27,
3.31-3.37 (m, 2H), 3.87, 3.88, 3.90 (s, 6H), 4.53 (s, 2H), 6.25,
6.31 (d, 2H, J ) 10.2, 9.9 Hz), 6.68 (s, 1H), 6.74, 6.91 (d, 2H,
J ) 10.2, 9.9 Hz), 6.79, 6.86 (d, 2H, J ) 7.9 Hz); 13C NMR
(68.7 MHz, CDCl3) δ 23.5, 36.5, 42.0, 51.9, 54.5, 56.0, 110.5,
111.3, 120.5, 125.9, 129.3, 130.0, 147.0, 149.2, 149.5, 149.6,
170.1, 184.7; HRMS calcd for C21H23N2O5F3 (M+) 440.1559,
found 440.1566.
(3S)-(+)-Met h yl 2-(Tr iflu or oa cet yl)-7,8-d im et h oxy-4′-
oxo-2,3,4,5-tetr a h yd r o-1H-[2]ben za zep in e-5′-sp ir o-1′-cy-
cloh exa -2′,5′-d ien e-3-ca r boxyla te (7). Reactants: 6 (22.0
mg, 0.0498 mmol) in CF3CH2OH (0.75 mL); PIFA (23.6 mg,
0.0548 mmol) in CF3CH2OH (0.5 mL). 7 (13.9 mg, 64%):
colorless solid; mp 176-179 °C (from Et2O-n-hexane): IR
1750, 1690, 1667, 1626; 1H NMR (270 MHz, CDCl3) δ 2.42 (dd,
1H, J ) 14.9, 4.6 Hz), 2.85 (dd, 1H, J ) 14.6, 13.4), 3.71, 3.73
(s, 3H), 3.80, 3.82 (s, 3H), 3.89, 3.90 (s, 3H), 4.75 (d, 1H, J )
17.5 Hz), 4.94 (d, 1H, J ) 17.5 Hz), 5.11 (dd, 1H, J ) 13.5, 4.6
Hz), 6.29, 6.39 (dd, 2H, J ) 10.2, 9.9, 2.0, 1.7 Hz), 6.46, 6.49,
6.62 (s, 2H), 6.77, 6.94 (dd, 2H, J ) 10.2, 9.9, 3.3, 3.0 Hz).
Sp ir ocycliza tion of Silyla ted Com p ou n d s (8a a n d 8b)
w ith P IF A. Reactants: 8a (61.2 mg, 0.134 mmol) in CF3CH2-
OH (2 mL); PIFA (63.6 mg, 0.148 mmol) at rt. 2a (29.3 mg,
57%); Reactants: 8b (29.1 mg, 0.0585 mmol) in CF3CH2OH
(1.2 mL); PIFA (27.7 mg, 0.0643 mmol) at rt. 2a (14.8 mg,
66%).
2-(Tr iflu or oa cet yl)-8-m et h oxy-2,3,4,5-t et r a h yd r o-1H -
[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien -4′-on e (11a).
Reactants: 10a (38.0 mg, 0.109 mmol) in CF3CH2OH (1 mL);
PIFA (51.6 mg, 0.120 mmol) in CF3CH2OH (1 mL). 11a (16.4
mg, 43%): colorless solid; mp 149-150 °C (from Et2O-CH2-
Cl2); IR 1694, 1669, 1620; 1H NMR (250 MHz, CDCl3) δ 2.36-
2.42 (m, 2H), 3.80 (s, 3H), 3.93-3.99 (m, 2H), 4.80, 4.84 (s,
2H), 6.29, 6.30 (d, 2H, J ) 9.8, 10.3 Hz), 6.72-7.04 (m, 3H),
6.92, 7.04 (d, 2H, J ) 10.3 Hz); 13C NMR (67.8 MHz, CDCl3)
δ 33.9, 35.9, 44.3, 45.4, 45.5, 47.8, 48.1, 49.0, 49.2, 49.3, 55.3,
113.6, 114.0, 116.0, 116.3 (q, J ) 278 Hz), 116.7, 127.0, 127.1,
127.7, 131.1, 131.6, 136.6, 152.5, 152.8, 156.7 (q, J ) 37 Hz),
158.8, 158.9, 185.2, 185.4; HRMS calcd for C18H16NO3F3 (M+)
351.1083, found 351.1084. Anal. Calcd for C18H16NO3F3: C,
61.54; H, 4.59; N, 3.99. Found: C, 61.33; H, 4.71; N, 3.91.
2-(Tr iflu or oa cet yl)-6-m et h oxy-2,3,4,5-t et r a h yd r o-1H -
[2]ben zazepin e-5-spir o-1′-cycloh exa-2′,5′-dien -4′-on e (12a)
was obtained by the same method as described above (6.6 mg,
17%) as a colorless solid: mp 135-137 °C (from Et2
O-n-
1
hexane); IR 1690, 1663, 1622; H NMR (250 MHz, CDCl3) δ
2.35-2.41 (m, 2H), 3.58, 3.59 (s, 3H), 3.86-3.95 (m, 2H), 4.86,
4.89 (s, 2H), 6.30 (d, 2H, J ) 10.3 Hz), 6.78-6.99 (m, 2H),
6.89, 6.94 (d, 2H, J ) 10.3, 10.5 Hz), 7.25, 7.26 (dd, 1H, J )
8.0 Hz);
13C NMR (67.8 MHz, CDCl3) δ 36.9, 38.2, 44.9, 45.5,
45.6, 47.5, 47.8, 48.1, 49.1, 49.2, 55.7, 55.8, 112.4, 123.2, 124.2,
125.4, 127.6, 129.7, 137.6, 137.7, 154.0, 154.2, 159.6, 159.7,
186.2, 186.3; HRMS calcd for C18H16NO3F3 (M+) 351.1083,
found 351.1074. Anal. Calcd for C18H16NO3F3: C, 61.54; H,
4.59; N, 3.99. Found: C, 61.77; H, 4.64; N, 3.98.
Sp ir ocycliza t ion of Com p ou n d s 10b . PIFA (41.7 mg,
0.0970 mmol) in CF3CH2OH (1 mL) was added to a solution
of 10b (40.0 mg, 0.0882 mmol) in CF3CH2OH (1 mL) at -40
°C under nitrogen, and the solution was stirred for 30 min.
The solution was concentrated in vacuo, and the residue was
purified by preparative TLC to give the mixture of 11b and
12b (15.9 mg, 40%), which could not be separated by chroma-
tography. Tetra-n-butylammonium fluoride (1.0 M solution
in THF, 0.040 mL) was added to the solution of the mixture
(16.7 mg, 0.0370 mmol) in THF (1 mL) at 0 °C under nitrogen,
and the solution was stirred for 30 min. After removal of the
11-(ter t-Bu t yld ip h en ylsiloxy)-6-(t r iflu or oa cet yl)-2,3-
d im et h oxy-5,6,7,8-t et r a h yd r od ib en z[c,e]a zocin e
Reactants: 8c (49.9 mg, 0.0803 mmol) in CF3CH2OH (1.5 mL);
PIFA (38.0 mg, 0.0883 mmol) at rt. 9c (6.0 mg, 12%) and 2a
(7.1 mg, 23%). 9c: colorless solid; mp 213-214 °C (from Et2O);
(9c).

5864 J . Org. Chem., Vol. 61, No. 17, 1996
Kita et al.
solvent, a residue was purified by preparative TLC to give 11c
(8.0 mg, 0.0237 mmol) and 13 (3.9 mg, 0.0115 mmol).
2-(Tr iflu or oacetyl)-8-h ydr oxy-2,3,4,5-tetr ah ydr o-1H-[2]-
ben za zep in e-5-sp ir o-1′-cycloh exa -2′,5′-d ien -4′-on e (11c):
colorless solid; mp 220-222 °C (from EtOH); IR 3220, 1690,
(dd, 1H, J ) 11.1, 10.3 Hz), 6.77-6.78 (d, 2H, J ) 8.6 Hz),
6.81 (m, 0.5H), 6.87 (dd, 0.5H, J ) 10.3, 1.8 Hz), 6.93 (d, 0.5H,
J ) 6.8 Hz), 7.16 (d, 1H, J ) 7.7 Hz); HRMS calcd for C17H14
-
NO3F3 (M+) 337.0926, found 337.0923.
7,8-Dim eth oxy-2,3,4,5-tetr ah ydr o-1H-[2]ben zazepin iu m -
5-sp ir o-1′-cycloh exa -2′,5′-d ien -4′-on e Ch lor id e (5). HCl
(10%, 5 mL) was added to a solution of 2b (391.8 mg, 1.02
mmol) in MeOH (10 mL) under ice bath cooling. After the
mixture was stirred for 40 min at rt, 10% HCl (5 mL) was
added at 0 °C. After an additional 30 min of stirring at rt,
10% HCl (15 mL) was added slowly to the stirred solution for
2 h at rt. After being stirred overnight, the mixture was
concentrated and dried in vacuo to give 5 (337.2 mg, quant)
as a colorless solid: IR 3382, 2150, 1663; 1H NMR (250 MHz,
CD3OD) δ 2.40 (t, 2H, J ) 5.0 Hz), 3.55 (t, 2H, J ) 5.0 Hz),
3.75 (s, 3H), 3.87 (s, 3H), 4.55 (s, 2H), 6.34 (d, 2H, J ) 9.8
Hz), 6.67 (s, 1H), 7.00 (s, 1H), 7.41 (d, 2H, J ) 10.5 Hz).
1
1686, 1662; H NMR (500 MHz, CDCl3) δ 2.34-2.40 (m, 2H),
3.93-3.97 (m, 2H), 4.77, 4.80 (s, 2H), 6,29, 6.31 (d, 2H, J )
10.3 Hz), 6.68-6.71 (m, 1.5H), 6.86 (d, 0.5H, J ) 2.6 Hz), 6.92,
7.04 (d, 2H, J ) 10.3 Hz), 6.95 (d, 1H, J ) 8.6 Hz). Anal. Calcd
for C17H14NO3F3: C, 60.54; H, 4.18; N, 4.15. Found: C, 60.31;
H, 4.29; N, 4.12.
(()-7-Dem et h oxy-N-(t r iflu or oa cet yl)n a r w ed in e (13):
colorless amorphus: IR 1687, 1590; 1H NMR (500 MHz, CDCl3)
δ 2.09-2.26 (m, 2H), 2.77 (ddd, 1H, J ) 18.0, 6.8, 3.4 Hz),
3.10 (d, 1H. J ) 18.0 Hz), 3.39 (dd, 0.5H, J ) 12.8, 12.0 Hz),
3.73-3.79 (dd, 0.5H, J ) 14.5, 13.6 Hz), 4.19 (d, 0.5H, J )
15.4 Hz), 4.37 (d, 0.5H, J ) 15.4 Hz), 4.60 (d, 0.5H, J ) 16.3
Hz), 4.68 (d, 0.5H, J ) 2.6 Hz), 4.77 (d, 0.5H, J ) 13.7 Hz),
4.95 (d, 0.5H, J ) 16.2 Hz), 5.35 (d, 0.5H, J ) 14.5 Hz), 6.07
J O9606766