An intramolecular cyclization of phenol derivatives bearing aminoquinones using a hypervalent iodine reagent

Article abstract of DOI:10.1021/jo951439q

The hypervalent iodine oxidation of phenol derivatives bearing aminoquinones at the ortho (9) or meta positions (19) in 2,2,2-trifluoroethanol was investigated with the aim of preparing novel antitumor compounds. Azacarbocyclic spirodienone derivatives (13) or phenol derivatives containing the 2,3-dihydro-1H-azepine systems (17, 20) were selectively obtained by the reaction of these phenol derivatives and the hypervalent iodine reagent, phenyliodine(III) bis(trifluoroacetate). The application of this reaction to phenol derivatives bearing aminoquinones (10-12) is also described.

Full text of DOI:10.1021/jo951439q

J . Org. Chem. 1996, 61, 223-227
223
An In tr a m olecu la r Cycliza tion of P h en ol Der iva tives Bea r in g
Am in oqu in on es Usin g a Hyp er va len t Iod in e Rea gen t
Yasuyuki Kita,* Takeshi Takada, Megumi Ibaraki, Michiyo Gyoten, Sachiko Mihara,
Shigekazu Fujita, and Hirofumi Tohma
Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565, J apan
Received August 3, 1995X
The hypervalent iodine oxidation of phenol derivatives bearing aminoquinones at the ortho (9) or
meta positions (19) in 2,2,2-trifluoroethanol was investigated with the aim of preparing novel
antitumor compounds. Azacarbocyclic spirodienone derivatives (13) or phenol derivatives containing
the 2,3-dihydro-1H-azepine systems (17, 20) were selectively obtained by the reaction of these phenol
derivatives and the hypervalent iodine reagent, phenyliodine(III) bis(trifluoroacetate). The
application of this reaction to phenol derivatives bearing aminoquinones (10-12) is also described.
Sch em e 1. Sp ir ocycliza tion of P a r a -Su bstitu ted
In tr od u ction
P h en ol Der iva tives w ith P IF A
Hypervalent iodine compounds have attracted much
attention as useful synthetic reagents,1 first because of
their reactivity which closely resembles that of heavy
metal salts such as Hg(II), Tl(III), or Pb(IV) and second
because of their lower toxicity and ready availability. As
part of our continuing studies on hypervalent iodine
chemistry,2,3 we have reported the intramolecular cy-
clization of para-substituted phenolic aminoquinones (1)
using phenyliodine(III) bis(trifluoroacetate) (PIFA)4
(Scheme 1) and applied this method to the total synthesis
of discorhabdin C,5 which was isolated from the sponge
of Latrunculia du Bocage in New Zealand, as exemplified
in Scheme 1.
We now report that the intramolecular cyclization of
phenol derivatives bearing aminoquinones at the ortho
or meta positions provides a versatile route to the
otherwise difficult to obtain heterocyclic compounds.
Resu lts a n d Discu ssion
1. Rea ction of P h en ol Der iva tives Bea r in g Am i-
n oqu in on es a t th e Or th o P osition . We first examined
the reactivity of phenol derivatives bearing aminoquino-
nes at the ortho position. The starting ortho-substituted
phenol derivatives (9-12) were prepared from 2-hy-
droxybenzaldehyde (2) via 2-hydroxy-â-phenethylamine
(5). Thus, the aldehyde 2 was alkylated to give the
benzyl ether (3). Condensation of 3 with nitromethane
under standard conditions gave the R,â-unsaturated nitro
compound (4), which was reduced with lithium aluminum
hydride (LAH) in tetrahydrofuran (THF) followed by
catalytic hydrogenation to give 5. To a solution of 5 in
ethanol was added the naphthoquinone derivatives (6-
8)6 to give the corresponding ortho-substituted phenol
derivatives (9a , 10-12). The silyl ethers (9b,c) were
readily prepared from 9a by standard methods7 (Scheme
2).
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) 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,
Supplement D; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, 1983;
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.
(2) (a) Tamura, Y.; Yakura, T.; Haruta, J .; Kita, Y. Tetrahedron Lett.
1985, 26, 3837. (b) Kita, Y.; Yakura, T.; Terashi, H.; Haruta, J .;
Tamura, Y. Chem. Pharm. Bull. 1989, 37, 891 and references cited
therein.
(3) (a) Tamura, Y.; Yakura, T.; Haruta, J .; Kita, Y. J . Org. Chem.
1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.;
Yakura, T. Ibid. 1991, 56, 435. (c) Tamura, Y.; Yakura, T.; Tohma, H.;
Kikuchi, K.; Kita, Y. Synthesis 1989, 126.
(4) (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.
(5) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J .
Am. Chem. Soc. 1992, 114, 2175.
Treatment of the ortho-substituted phenol derivative
9a with PIFA in CF3CH2OH at room temperature gave
the azacarbocyclic spirodienone derivative (13) in 74%
yield. Similarly, the (trimethylsilyl)oxy and (tert-bu-
tyldimethylsilyl)oxy phenol derivatives 9b and 9c were
converted to 13 in good yields (75-76%). Treatment of
other phenol derivatives (10-12) with PIFA in CF3CH2-
OH gave the corresponding spirodienone derivatives (14-
16) under similar conditions. These results are summa-
rized in Table 1. A reasonable mechanism for these
(6) (a) Otsuji, T. Bull. Chem. Soc. J pn. 1976, 49, 2596. (b) Prett, Y.
T.; Drake, N. L. J . Am. Chem. Soc. 1960, 82, 1155. (c) Warren, J . D.;
Lee, V. J .; Angier, R. B. J . Hetrocycl. Chem. 1979, 16, 1617.
(7) The trimethylsilyl ether (9b) was prepared by the reaction of
9a with the O-silylated ketene acetal in CH2Cl2 under nitrogen and
used without further purification; see ref 4a.
0022-3263/96/1961-0223$12.00/0 © 1996 American Chemical Society

224 J . Org. Chem., Vol. 61, No. 1, 1996
Sch em e 2. Syn th etic Meth od for Or th o-Su bstitu ted P h en ol Der iva tives
Kita et al.
Ta ble 1. Sp ir ocycliza tion of Or th o-Su bstitu ted P h en ol
Sch em e 3. A Rea son a ble Mech a n ism for th e
Sp ir ocycliza tion of Or th o-Su bstitu ted P h en ol
Der iva tives w ith P IF A
Der iva tives
a dienone/phenol rearrangement from one side by elec-
tron donation of the nitrogen atom, to give the azepine
derivatives 17. A similar rearrangement took place with
the reaction of the spirodienone product 13 with BF3‚-
Et2O to give a single product (18) in an almost quantita-
tive yield based on the reacted spirodienone product
(Scheme 4).
2. Rea ction of P h en ols Bea r in g Am in oqu in on es
a t th e Meta P osition . Meta-substituted phenol deriva-
tives (19a -d ) are obtained using a method8 similar to
that for the preparation of ortho-substituted phenol
derivatives 9. Using these phenol derivatives 19a -d , we
examined the reactivity of meta-substituted compounds
with PIFA. It was found that treatment of the tert-
butyldimethylsilyl ether 19a or the methyl ether 19b
with PIFA in CF3CH2OH at room temperature gave the
corresponding substitution products 2,3-dihydro-1H-
azepine derivatives (20a and 20b), respectively, in mod-
erate yields (Scheme 5).
transformation is explained in Scheme 3. PIFA reacts
selectively with the aminoquinone moiety of the ortho-
substituted phenol derivatives 9a -c, 10a ,b, 11, and 12
to give the intermediates (i), which cyclize to the spiro-
dienones 13-16. This is probably due to the ready
cleavage of the R-O bond (R ) H or SiR3) of the
spirodienone intermediates (ii) by a nucleophilic attack
of the generated trifluoroacetoxy anion.
The methyl ether 9d , on the other hand, when treated
with PIFA gave the rearrangement product, the 2,3-
dihydro-1H-azepine derivative (17) in 61% yield, with
none of the spirodienone derivative 13 being obtained.
The reaction presumably proceeds first with spirocy-
clization to give the intermediate (iii), which undergoes
(8) 3-Hydroxy-â-phenethylamine and 3-methoxy-â-phenethylamine
were prepared by the reported method: Dally, L.; Horner, L.; Witkop,
B. J . Am. Chem. Soc. 1961, 83, 4787.

Cyclization of Phenol Derivatives Using Iodinane
J . Org. Chem., Vol. 61, No. 1, 1996 225
Sch em e 4. Cycliza tion of th e Or th o-Su bstitu ted
Sch em e 7. Rea ction of Mod el Com p ou n d s Ea ch
Ha vin g th e Rea ctive Moieties of 19 w ith P IF A
An isole w ith P IF A
Sch em e 5. Cycliza tion of Meta -Su bstitu ted
P h en ol Der iva tives w ith P IF A
of 19. Treatment of 21 or 22 with PIFA in CF3CH2OH
produced the diaryliodonium salt (23) or the naphtho-
quinone derivative (24), respectively. To a solution
containing equimolar amounts of 21 and 22 was added
PIFA, which gave similar amounts of 23 and 24. There
is, therefore, little difference in the reactivity toward
PIFA between 21 and 22. Compound 21 was treated
with PIFA in CF3CH2OH containing a small quantity of
methanol to give the diaryliodonium salt 23, while 22,
when treated with PIFA under similar conditions, gave
compound 25 having the methoxy group on the quinone
ring due to nucleophilic attack of methanol on the
intermediate vi. The reactivity of the intermediate vi
derived from 22 is, therefore, higher than that of the
diaryliodonium salt 23 derived from 21 (Scheme 7).
In addition, diaryliodonium salts having electron-
donating groups such as 23 are usually very stable and
may react with only very strong nucleophiles to give
substituted products;10 therefore, nucleophilic substitu-
tion of 19 may not proceed because of the weak nucleo-
philicity of the aminoquinone site of 19.
Sch em e 6. Rea ction Mech a n ism of th e
Cycliza tion of Meta -Su bstitu ted P h en ol
Der iva tives w ith P IF A
The cyclization reaction presumably proceeds with the
initial attack of the PIFA iodo center on the amino-
quinone site of 19 and subsequent nucleophilic attack of
the aromatic ring to give 20.
In general, meta-substituted phenol ethers usually
react with PIFA to give diaryliodonium salts.9 Therefore,
meta-substituted phenol derivatives 19 react with PIFA
to give the diaryliodonium salt (iv) or the intermediate
(v) by the nucleophilic attack of the aminoquinone site
of 19 on the iodo center of PIFA (Scheme 6).
Con clu sion s
To confirm the reaction mechanism of this reaction,
we performed the following experiment using the meta-
substituted phenol ether (21) and the aminoquinone (22)
as model compounds, each having the reactive moieties
Azacarbocyclic spirodienones or phenol derivatives
containing the 2,3-dihydro-1H-azepine systems were
selectively obtained by the reaction of ortho-substituted
(9) An intramolecular nucleophilic substitution on an aryliodonium
salt has been reported by us, see: Kita, Y.; Okunaka, R.; Kondo, M.;
Tohma, H.; Inagaki, M.; Hatanaka, K. J . Chem. Soc., Chem. Commun.
1992, 429.
(10) Iodonium salts of phenols having electron-withdrawing groups
react with strong nucleophiles such as -OH, -OR, or H2NR, while they
are nonreactive in the presence of weak nucleophiles; Spiroudis, A.;
Varvoglis, A. J . Chem. Soc., Perkin Trans. 1 1984, 135.

226 J . Org. Chem., Vol. 61, No. 1, 1996
Kita et al.
1H, J ) 7.6, 1.3 Hz), 8.00 (dd, 1H, J ) 7.4, 1.2 Hz), 8.10 (dd,
1H, J ) 7.4, 1.2 Hz). Anal. Calcd for C24H29NO3Si: C, 70.71;
H, 7.19; N, 3.44. Found: C, 70.70; H, 7.21; N, 3.41.
phenol derivatives and PIFA. This intramolecular cy-
clization was applied to the preparation of spirodienone
compounds bearing aminoquinones. Furthermore, treat-
ment of meta-substituted phenol derivatives with PIFA
only gave phenol derivatives containing the 2,3-dihydro-
1H-azepine systems. In conclusion, we confirmed the
difference in reactivities between the ortho- and meta-
substituted phenol derivatives protected by methyl or
silyl groups and could selectively obtain the pharmaco-
logically important azacarbocyclic spirodienones or 1H-
azepine derivatives in good yields.
2-[[2-(2-Me t h oxyp h e n yl)e t h yl]a m in o]-1,4-n a p h t h o-
qu in on e (9d ). To a solution of 2-methoxy-â-phenethylamine
(149.5 mg, 0.990 mmol) in ethanol (12 mL) was added 6 (186.1
mg, 0.990 mmol) at room temperature under nitrogen. The
reaction mixture was refluxed for 3 h and then concentrated
in vacuo. The residue was purified by column chromatography
with n-hexane-ethyl acetate to give 9d (236.1 mg, 78%) which
was recrystallized from n-hexane-CH2Cl2 to give a pure
sample as brown crystals: mp 140-141 °C; IR 3390, 3020,
1680, 1610, 1570, 1510, 1490, 1350; 1H NMR (270 MHz, CDCl3)
δ 3.02 (t, 2H, J ) 6.6 Hz), 3.38 (q, 2H, J ) 6.3 Hz), 3.96 (s,
3H), 5.75 (s, 1H), 6.50 (brs, 1H), 6.80-6.95 (m, 2H), 7.15-
7.28 (m, 2H), 7.59 (td, 1H, J ) 7.3, 1.3 Hz), 7.70 (td, 1H, J )
7.3, 1.3 Hz), 8.01 (d, 1H, J ) 7.7 Hz), 8.09 (d, 1H, J ) 7.9 Hz).
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56.
Found: C, 73.97; H, 5.69; N, 4.49.
Exp er im en ta l Section
All melting points are uncorrected. Infrared (IR) absorption
spectra were recorded with CHCl3 as a solvent. E. Merck silica
gel 60 for column chromatography and E. Merck precoated
TLC plates, silica gel F254 for preparative thin layer chroma-
tography (preparative TLC) were used. Organic layers were
dried with anhydrous Na2SO4. PIFA is commercially avail-
able. Starting materials (2, 21) were purchased, and com-
pounds 6,6a 7,6b 8,6c and 2211 were prepared by the reported
methods.
2-Hydr oxy-â-ph en eth ylam in e (5). To a solution of 2-(benz-
yloxy)benzaldehyde (3) (10.5 g, 49.6 mmol) in acetic acid (40
mL) containing ammonium acetate (1.5 g, 19.8 mmol) was
added nitromethane (9.1 g, 148.9 mmol). The reaction mixture
was refluxed for 1.5 h and then concentrated in vacuo. The
residue was dissolved in methylene chloride (CH2Cl2) and
washed with water. The solution was dried and evaporated
to give 2-(benzyloxy)-â-nitrostyrene (4) (11.5 g, 91%). To a
suspension of LAH (0.38 g, 10.0 mmol) in THF (10 mL) was
added a solution of 4 (1.03 g, 4.01 mmol) in THF (10 mL) at 0
°C under nitrogen, and then the solution was stirred at room
temperature for 3 h. Water (0.40 mL) and 15% aqueous NaOH
(0.40 mL) were added to a reaction mixture. The organic layer
was dried and evaporated. The residue was hydrogenated in
ethanol (90 mL) over 10% Pd-C (90 mg) at room temperature
for 24 h under a hydrogen atmosphere (3.8 atm). After
filtration, the filtrate was evaporated to give 5 (793.7 mg, 85%).
The spectra (1H NMR and IR) data of 5 were in good accord
with the literature.12
2-[[2-(2-Hydr oxyph en yl)eth yl]am in o]-1,4-n aph th oqu in o-
n e (9a ). To a solution of 5 (55.0 mg, 0.365 mmol) in ethanol
(5 mL) was added 6 (68.6 mg, 0.365 mmol) at room tempera-
ture under nitrogen. The reaction mixture was refluxed for 5
h and then concentrated in vacuo. The residue was purified
by column chromatography with CH2Cl2 to give 9a (59.4 mg,
59%) which was recrystallized from n-hexane-ethyl acetate
to give a pure sample as a dark brown powder: mp 184-185
°C; IR 3300, 3250, 3010, 1680, 1610, 1570, 1510, 1360, 1260;
1H NMR (270 MHz, CDCl3) δ 3.03 (t, 2H, J ) 6.9 Hz), 3.45 (q,
2H, J ) 6.9 Hz), 5.81 (s, 1H), 6.48 (brs, 1H), 6.80 (d, 1H, J )
7.9 Hz), 6.89 (t, 1H, J ) 7.6 Hz), 7.10-7.16 (m, 2H), 7.60 (td,
1H, J ) 7.6, 1.3 Hz), 7.72 (td, 1H, J ) 7.6, 1.3 Hz), 8.01 (dd,
1H, J ) 7.6, 1.3 Hz), 8.10 (dd, 1H, J ) 7.6, 1.3 Hz). Anal.
Calcd for C18H15NO3: C, 73.70; H, 5.15; N, 4.78. Found: C,
73.43; H, 5.24; N, 4.70.
7-[[2-(2-Hyd r oxyp h en yl)eth yl]a m in o]qu in olin e-5,8-d i-
on e (10a ). To a solution of 5 (414.4 mg, 3.02 mmol) in ethanol
(39 mL) was added 7 (480.9 mg, 3.02 mmol) at room temper-
ature under nitrogen. The mixture was stirred for 15 min and
then concentrated in vacuo. The residue was purified by
column chromatography with MeOH-CH2Cl2 to give 10 (277.8
mg, 31%) which was recrystallized from CH2Cl2-ethyl acetate
to give a pure sample as red crystals: mp 239-242 °C; IR 3030,
1
1690, 1605, 1570, 1460, 1330; H NMR (270 MHz, CD3OD) δ
2.98 (t, 2H, J ) 7.2 Hz), 3.49 (q, 2H, J ) 6.9 Hz), 5.97 (s, 1H),
6.72-6.80 (m, 2H), 7.01-7.12 (2H, m), 7.69 (q, 1H, J ) 7.9
Hz), 8.41 (dd, 1H, J ) 7.7, 1.7 Hz), 8.89 (d, 1H, J ) 4.0 Hz);
HRMS calcd for C17H14N2O3 (M+) 294.1002, found 294.0987.
6-[[2-(2-Hyd r oxyp h en yl)eth yl]a m in o]qu in olin e-5,8-d i-
on e (11) was obtained by the same method as described (242.0
mg, 27%) as red crystals: mp 225-227 °C; IR 3300, 3030, 1690,
1
1630, 1570, 1510, 1460, 1340; H NMR (270 MHz, CDCl3) δ
3.07 (t, 2H, J ) 7.2 Hz), 3.48 (q, 2H, J ) 6.9 Hz), 5.85 (s, 1H),
6.79-6.96 (m, 2H), 7.09-7.12 (m, 2H), 7.64 (dd, 1H, J ) 7.8,
4.8 Hz), 8.41 (dd, 1H, J ) 7.9, 1.7 Hz), 8.87 (dd, 1H, J ) 4.8,
1.8 Hz); HRMS calcd for C17H14N2O3 (M+) 294.1002, found
294.0993. Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N,
9.52. Found: C, 69.02; H, 4.90; N, 9.47.
2,3-Dim eth yl-6-[[2-(2-h yd r oxyp h en yl)eth yl]a m in o]qu i-
n oxa lin e-5,8-d ion e (12a ). To a solution of 5 (161.7 mg, 1.18
mmol) in ethanol (16 mL) was added 8 (222.4 mg, 1.18 mmol)
at room temperature under nitrogen. The mixture was stirred
for 20 min and then concentrated in vacuo. The residue was
purified by column chromatography with MeOH-CH2Cl2 to
give 12a (307.4 mg, 81%) which was recrystallized from
n-hexane-CH2Cl2 to give a pure sample as red crystals: mp
1
226-227 °C; IR 3030, 1690, 1610, 1460, 1340; H NMR (270
MHz, CDCl3) δ 2.62 (s, 3H), 2.67 (s, 3H), 2.97 (t, 2H, J ) 6.4
Hz), 3.39-3.43 (m, 2H), 5.88 (s, 1H), 6.73-6.79 (m, 2H), 7.02
(t, 2H, J ) 7.6 Hz); HRMS calcd for C18H17N3O3 (M+) 323.1270,
found 323.1271.
Gen er a l P r oced u r e for th e Oxid a tion of Or th o-Su b-
stitu ted P h en ol Der iva tives to Sp ir od ien on s. To a stirred
suspension of the phenol derivative (0.1 mmol) in CF3CH2OH
(2 mL) was added PIFA (0.12 mmol) at room temperature
under nitrogen, and the solution was stirred for 0.5 h. Water
was added to the reaction mixture, and then the solution was
extracted with CH2Cl2. The organic layer was washed with
saturated sodium chloride, dried, and evaporated. The residue
was purified by column chromatography to give the spirodi-
enone derivative in reasonable yield.
1,2,3,4,5,10-Hexa h yd r oben zo[g]qu in olin e-5,10-d ion e-4-
sp ir o-1′-cycloh exa -3′,5′-d ien -2′-on e (13). Reactants: 9a
(107.0 mg, 0.365 mmol); PIFA (188.4 mg, 0.438 mmol); CF3-
CH2OH (8 mL). 13 (78.1 mg, 74%): red crystals; mp 240-
243 °C (from CH2Cl2-ethyl acetate); IR 3410, 3010, 1680, 1660,
1630, 1610, 1570, 1520, 1360, 1350; 1H NMR (270 MHz, CDCl3)
δ 1.88-2.10 (m, 2H), 3.40-3.68 (m, 2H), 6.18 (brs, 1H), 6.28
(d, 1H, J ) 9.9 Hz), 6.35-6.37 (m, 2H), 7.13 (ddd, 1H, J ) 7.4,
4.8, 2.5 Hz), 7.65 (td, 1H, J ) 7.5, 1.4 Hz), 7.66 (td, 1H, J )
7.5, 1.4 Hz), 7.98 (dd, 1H, J ) 2.8, 1.3 Hz), 8.00 (dd, 1H, J )
2.6, 1.7 Hz); HRMS calcd for C18H13NO3 (M+) 291.0893, found
2-{[2-[2-((ter t-Bu t yld im et h ylsilyl)oxy)p h en yl]et h yl]-
a m in o}-1,4-n a p h th oqu in on e (9c). To a solution of 9a (50.6
mg, 0.173 mmol) in DMF (0.5 mL) were added imidazole (35.3
mg, 0.519 mmol) and tert-butyldimethylsilyl chloride (39.0 mg,
0.259 mmol) at room temperature under nitrogen. The
mixture was stirred for 3.5 h and then concentrated in vacuo.
The residue was purified by column chromatography with
n-hexane-ethyl acetate to give 9c (67.0 mg, 95%) which was
recrystallized from n-hexane-CH2Cl2 to give a pure sample
as red crystals: mp 105-106 °C; IR 3390, 2930, 2860, 1680,
1
1610, 1570, 1510, 1470, 1360; H NMR (270 MHz, CDCl3) δ
0.28 (s, 6H), 1.01 (s, 9H), 2.97 (t, 2H, J ) 6.8 Hz), 3.42 (q, 2H,
J ) 6.8 Hz), 5.72 (s, 1H), 6.11 (brs, 1H), 6.87 (m, 2H), 7.12 (td,
2H, J ) 7.3, 2.0 Hz), 7.57 (td, 1H, J ) 7.6, 1.3 Hz), 7.69 (td,
(11) Velluz, L.; Amiard, G.; Heymes, R. Bull. Soc. Chim. Fr. 1954,
1012.
(12) Rastetter, W. H.; Nummy, L. J . J . Org. Chem. 1980, 45, 3149.

Cyclization of Phenol Derivatives Using Iodinane
J . Org. Chem., Vol. 61, No. 1, 1996 227
291.0893. Anal. Calcd for C18H13NO3: C, 69.38; H, 4.79; N,
9.52. Found: C, 69.02; H, 4.90; N, 9.47.
for C24H29NO3Si: C, 70.71; H, 7.19; N, 3.44. Found: C, 70.49;
H, 7.27; N, 3.31.
5,6,7,8,9,10-Hexa h yd r op yr id o[3,2-g]qu in olin e-5,10-d i-
on e-6-sp ir o-1′-cycloh exa -3′,5′-d ien -2′-on e (14). Reactants:
10a (20.1 mg, 0.0634 mmol); PIFA (44.1 mg, 0.103 mmol); CF3-
CH2OH (3 mL). 14 (7.4 mg, 40%): orange crystals; mp >300
°C (from CH3OH-CH2Cl2); IR 3400, 3250, 1680, 1660, 1620,
2-[[2-(3-Me t h oxyp h e n yl)e t h yl]a m in o]-1,4-n a p h t h o-
qu in on e (19b). To a solution of 3-methoxy-â-phenethylamine
(576.3 mg, 3.82 mmol) in ethanol (45 mL) was added 6 (717.5
mg, 3.82 mmol) at room temperature under nitrogen. The
mixture was stirred for 48 h and then concentrated in vacuo.
The residue was purified by column chromatography with CH2-
Cl2 to give 19b (640.4 mg, 55%) which was recrystallized from
n-hexane-CH2Cl2 to give a pure sample as dark brown
crystals: mp 126-127 °C; IR 3390, 3020, 1680, 1610, 1570,
1510, 1490, 1350, 1330; 1H NMR (270 MHz, CDCl3) δ 2.92 (t,
2H, J ) 7.1 Hz), 3.45 (q, 2H, J ) 6.7 Hz), 3.81 (s, 3H), 5.79 (s,
1H), 5.96 (brs, 1H), 6.76-6.86 (m, 3H), 7.26 (t, 1H, J ) 7.8
Hz), 7.61 (td, 1H, J ) 7.4, 1.0 Hz), 7.72 (td, 1H, J ) 7.4, 1.3
Hz), 8.03 (d, 1H, J ) 7.6 Hz), 8.10 (d, 1H, J ) 7.9 Hz). Anal.
Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.00; H, 5.64; N, 4.51.
1
1610, 1570, 1520, 1330, 1320; H NMR (270 MHz, CDCl3) δ
1.90-2.12 (m, 2H), 3.44-3.66 (m, 2H), 6.18 (brs, 1H), 6.25 (d,
1H, J ) 9.9 Hz), 6.34 (d, 1H, J ) 3.6 Hz), 7.12 (td, 1H, J )
9.9, 3.7 Hz), 7.51(dd, 1H, J ) 7.8, 4.8 Hz), 8.30 (dd, 2H, J )
7.8, 2.0 Hz), 8.92 (d, 1H, J ) 3.6 Hz); HRMS calcd for
C17H12N2O3 (M+) 292.0847, found 292.0847.
5,6,7,8,9,10-Hexa h yd r op yr id o[2,3-g]qu in olin e-5,10-d i-
on e-9-sp ir o-1′-cycloh exa -3′,5′-d ien -2′-on e (15). Reactants:
11 (34.5 mg, 0.117 mmol); PIFA (60.5 mg, 0.141 mmol), CF3-
CH2OH (3 mL). 15 (16.6 mg, 51%): red powder; mp 270-273
°C (from CH3OH-CH2Cl2); IR 3400, 3020, 1730, 1690, 1660,
1
1600, 1560, 1520, 1330; H NMR (270 MHz, CDCl3) δ 1.92-
2.13 (m, 2H), 3.42-3.74 (m, 2H), 6.29 (d, 1H, J ) 9.6 Hz), 6.38
(d, 2H, J ) 8.9 Hz), 6.45 (brs, 1H) 7.13-7.20 (m, 1H), 7.57-
7.62 (m, 1H), 8.32 (dd, 2H, J ) 7.9, 1.7 Hz), 8.88 (dd, 2H, J )
4.6, 1.3 Hz); HRMS calcd for C17H12N2O3 (M+) 292.0846, found
292.0839.
5,6,7,8,9,10-H e x a h y d r o -2,3-d im e t h y lp y r id o [2,3-g ]-
qu in oxa lin e-5,10-d ion e-9-sp ir o-1′-cycloh exa -3′,5′-d ien -2′-
on e (16). Reactants: 12a (134.2 mg, 0.415 mmol); PIFA (268.0
mg, 0.623 mmol); CF3CH2OH (8 mL). 16 (46.6 mg, 35%): red
crystals; mp >300 °C (from CH3OH-CH2Cl2); IR 3400, 3010,
1690, 1660, 1630, 1610, 1560, 1540, 1520, 1340; 1H NMR (270
MHz, CD3OD) δ 1.91-1.95 (m, 2H), 2.66 (s, 6H), 3.43-3.64
(m, 2H), 6.18 (d, 1H, J ) 9.6 Hz), 6.34 (dd, 1H, J ) 9.2, 5.9
Hz), 6.53 (d, 1H, J ) 9.6 Hz), 7.21 (dd, 1H, J ) 8.7, 4.7 Hz);
HRMS calcd for C18H13NO3 (M+) 321.1114, found 321.1117.
2-[[2-(3-H yd r oxyp h e n yl)e t h yl]a m in o]-1,4-n a p h t h o-
qu in on e (19c). To a solution of 3-hydroxy-â-phenethylamine
(42.0 mg, 0.223 mmol) in ethanol (3 mL) was added 6 (30.6
mg, 0.223 mmol) at room temperature under nitrogen. The
mixture was refluxed for 3 h and then cooled. The mixture
was concentrated in vacuo, and the residue was purified by
column chromatography with CH2Cl2 to give 19c (50.2 mg,
77%) which was recrystallized from n-hexane-CH2Cl2 to give
a pure sample as a reddish brown powder: mp 171-173 °C;
1
IR 3390, 3030, 1680, 1610, 1570, 1510, 1460, 1360, 1330; H
NMR (270 MHz, CDCl3) δ 2.91 (t, 2H, J ) 7.1 Hz), 3.44 (q,
2H, J ) 6.4 Hz), 5.79 (s, 1H), 6.07 (brs, 1H), 6.73-6.75 (m,
3H), 7.18 (td, 1H, J ) 7.6, 1.5 Hz), 7.61 (td, 1H, J ) 7.6, 1.3
Hz), 7.73 (td, 1H, J ) 7.6, 1.3 Hz), 8.02 (dd, 1H, J ) 7.6, 1.3
Hz), 8.09 (dd, 1H, J ) 7.6, 1.3 Hz). Anal. Calcd for C18H15
-
5,6,8,13-Te t r a h yd r o-4-m e t h oxyn a p h t h o[a ][3]b e n z-
a zep in e-8,13-d ion e (17a ). Reactants: 9d (20.0 mg, 0.065
mmol); PIFA (33.6 mg, 0.078 mmol); CF3CH2OH (3 mL). 17a
(12.1 mg, 61%): red crystals; mp 195-196 °C (from n-hexane-
CH2Cl2); IR 3350, 3000, 1670, 1630, 1600, 1530, 1460, 1440,
NO3: C, 73.70; H, 5.15; N, 4.78. Found: C, 73.29; H, 5.29; N,
4.66.
Gen er a l P r oced u r e for th e Oxid a tion of Meta -Su bsti-
tu ted P h en ol Der iva tives. To a stirred suspension of the
phenol derivative (0.1 mmol) in CF3CH2OH (2 mL) was added
PIFA (0.12 mmol) at room temperature under nitrogen, and
the solution was stirred for 20 min. Water was added to the
reaction mixture, which was then extracted with CH2Cl2. The
organic layer was washed with saturated sodium chloride,
dried, and evaporated. The residue was purified by prepara-
tive TLC to give the dihydroazepine derivative in moderate
yield.
1
1330; H NMR (270 MHz, CDCl3) δ 3.19 (t, 2H, J ) 4.6 Hz),
3.78-3.83 (m, 2H), 3.74 (s, 3H), 6.53 (d, 1H, J ) 9.6 Hz), 7.21
(dd, 1H, J ) 8.7, 4.7 Hz); HRMS calcd for C19H15NO3 (M+)
305.1051, found 305.1051. Anal. Calcd for C19H15NO3: C,
74.73; H, 4.96; N, 4.59. Found: C, 74.45; H, 4.98; N, 4.56.
Th e Dien on e P h en ol-Typ e Rea r r a n gem en t of th e
Sp ir od ien on e Com p ou n d 13. To a solution of 13 (23.2 mg,
0.080 mmol) in CH2Cl2 (4 mL) was added BF3‚Et2O (22.6 mg,
0.159 mmol) at room temperature under nitrogen and stirred
for 48 h. The solution was evaporated, and the residue was
purified by preparative TLC to give 18 (15.2 mg, 66%) and
unreacted starting material 13 (7.9 mg, 34%).
To a solution of 18 (6.4 mg, 0.022 mmol) in anhydrous
acetone containing potassium carbonate (15.2 mg, 0.110 mmol)
was added dimethyl sulfate (0.008 mL, 0.084 mmol) at room
temperature, and the solution was refluxed for 3 h. The
solution was evaporated, and a saturated aqueous solution of
sodium bicarbonate was then added which was then extracted
with CH2Cl2. The organic layer was dried and evaporated. The
residue was purified by preparative TLC to give 17a (3.0 mg,
47%).
3 -[(t e r t -B u t y l d i m e t h y l s i l y l )o x y ]-5 ,6 ,8 ,1 3 -t e t r a -
h yd r on a p h th o[a ][3]ben za zep in e-8,13-d ion e (20a ). React-
ants: 19a (22.2 mg, 0.056 mmol); PIFA (29.0 mg, 0.067 mmol);
CF3CH2OH (3 mL). 20a (8.6 mg, 39%): red crystals; mp 116-
117 °C (from n-hexane-CH2Cl2); IR 3360, 3010, 2960, 2930,
2860, 1670, 1600, 1570, 1530, 1470, 1350, 1330; 1H NMR (270
MHz, CDCl3) δ 0.23 (s, 6H), 1.25 (s, 9H), 2.96 (t, 2H, J ) 4.6
Hz), 3.82 (q, 2H, J ) 4.6 Hz), 6.27 (brs, 1H), 6.38 (d, 1H, J )
2.3 Hz), 6.78 (dd, 1H, J ) 8.6, 2.6 Hz), 7.24 (d, 1H, J ) 8.6
Hz), 7.62 (td, 1H, J ) 7.6, 1.3 Hz), 7.74 (td, 1H, J ) 7.6, 1.1
Hz), 8.06 (dd, 1H, J ) 7.6, 1.3 Hz), 8.19 (dd, 1H, J ) 7.6, 1.3
Hz); HRMS calcd for
C
24H27NO3Si (M+) 405.1758, found
405.1758. Anal. Calcd for C24H27NO3Si: C, 71.08; H, 6.71;
N, 3.45. Found: C, 70.94; H, 6.86; N, 3.45.
2-{[2-[3-[(ter t-Bu t yld im et h ylsilyl)oxy]p h en yl]et h yl]-
a m in o}-1,4-n a p h th oqu in on e (19a ). To a solution of 19c
(22.6 mg, 0.0771 mmol) in DMF (1 mL) were added imidazole
(15.8 mg, 0.231 mmol) and tert-butyldimethylsilyl chloride
(17.4 mg, 0.116 mmol) at room temperature under nitrogen.
The mixture was stirred for 4.5 h and then concentrated in
vacuo. The residue was purified by preparative TLC with
n-hexane-ethyl acetate to give 19a (21.9 mg, 70%) which was
recrystallized from n-hexane-CH2Cl2 to give a pure sample
as red crystals: mp 135-136 °C; IR 3390, 3010, 1680, 1610,
5 ,6 ,8 ,1 3 -T e t r a h y d r o -3 -m e t h o x y n a p h t h o [ a ][3 ]-
ben za zep in e-8,13-d ion e (20b). Reactants: 19b (31.0 mg,
0.101 mmol); PIFA (52.1 mg, 0.121 mmol); CF3CH2OH (3 mL).
20b (18.3 mg, 59%): red crystals; mp 228-230 °C (from
n-hexane-CH2Cl2); IR 3360, 3010, 1670, 1600, 1570, 1520,
1
1500, 1470, 1350, 1330; H NMR (270 MHz, CDCl3) δ 3.00 (t,
2H, J ) 4.6 Hz), 3.76-3.91 (m, 2H), 3.84 (s, 3H), 6.51 (brs,
1H), 6.65 (d, 1H, J ) 2.6 Hz), 6.86 (dd, 1H, J ) 8.9, 3.0 Hz),
7.50 (d, 1H, J ) 8.9 Hz), 7.62 (td, 1H, J ) 7.6, 1.3 Hz), 7.73
(td, 1H, J ) 7.6, 1.1 Hz), 8.05 (dd, 1H, J ) 7.6, 1.3 Hz), 8.18
(dd, 1H, J ) 7.6, 1.3 Hz); HRMS calcd for C19H15NO3 (M+)
305.1052, found 305.1063.
1
1570, 1510, 1490, 1350, 1330; H NMR (270 MHz, CDCl3) δ
0.97 (s, 6H), 1.57 (s, 9H), 2.92 (t, 2H, J ) 7.1 Hz), 3.44 (q, 2H,
J ) 6.6 Hz), 5.78 (s, 1H), 5.98 (brs, 1H), 6.70-6.76 (m, 2H),
6.82 (d, 1H, J ) 7.9 Hz), 7.19 (t, 1H, J ) 7.7 Hz), 7.61 (td, 1H,
J ) 7.4, 1.3 Hz), 7.73 (td, 1H, J ) 7.6, 1.3 Hz), 8.03 (dd, 1H,
J ) 7.6, 1.3 Hz), 8.10 (dd, 1H, J ) 7.6, 1.3 Hz). Anal. Calcd
J O951439Q