Synthesis, conformational analysis and free radical scavenging activity of some new spiropyranoquinolinones.

Article abstract of DOI:10.1248/cpb.51.522

A series of novel spiroadamantyl- and spirocyclical substituted pyranoquinolin-2-ones were synthesized and the conformation of the pyran ring was investigated. The free radical scavenging activity of the synthesized compounds was determined by their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). All compounds tested scavenged the DPPH radical and among them derivatives possessing extended conjugation showed the highest activity.

Full text of DOI:10.1248/cpb.51.522

522
Chem. Pharm. Bull. 51(5) 522—529 (2003)
Vol. 51, No. 5
Synthesis, Conformational Analysis and Free Radical Scavenging Activity
of Some New Spiropyranoquinolinones
Vassiliki PANTELEON, Panagiotis MARAKOS, Nicole POULI,* Emmanuel MIKROS, and
Ioanna ANDREADOU
Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens; Panepistimiopolis Zografou 15771,
Athens, Greece. Received December 16, 2002; accepted January 30, 2003
A series of novel spiroadamantyl- and spirocyclical substituted pyranoquinolin-2-ones were synthesized and
the conformation of the pyran ring was investigated. The free radical scavenging activity of the synthesized com-
pounds was determined by their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH).
All compounds tested scavenged the DPPH radical and among them derivatives possessing extended conjugation
showed the highest activity.
Key words pyranoquinolinone; conformation; radical scavenging effect; 1,1-diphenyl-2-picrylhydrazyl (DPPH)
The cellular damage caused by the reactions of oxygen derivatives have been described as powerful antioxidants for
centered free radicals and reactive oxygen species (ROS) the potential treatment of pathologies implicating central ox-
with DNA, structural or enzymatic proteins, polyunsaturated idative stress.8—10) With these in mind, we have synthesized a
fatty acids and other macromolecules has been implicated in number of structurally related derivatives in an effort to in-
a variety of pathological events underlying age-related and vestigate their potential to act as radical scavengers and to
post ischemic neurodegeneration1) and other biological disor- exhibit antioxidant activity thereof. The new compounds pos-
ders such as heart disease, atherosclerosis, stroke, inflamma- sess the quinolin-2-one ring system fused to a pyrane or di-
tion and cancer.2—4) Mammalian cells have evolved an array hydropyrane ring, which bears spiro- substituents of various
of biochemical defense systems, including enzymes (super- sizes. We investigated the importance of the extended conju-
oxide dismutase, catalase and peroxidase) and low molecular gation, which is due to the presence of the pyrane ring, to-
weight compounds (ascorbic acid, vitamin E and glutathione) wards the flexibility adopted by the corresponding dihy-
for protecting their components against the ROS that arise dropyrane analogues.
from endogenous metabolic processes or from various exoge-
nous sources. However, the overproduction of these species Results and Discussion
and/or the decreased production of cellular antioxidants are
Chemistry For the synthesis of the target derivatives we
responsible for the oxidative stress state, in which oxidant used the 2-spirocyclical substituted 4-chromanones 3a,11)
production surpasses the endogenous antioxidant capacities. 3b11) and 3c (Chart 1), which were prepared through nitration
Some tissues and the brain in particular are easily susceptible of the commercial 2-hydroxyacetophenone (1)12) and subse-
to oxidative damage under conditions of oxidative stress, due quent treatment with the appropriate carbocyclic ketone
to their high levels of oxygen consumption and the elevated in the presence of pyrrolidine.13) The nitro group of the
unsaturated fatty acids and iron stores.5)
chromanones 3a—c was then reduced with tin(II) chloride
Consequently, elucidation of the mechanism of action and in refluxing acetone to result in the corresponding anilines
research on more active antioxidants of natural or synthetic 4a—c, which upon treatment with acetic anhydride gave
origin continue to receive a great deal of attention for use in the acetamides 5a—c. Nitration of these acetamides with
the development of potential chemoprotective therapeutics fuming nitric acid in acetic acid14) provided the 2-spirocycli-
able to prevent or reduce oxidative stress-induced damage.
cal substituted 5-nitro-6-acetamido-4-chromanones 6a—c,
A number of quinolinones, including the novel antiulcer which were subjected to borohydride reduction, followed
agent rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quino- by dehydration of the resulting 2-spiro-4-chromanols 7a—
linon-4-yl]propionic acid, Fig. 1) have been shown to scav- c, in the presence of an acidic catalyst, to furnish the 2-
enge hydroxyl radicals and inhibit superoxide production spirochromenes 8a—c.
from polymorphonuclear leukocytes.6,7) On the other hand,
For the preparation of the corresponding spiroadamantyl-
ethoquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, Fig. chromene 14, we used 3-nitro-4-acetamidophenol (12)15)
1) and several 1,2-dihydro and 1,2,3,4-tetrahydroquinoline as starting material, obtained from commercial 4-acetami-
dophenol (9), as depicted in Chart 2. Reaction of 12 with 2-
chloro-2-ethynyladamantane16) provided the acetylenic ether
13 which upon thermal cyclization in refluxing N,N-diethyl-
aniline provided the isomeric chromenes 14 and 15. Both
isomers were easily separated by flash chromatography on
silica gel and fully characterized on the basis of NMR data.
Acid hydrolysis of the acetamides 8a—c and 14 with a 5 N
HCl solution resulted in the corresponding 6-aminoderiva-
tives 16a—d (Chart 3), which via diazotization and reaction
with potassium iodide were converted to the corresponding
Fig. 1. Structures of Rebamipide and Ethoxyquin
* To whom correspondence should be addressed. e-mail: pouli@pharm.uoa.gr
© 2003 Pharmaceutical Society of Japan

May 2003
523
a: conc. HNO3, AcOH, 30 °C, 56%, b: carbocyclic ketone, pyrrolidine, toluene, reflux, 70—90%, c: SnCl2·2H2O, acetone,
reflux, 80—85%, d: Ac2O, r.t., 90—95%, e: fuming HNO3, AcOH, r.t., 80—87%, f: NaBH4, MeOH, r.t., 95%, g: p-TsOH,
toluene, reflux, 90—95%.
Chart 1
the benzylic OH group in pseudoequatorial position.20) On
the other hand the biological activity of some pyranothioxan-
thenone derivatives has been related to the possibility of dim-
mer formation via hydrogen bonds through the suitably ori-
ented hydroxyl groups of the pyran ring.21) Therefore, it was
of interest to investigate the pyran ring conformation of the
synthesized spiroquinolinones reported herein.
The pyran ring is expected to adopt two half-chair confor-
mations, with 8Ј-C and 9Ј-C on opposite sides of the ring
plane. Those conformations were constructed using Macro-
model software,22) geometry was optimized using MM2*
force field and the resulting structures, represented by 21c,
are shown in Fig. 2 along with their relative energies. Calcu-
lated energy differences between conformers I and II for de-
rivatives 21a—d were found to vary from 2.2 kcal/mol for
21c up to 5.7 kcal/mol for 21d.
a: Ac2O, reflux, 96%, b: fuming HNO3, AcOH, reflux, 40%, c: 40% NaOH, r.t., 85%,
d: 2-chloro-2-ethynyladamantane, K2CO3, KI, CuI, acetone, reflux, 82%, e: N,N-diethyl-
aniline, reflux, 64% of 14, 4% of 15.
Protons at 9Ј-C and 10Ј-C are gauche in both conformers,
thus the corresponding coupling constant is not useful for
conformational analysis since it is expected to be similar for
Chart 2
iodides 17a—d. The palladium-mediated coupling of these both conformers. Consequently, nuclear Overhauser effects
halides with acrylic acid in aqueous N,N-dimethylformamide (NOE’s) were used in order to fully characterize the com-
(DMF) in the presence of potassium carbonate17) resulted in pound’s structure and are exemplified here for the cyclohep-
the nitrocinnamic acids 18a—d.
tyl-substituted derivative 21c. Correlation detected in the nu-
Reduction of the nitro group of compounds 18a—d with clear Overhauser effect spectroscopy (NOESY) spectrum be-
tin(II) chloride in refluxing acetone gave the amino acids tween the 10Ј-H with protons of the cycloheptyl ring resonat-
19a—d, which were subsequently ring-closed under reflux ing at 1.58 and 1.70 ppm, suggests that 10Ј-H adopts a
conditions in 4% HCl solution, to afford the corresponding pseudoaxial orientation (conformer I), and thus these cyclo-
pyranoquinolin-2-ones 20a—d. Catalytic syn-hydroxylation heptyl protons were assigned as 7Љ-H. If conformer II exists
of compounds 20a—d with osmium tetroxide and N-methyl- in solution one should expect to observe NOE’s between 10Ј-
morpholine-N-oxide as oxidizing reagent18) yielded the cor- OH and the cycloheptyl ring protons at 2Љ-C, but these were
responding cis-diols 21a—d.
not detected.
Conformational Analysis To our knowledge the confor-
The above observations suggest that conformer I is pre-
mation adopted by the pyran ring of dihydropyranoquinoli- dominant in solution, probably due to stabilization through
nones has not been extensively studied. On the contrary, the formation of a hydrogen bond between NH and 10Ј-O, in
there are a number of reports on structurally analogous com- agreement with the MM2 calculated energy difference.
pounds bearing a dihydropyran ring, with hydroxyl substitu-
It should be noted here that the energy values resulting
tions. The crystal structure of pyranocoumarin derivatives re- from the calculations showed that the spirocyclohexyl deriva-
veals that the pyran ring conformation depends on the pres- tive is, as expected, the most stable (values expressed in
ence or absence of substituent on the hydroxyl group adja- kcal/mol: 21a: Ϫ11.8, 21b: Ϫ14.4, 21c: Ϫ5.2, 21d: Ϫ1.5).
cent to the benzylic position.19) The pyran ring of some de- The same is also true for compounds 20a—d (values ex-
rivatives of 1,2-dihydro-1,2-dihydroxyacronycine proved to pressed in kcal/mol: 20a: 10.1, 20b: 5.6, 20c: 14.0, 20d:
be more rigid and to adopt only one conformation, orienting 18.6).

524
Vol. 51, No. 5
a: 5 N HCl, reflux, 86—96%, b: i) NaNO2, H2SO4, H2O, ii) KI, r.t., 53—71%, c: Pd(OAc)2, PPh3, K2CO3, acrylic acid, DMF,
H2O, 100 °C, 45—60%, d: SnCl2·2H2O, acetone, reflux, 49—60%, e: 4% HCl, reflux, 75—88%, f: OsO4, 4-methylmorpholine-
N-oxide, t-BuOH/THF/H2O, r.t., 59—84%.
Chart 3
Fig. 2. Representation of the Low Energy Conformations for Derivative
21c Derived from Molecular Mechanics Calculations
Fig. 4. DPPH Reduction, as Evaluated by the Decrease in Absorbance, at
517 nm, as a Function of Time at 200 mM Concentration of Compounds
21a—d
Table 1. Effect of the Examined Compounds on Their Interaction with
DPPH (200 mM)
Percentage of interaction with DPPH
Comp.
a)
[DPPH] mM
5
10
50
100
200
400
Fig. 3. DPPH Reduction, as Evaluated by the Decrease in Absorbance, at
517 nm, as a Function of Time at 200 mM Concentration of Compounds
20a—d
20a
20b
20c
20d
21a
21b
21c
21d
1
11
14
2
0
8
14
2
1
5
14
18
3
7
20
21
6
11
42
38
10
7
25
20
4
36
48
48
16
16
35
21
5
45
66
50
19
20
36
32
8
1
4
Antioxidant Activity In the last years considerable re-
search interest has focused on investigating the antioxidant
properties of pharmacologically active compounds and sev-
eral experimental protocols have been developed for this pur-
pose.23) The antioxidant action is considered to be a complex
process which may include prevention of formation or scav-
enging of free radicals, consequently, it was of interest to in-
vestigate the interaction of the synthesized compounds
13
19
3
20
20
4
Ascorbic acid
14
73
97
98
98
a) Based on absorbance values of samples with the tested compounds, against con-
trols containing equal volume of the solvent. Standard deviation of absorbance values
was less than Ϯ10%, nϭ3—5.
20a—d and 21a—d with the stable 2,2-diphenyl-1-picrylhy- course dependent DPPH radical scavenging activity of com-
drazyl (DPPH) free radical. In this assay antioxidants react pounds 20a—d and 21a—d, respectively, at a concentration
with DPPH (which gives a strong absorption at 517 nm) and of 200 mM. The percentage of interaction of the examined
produce a colorless 2, 2-diphenyl-1-picrylhydrazine.24) The compounds with DPPH was measured in six different sample
change of absorbance produced in this reaction has been concentrations and is presented in Table 1.
widely used to test the ability of several molecules to act as
All the tested compounds were found to interact with
free radical scavengers.25) Figures 3 and 4 show the time DPPH (Figs. 3, 4). Nevertheless, compounds 20a—d were

May 2003
525
more potent than compounds 21a—d. It seems that the ex- D2O exchangeable), 6.75 (1H, d, Jϭ8.8 Hz, H-8Ј), 6.84 (1H, dd, Jϭ8.8,
2.9 Hz, H-7Ј), 7.08 (1H, d, Jϭ2.9 Hz, H-5Ј). 13C-NMR (CDCl3, 50 MHz) d:
tended conjugation of 20a—d against 21a—d is a favorable
characteristic for the increased free radical scavenging activ-
ity. The order of interaction with DPPH at 400 mM was found
to be: 20bഠ20cϾ20aϾ21bഠ21cϾ21aϾ20dϾ21d. It can be
21.77, 29.11, 37.89 (cycloheptane C), 48.88 (C-3Ј), 83.43 (C-2Ј), 110.37 (C-
5Ј), 118.94 (C-8Ј), 120.66 (C-4Јa), 124.42 (C-7Ј), 139.76 (C-6Ј), 152.82 (C-
8Јa), 192.98 (C-4Ј). Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.32; H, 7.84; N, 5.95.
3؅,4؅-Dihydro-4؅-oxospiro[cyclopentane-1,2؅(2؅H)[1]benzopyran]-6؅-
acetamide (5a) A solution of the amine 4a (4.1 g, 0.019 mol) in acetic an-
hydride (50 ml) was stirred for 12 h at room temperature. The bulk of acetic
anhydride was removed in vacuo, water was added to the residue and it was
extracted with dichloromethane. The product was purified by column chro-
matography (silica gel) using a mixture of cyclohexane/EtOAc 2/1 as the
assumed that concerning the size of the spiro group, the cy-
clohexyl substituted derivative possesses the highest scav-
enging activity in both series of compounds. This is in agree-
ment with the relative stability resulting from the theoretical
calculations. On the other hand, the presence of the adaman-
tane moiety (20d and 21d) results in a considerable decrease
of activity against DPPH. This could be correlated to a nega-
tive contribution of steric parameters to the reducing ability
of DPPH.26)
1
eluent to give 5a (4.45 g, 91%). mp: 160 °C (Et2O). H-NMR (CDCl3, 400
MHz) d: 1.5—2.1 (8H, m, cyclopentane H), 2.15 (3H, s, CH3), 2.78 (2H, s,
H-39), 6.88 (1H, d, Jϭ8.8 Hz, H-89), 7.32 (1H, br s, NH, D2O exchange-
able), 7.65 (1H, d, Jϭ2.6 Hz, H-59), 7.91 (1H, dd, Jϭ8.8, 2.6 Hz, H-79).
13C-NMR (CDCl3, 50 MHz) d: 23.84 (cyclopentane C), 24.30 (CH3), 37.42
(cyclopentane C), 47.01 (C-39), 90.08 (C-29), 117.50 (C-59), 119.16 (C-
89), 120.59 (C-49a), 129.50 (C-79), 131.41 (C-69), 157.20 (C-89a), 168.64
(NHCO), 192.66 (C-49). Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N,
5.40. Found: C, 69.20; H, 6.44; N, 5.78.
Experimental
General Remarks Melting points were determined on a Büchi apparatus
and are uncorrected. 1H-NMR spectra and two dimensional (2D) spectra
were recorded on a Bruker Avanche 400 instrument, whereas 13C-NMR
spectra were recorded on a Bruker AC 200 spectrometer in deuterated sol-
vents and were referenced to TMS (d scale). The signals of 1H and 13C spec-
tra were unambiguously assigned by using 2D NMR techniques: correlation
spectroscopy (COSY), NOESY 1H-detected heteronuclear multiple quantum
coherence (HMQC) and heteronuclear multiple bond connectivity (HMBC).
Flash chromatography was performed on Merck silica gel 60 (0.040—
0.063 mm). Analytical thin layer chromatography (TLC) was carried out on
precoated (0.25 mm) Merck silica gel F-254 plates. Elemental analyses were
within Ϯ0.4% of the theoretical values.
The following compounds were prepared according to the procedure de-
scribed for 5a.
3Ј,4Ј-Dihydro-4Ј-oxospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-ac-
1
etamide (5b): Yield: 95%. mp: 179 °C (Et2O). H-NMR (CDCl3, 400 MHz)
d: 1.2—2.0 (10H, m, cyclohexane H), 2.15 (3H, s, CH3), 2.66 (2H, s, H-3Ј),
6.93 (1H, d, Jϭ8.8 Hz, H-8Ј), 7.56 (1H, br s, NH, D2O exchangeable), 7.62
(1H, d, Jϭ2.6 Hz, H-5Ј), 7.88 (1H, dd, Jϭ8.8, 2.6 Hz, H-7Ј). 13C-NMR
(CDCl3, 50 MHz) d: 21.35 (cyclohexane C), 24.26 (CH3), 25.14, 34.66 (cy-
clohexane C), 48.18 (C-3Ј), 80.08 (C-2Ј), 117.32 (C-5Ј), 119.01 (C-8Ј),
120.44 (C-4Јa), 129.66 (C-7Ј), 131.25 (C-6Ј), 156.42 (C-8Јa), 168.55
(NHCO), 192.55 (C-4Ј). Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N,
5.12. Found: C, 70.65; H, 6.84; N, 5.01.
3؅,4؅-Dihydro-6؅-nitrospiro[cycloheptane-1,2؅(2؅H)[1]benzopyran]-4؅-
one (3c) A solution of 2-hydroxy-5-nitroacetophenone12) (2) (4.0 g, 0.022
mol), cycloheptanone (3.39 ml, 0.029 mol) and pyrrolidine (0.46 ml, 5.52
mmol) in anhydrous toluene was refluxed for 4 h in a Dean–Stark apparatus.
The reaction mixture was then extracted with a 9% HCl solution and the or-
ganic phase was dried (Na2SO4) and evaporated to dryness. The residue was
purified by column chromatography (silica gel) using a mixture of cyclo-
hexane/EtOAc 10/1 to 6/1 as the eluent to provide 3c (4.3 g, 71%). mp:
3Ј,4Ј-Dihydro-4Ј-oxospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-ac-
1
etamide (5c): Yield: 93%. mp: 137 °C (Et2O). H-NMR (CDCl3, 400 MHz)
d: 1.4—2.1 (12H, m, cycloheptane H), 2.14 (3H, s, CH3), 2.69 (2H, s, H-3Ј),
6.90 (1H, d, Jϭ8.9 Hz, H-8Ј), 7.64 (1H, d, Jϭ2.5 Hz, H-5Ј), 7.76 (1H, br s,
NH, D2O exchangeable), 7.90 (1H, dd, Jϭ8.9, 2.5 Hz, H-7Ј). 13C-NMR
(CDCl3, 50 MHz) d: 21.89, 29.24 (cycloheptane C), 24.20 (CH3), 38.13 (cy-
cloheptane C), 48.88 (C-3Ј), 84.28 (C-2Ј), 117.23 (C-5Ј), 118.95 (C-8Ј),
120.30 (C-4Јa), 129.67 (C-7Ј), 131.39 (C-6Ј), 156.53 (C-8Јa), 168.81
(NHCO), 192.83 (C-4Ј). Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N,
4.87. Found: C, 71.40; H, 7.47; N, 4.62.
1
96 °C (Et2O). H-NMR (CDCl3, 400 MHz) d: 1.3—2.2 (12H, m, cyclohep-
tane H), 2.79 (2H, s, H-3Ј), 7.04 (1H, d, Jϭ9.1 Hz, H-8Ј), 8.29 (1H, dd,
Jϭ9.1, 2.9 Hz, H-7Ј), 8.70 (1H, d, Jϭ2.9 Hz, H-5Ј). 13C-NMR (CDCl3,
50 MHz) d: 21.87, 29.26, 38.26 (cycloheptane C), 48.33 (C-3Ј), 86.56 (C-
2Ј), 119.62 (C-8Ј), 120.06 (C-4Јa), 123.16 (C-5Ј), 130.48 (C-7Ј), 141.48 (C-
6Ј), 164.00 (C-8Јa), 190.60 (C-4Ј). Anal. Calcd for C15H17NO4: C, 65.44; H,
6.22; N, 5.09. Found: C, 65.80; H, 6.13; N, 4.81.
3؅,4؅-Dihydro-5؅-nitro-4؅-oxospiro[cyclopentane-1,2؅(2؅H)[1]benzopy-
ran]-6؅-acetamide (6a) To a stirred solution of 5a (4.4 g, 0.017 mol) in
glacial acetic acid (10 ml) at 5 °C was added dropwise fuming nitric acid
(2 ml) and the resulting mixture was refluxed for 4 h. The solution was then
poured onto ice and the precipitate was filtered, washed with water and air-
3؅,4؅-Dihydro-4؅-oxospiro[cyclopentane-1,2؅(2؅H)[1]benzopyran]-6؅-
amine (4a) To a solution of 3a (1 g, 4.05 mmol) in acetone (50 ml) was
added SnCl2·2H2O (3.66 g, 16.20 mmol) and the mixture was heated at
reflux for 6 h. The reaction mixture was filtered through a celite pad, the
filtrate was made alkaline with aqueous ammonia and extracted with
dichloromethane. The organic phase was dried (Na2SO4) and evaporated to
dryness to give pure 4a (720 mg, 82%). mp: 128 °C (Et2O). 1H-NMR
(CDCl3, 400 MHz) d: 1.5—2.1 (8H, m, cyclopentane H), 2.75 (2H, s, H-3Ј),
3.49 (2H, br s, NH2, D2O exchangeable), 6.73 (1H, d, Jϭ8.8 Hz, H-8Ј), 6.85
(1H, dd, Jϭ8.8, 2.6 Hz, H-7Ј), 7.12 (1H, d, Jϭ2.6 Hz, H-5Ј). 13C-NMR
(CDCl3, 50 MHz) d: 23.78, 37.25 (cyclopentane C), 47.17 (C-3Ј), 89.50 (C-
2Ј), 110.85 (C-5Ј), 119.19 (C-8Ј), 121.01 (C-4Јa), 124.39 (C-7Ј), 139.85 (C-
6Ј), 153.67 (C-8Јa), 193.07 (C-4Ј). Anal. Calcd for C13H15NO2: C, 71.87; H,
6.96; N, 6.45. Found: C, 71.93; H, 6.66; N, 6.70.
1
dried to give pure 6a (4.5 g, 87%). mp: 195 °C (EtOH). H-NMR (CDCl3,
400 MHz) d: 1.5—2.1 (8H, m, cyclopentane H), 2.14 (3H, s, CH3), 2.84
(2H, s, H-3Ј), 7.06 (1H, d, Jϭ9.1 Hz, H-8Ј), 7.44 (1H, br s, NH, D2O ex-
changeable), 8.04 (1H, d, Jϭ9.1 Hz, H-7Ј). 13C-NMR (CDCl3, 50 MHz) d:
23.68 (cyclopentane C), 24.03 (CH3), 37.32 (cyclopentane C), 46.69 (C-3Ј),
91.19 (C-2Ј), 112.20 (C-4Јa), 121.68 (C-8Ј), 122.71 (C-6Ј), 132.60 (C-7Ј),
140.33 (C-5Ј), 157.52 (C-8Јa), 169.04 (NHCO), 188.60 (C-4Ј). Anal. Calcd
for C15H16N2O5: C, 59.21; H, 5.30; N, 9.21. Found: C, 59.46; H, 5.08; N,
8.91.
The following compounds were prepared according to the procedure de-
scribed for 6a.
3Ј,4Ј-Dihydro-5Ј-nitro-4Ј-oxospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopy-
1
ran]-6Ј-acetamide (6b): Yield: 79%. mp: 202 °C (EtOH). H-NMR (CDCl3,
The following compounds were prepared according to the procedure de-
scribed for 4a.
400 MHz) d: 1.2—2.0 (10H, m, cyclohexane H), 2.16 (3H, s, CH3), 2.72
(2H, s, H-3Ј), 7.12 (1H, d, Jϭ9.2 Hz, H-8Ј), 7.39 (1H, br s, NH, D2O ex-
changeable), 8.07 (1H, d, Jϭ9.2 Hz, H-7Ј). 13C-NMR (CDCl3, 50 MHz) d:
21.31 (cyclohexane C), 24.14 (CH3), 24.92, 34.51 (cyclohexane C), 47.99
(C-3Ј), 81.51 (C-2Ј), 112.07 (C-4Јa), 121.60 (C-8Ј), 122.67 (C-6Ј), 132.66
(C-7Ј), 140.14 (C-5Ј), 156.81 (C-8Јa), 168.93 (NHCO), 188.63 (C-4Ј). Anal.
Calcd for C16H18N2O5: C, 60.37; H, 5.70; N, 8.80. Found: C, 60.29; H, 5.74;
N, 8.92.
3Ј,4Ј-Dihydro-5Ј-nitro-4Ј-oxospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopy-
ran]-6Ј-acetamide (6c): Yield: 85%. mp: 210—211 °C (dec) (EtOH). 1H-
NMR (CDCl3, 400 MHz) d: 1.4—2.1 (12H, m, cycloheptane H), 2.14 (3H,
s, CH3), 2.75 (2H, s, H-3Ј), 7.09 (1H, d, Jϭ9.3 Hz, H-8Ј), 7.45 (1H, br s,
NH, D2O exchangeable), 8.05 (1H, d, Jϭ9.3 Hz, H-7Ј). 13C-NMR (CDCl3,
3Ј,4Ј-Dihydro-4Ј-oxospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-
amine (4b): Yield: 85%. mp: 162 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d:
1.2—2.0 (10H, m, cyclohexane H), 2.60 (2H, s, H-3Ј), 3.53 (2H, br s, NH2,
D2O exchangeable), 6.74 (1H, d, Jϭ8.8 Hz, H-8Ј), 6.83 (1H, dd, Jϭ8.8,
2.9 Hz, H-7Ј), 7.08 (1H, d, Jϭ2.9 Hz, H-5Ј). 13C-NMR (CDCl3, 50 MHz) d:
21.32, 25.10, 34.51 (cyclohexane C), 48.22 (C-3Ј), 79.28 (C-2Ј), 110.52 (C-
5Ј), 118.94 (C-8Ј), 120.81 (C-4Јa), 124.48 (C-7Ј), 139.88 (C-6Ј), 152.68 (C-
8Јa), 192.96 (C-4Ј). Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Found: C, 72.55; H, 7.52; N: 5.90.
3Ј,4Ј-Dihydro-4Ј-oxospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-
amine (4c): Yield: 83%. mp: 184 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d:
1.3—2.2 (12H, m, cycloheptane H), 2.65 (2H, s, H-3Ј), 3.48 (2H, br s, NH2,

526
Vol. 51, No. 5
1
50 MHz) d: 21.76, 29.15 (cycloheptane C), 24.00 (CH3), 37.97 (cyclohep-
tane C), 48.63 (C-3Ј), 85.75 (C-2Ј), 111.92 (C-4Јa), 121.58 (C-8Ј), 122.50
(C-6Ј), 132.72 (C-7Ј), 140.19 (C-5Ј), 156.94 (C-8Јa), 169.03 (NHCO),
188.69 (C-4Ј). Anal. Calcd for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43.
Found: C, 61.18; H, 6.03; N, 8.38.
Yield: 95%. mp: 124 °C (EtOAc). H-NMR (CDCl3, 400 MHz) d: 1.3—2.1
(12H, m, cycloheptane H), 2.14 (3H, s, CH3), 5.84 (1H, d, Jϭ10.2 Hz, H-3Ј),
6.34 (1H, d, Jϭ10.2 Hz, H-4Ј), 6.98 (1H, d, Jϭ8.8 Hz, H-8Ј), 7.80 (1H, d,
Jϭ8.8 Hz, H-7Ј), 8.29 (1H, br s, NH, D2O exchangeable). 13C-NMR (CDCl3,
50 MHz) d: 21.50, 29.40 (cycloheptane C), 24.58 (CH3), 38.81 (cyclohep-
tane C), 80.97 (C-2Ј), 115.88 (C-4Ј, C-4Јa), 121.25 (C-8Ј), 123.93 (C-6Ј),
124.61 (C-7Ј), 134.98 (C-3Ј), 139.00 (C-5Ј), 150.06 (C-8Јa), 168.59 (CϭO).
Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37; N, 8.85. Found: C, 64.19; H,
6.50; N, 8.81.
(؎)-3؅,4؅-Dihydro-4؅-hydroxy-5؅-nitrospiro[cyclopentane-1,2؅(2؅H)-
[1]benzopyran]-6؅-acetamide (7a) NaBH4 (567 mg, 15 mmol) was added
to a solution of 6a (4 g, 13.2 mmol) in methanol (25 ml) at 0 °C. The reaction
mixture was stirred at room temperature for 24 h, the solvent was then vac-
uum-evaporated, 2 M HCl was added and the product was extracted into
dichloromethane, the solvent was dried (Na2SO4) and evaporated to dryness.
The residue was purified by column chromatography (silica gel) using a
mixture of cyclohexane/EtOAc 6/1 as the eluent to give 7a (3.9 g, 96%). mp:
4-[(2-Ethynyltricyclo[3,3,1,13,7]decan-2-yl)oxy]-2-nitro-acetamide (13)
2-Chloro-2-ethynyladamantane16) (486 mg, 2.50 mmol) was added to a mix-
ture of 3-nitro-4-acetamidophenol15) (12) (330 mg, 1.68 mmol), anhydrous
K2CO3 (465 mg, 3.37 mmol), KI (475 mg, 2.86 mmol) and CuI (6.5 mg,
0.034 mmol) in acetone (50 ml) under argon and the reaction mixture was
stirred at 70 °C for 12 h. The solvent was removed under vacuum, water was
added to the residue and the product was extracted into dichloromethane, the
organic phase was dried (Na2SO4) and evaporated to dryness. The crude ma-
terial was purified by column chromatography (silica gel) using a mixture of
cyclohexane/EtOAc 10/1 as the eluent to give 13 as an oil (489 mg, 82%).
1H-NMR (CDCl3, 400 MHz) d: 1.5—2.4 (14H, m, adamantane H), 2.24
(3H, s, CH3), 2.76 (1H, s, CϵCH), 7.53 (1H, dd, Jϭ9.1, 2.2 Hz, H-5), 8.10
(1H, d, Jϭ2.2 Hz, H-3), 8.58 (1H, d, Jϭ9.1 Hz, H-6), 10.07 (1H, br s, NH,
D2O exchangeable). 13C-NMR (CDCl3, 50 MHz) d: 25.44 (CH3), 26.32,
26.65, 31.46, 34.77, 36.09, 37.34 (adamantane C), 78.25 (CϵC–H), 80.60
(CϵC–H), 84.06 (C-2Ј), 115.48 (C-3), 122.98 (C-6), 127.98 (C-5), 129.04
(C-1), 136.61 (C-2), 150.62 (C-4), 168.81 (CϭO). Anal. Calcd for
C20H22N2O4: C, 67.78; H, 6.26; N, 7.90. Found C, 68.01; H, 6.13; N, 7.79.
5؅-Nitrospiro[tricyclo[3,3,1,13,7]decane-2,2؅(2؅H)[1]benzopyran]-6؅-ac-
etamide (14) A mixture of 13 (550 mg, 1.55 mmol) in N,N-diethylaniline
was heated at 180 °C for 90 min. After cooling, a 9% HCl solution was
added to the reaction mixture and the product was extracted into dichloro-
methane. The organic phase was then washed twice with a 9% HCl solution,
dried (Na2SO4) and evaporated to dryness. The crude material was purified
by column chromatography (silica gel) using a mixture of cyclohexane/
EtOAc 8/1 as the eluent and the isomer 15 (7Ј-nitrospiro[tricyclo[3,3,1,13,7]-
decane-2,2Ј-(2ЈH)[1]benzopyran]-6Ј-acetamide) was eluted first (22 mg,
4%). Data for 15: mp: 202 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d: 1.5—
2.4 (14H, m, adamantane H), 2.24 (3H, s, CH3), 6.47 (2H, m, H-3Ј, H-4Ј),
7.68 (1H, s, H-8Ј), 8.38 (1H, s, H-5Ј), 10.21 (1H, br s, NH, D2O exchange-
able). 13C-NMR (CDCl3, 50 MHz) d: 25.56 (CH3), 26.59, 27.07, 32.40,
33.46, 35.96, 37.69 (adamantane C), 81.02 (C-2Ј), 112.70 (C-8Ј), 119.36 (C-
5Ј), 122.26, 135.09 (C-3Ј, C-4Ј), 129.17 (C-6Ј), 130.53 (C-4Јa), 135.82 (C-
7Ј), 147.88 (C-8Јa), 168.86 (CϭO). Anal. Calcd for C20H22N2O4: C, 67.78;
H, 6.26; N, 7.90. Found: C, 67.88; H, 6.09; N, 7.92. The next fraction was
eluted using cyclohexane/EtOAc 6/1 and contained 14, (350 mg, 64%). Data
1
145 °C (EtOAc). H-NMR (CDCl3, 400 MHz) d: 1.4—2.1 (10H, m, 8ϫcy-
clopentane H, H-3Ј), 2.01 (3H, s, CH3), 3.85 (1H, br s, OH, D2O exchange-
able), 4.99 (1H, dd, Jϭ6.1, 6.7 Hz, H-4Ј), 6.80 (1H, d, Jϭ9.1 Hz, H-8Ј), 7.48
(1H, d, Jϭ9.1 Hz, H-7Ј), 8.20 (1H, br s, NH, D2O exchangeable). 13C-NMR
(CDCl3, 50 MHz) d: 23.36 (cyclopentane C), 23.47 (CH3), 36.27 (C-3Ј),
38.05, 39.00 (cyclopentane C), 60.94 (C-4Ј), 86.63 (C-2Ј), 117.90 (C-4Јa),
120.88 (C-8Ј), 122.20 (C-6Ј), 126.27 (C-7Ј), 143.25 (C-5Ј), 151.18 (C-8Јa),
169.49 (CϭO). Anal. Calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15.
Found: C, 58.74; H, 5.69; N, 8.93.
The following compounds were prepared according to the procedure de-
scribed for 7a.
(Ϯ)-3Ј,4Ј-Dihydro-4Ј-hydroxy-5Ј-nitrospiro[cyclohexane-1,2Ј(2ЈH)[1]-
1
benzopyran]-6Ј-acetamide (7b): Yield: 96%. mp: 152 °C (EtOAc). H-NMR
(CDCl3, 400 MHz) d: 1.3—2.1 (10H, m, cyclohexane H), 2.00 (2H, m, H-3),
2.09 (3H, s, CH3), 3.76 (1H, br s, OH, D2O exchangeable), 5.02 (1H, dd,
Jϭ5.9, 6.5 Hz, H-4Ј), 6.86 (1H, d, Jϭ9.2 Hz, H-8Ј), 7.52 (1H, d, Jϭ9.2 Hz,
H-7Ј), 8.02 (1H, br s, NH, D2O exchangeable). 13C-NMR (CDCl3, 50 MHz)
d: 21.26 (cyclohexane C), 23.57 (CH3), 25.19 (cyclohexane C), 32.88 (C-3),
36.35 (cyclohexane C), 60.10 (C-4Ј), 76.82 (C-2Ј), 117.91 (C-4Јa), 120.83
(C-8Ј), 122.33 (C-6Ј), 126.28 (C-7Ј), 143.05 (C-5Ј), 150.74 (C-8Јa), 169.52
(CϭO). Anal. Calcd for C16H20N2O5: C, 59.99; H, 6.29; N, 8.74. Found: C,
60.30; H, 6.11; N, 8.40.
(Ϯ)-3Ј,4Ј-Dihydro-4Ј-hydroxy-5Ј-nitrospiro[cycloheptane-1,2Ј(2ЈH)[1]-
benzopyran]-6Ј-acetamide (7c): Yield: 94%. mp: 142—143 °C (EtOAc). 1H-
NMR (CDCl3, 400 MHz) d: 1.4—2.1 (12H, m, cycloheptane H), 2.14 (3H,
s, CH3), 2.26 (2H, m, H-3Ј), 3.79 (1H, br s, OH, D2O exchangeable), 5.13
(1H, dd, Jϭ6.2, 6.6 Hz, H-4Ј), 6.96 (1H, d, Jϭ9.2 Hz, H-8Ј), 7.78 (1H, d,
Jϭ9.2 Hz, H-7Ј), 8.02 (1H, br s, NH, D2O exchangeable). 13C-NMR (CDCl3,
50 MHz) d: 21.80, (cycloheptane C), 24.37 (CH3), 29.57, 40.04 (cyclohep-
tane C), 41.53 (C-3Ј), 60.92 (C-4Ј), 81.36 (C-2Ј), 117.98 (C-4Јa), 121.97 (C-
8Ј), 123.18 (C-6Ј), 126.06 (C-7Ј), 142.29 (C-5Ј), 150.80 (C-8Јa), 168.74
(CϭO). Anal. Calcd for C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C,
60.88; H, 6.80; N, 8.37.
1
for 14: mp: 182 °C (Et2O). H-NMR (CDCl3, 400 MHz) d: 1.3—2.4 (14H,
5؅-Nitrospiro[cyclopentane-1,2؅(2؅H)[1]benzopyran]-6؅-acetamide
(8a) A solution of 7a (4.6 g, 0.015 mol) and p-toluenesulfonic acid (279
mg, 1.47 mmol) was refluxed in anhydrous toluene for 4 h in a Dean–Stark
apparatus. The reaction mixture was washed with water and the organic
layer was dried (Na2SO4) and evaporated to dryness. The residue was puri-
fied by column chromatography (silica gel) using a mixture of cyclo-
hexane/EtOAc 8/1 to 4/1 as the eluent to give 8a (4 g, 93%). mp: 117 °C
(EtOAc). 1H-NMR (CDCl3, 400 MHz) d: 1.5—2.1 (8H, m, cyclopentane H),
2.15 (3H, s, CH3), 5.87 (1H, d, Jϭ10.2 Hz, H-3Ј), 6.42 (1H, d, Jϭ10.2 Hz,
H-4Ј), 6.94 (1H, d, Jϭ8.8 Hz, H-8Ј), 7.81 (1H, d, Jϭ8.8 Hz, H-7Ј), 8.27 (1H,
brs, NH, D2O exchangeable). 13C-NMR (CDCl3, 50 MHz) d: 23.56 (cy-
clopentane C), 24.63 (CH3), 39.07 (cyclopentane C), 87.14 (C-2Ј), 116.10
(C-4Јa), 117.70 (C-4Ј), 121.10 (C-8Ј), 124.10 (C-6Ј), 124.58 (C-7Ј), 133.45
(C-3Ј), 138.98 (C-5Ј), 150.23 (C-8Јa), 168.63 (CϭO). Anal. Calcd for
C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.70; H, 5.36; N, 9.54.
The following compounds were prepared according to the procedure de-
scribed for 8a.
5Ј-Nitrospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-acetamide (8b):
Yield: 91%. mp: 132—133 °C (EtOAc). 1H-NMR (CDCl3, 400 MHz) d:
1.3—2.0 (10H, m, cyclohexane H), 2.14 (3H, s, CH3), 5.82 (1H, d, Jϭ10.2
Hz, H-3Ј), 6.38 (1H, d, Jϭ10.2 Hz, H-4Ј), 7.00 (1H, d, Jϭ8.8 Hz, H-8Ј),
7.80 (1H, d, Jϭ8.8 Hz, H-7Ј), 8.32 (1H, br s, NH, D2O exchangeable). 13C-
NMR (CDCl3, 50 MHz) d: 21.24 (cyclohexane C), 24.55 (CH3), 25.06,
35.47 (cyclohexane C), 76.45 (C-2Ј), 116.21 (C-4Јa), 117.39 (C-4Ј), 121.14
(C-8Ј), 124.08 (C-6Ј), 124.81 (C-7Ј), 134.11 (C-3Ј), 139.15 (C-5Ј), 150.17
(C-8Јa), 168.70 (CϭO). Anal. Calcd for C16H18N2O4: C, 63.57; H, 6.00; N,
9.27. Found: C, 63.63; H, 5.77; N, 9.01.
m, adamantane H), 2.16 (3H, s, CH3), 6.32 (1H, d, Jϭ10.2 Hz, H-3Ј), 6.47
(1H, d, Jϭ10.2 Hz, H-4Ј), 7.09 (1H, d, Jϭ9.1 Hz, H-8Ј), 7.87 (1H, d, Jϭ
9.1 Hz, H-7Ј), 8.44 (1H, br s, NH, D2O exchangeable). 13C-NMR (CDCl3,
50 MHz) d (ppm): 26.56, 26.87, 26.96, 32.29, 32.43, 35.36, 37.53 (adaman-
tane C and CH3), 80.12 (C-2Ј), 117.12 (C-4Јa), 117.96 (C-4Ј), 121.49 (C-
8Ј), 124.36 (C-6Ј), 124.56 (C-7Ј), 132.53 (C-3Ј), 138.65 (C-5Ј), 149.79 (C-
8Јa), 168.61 (CϭO). Anal. Calcd for C20H22N2O4: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.42; H, 6.24; N, 7.74.
5؅-Nitrospiro[cyclopentane-1,2؅(2؅H)[1]benzopyran]-6؅-amine (16a)
A solution of 8a (438 mg, 1.52 mmol) in EtOH (50 ml) was refluxed with
HCl 5 N (25 ml) for 2 h. The organic phase was vacuum-evaporated, the re-
sulting solution was made alkaline and extracted with dichloromethane. The
solvent was dried (Na2SO4) and evaporated to dryness to yield 16a (322 mg,
86%). mp: 118—119 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d: 1.5—2.1
(8H, m, cyclopentane H), 5.05 (2H, br s, NH2, D2O exchangeable), 5.81 (1H,
d, Jϭ10.2 Hz, H-3Ј), 6.56 (1H, d, Jϭ8.8 Hz, H-7Ј), 6.74 (1H, d, Jϭ10.2 Hz,
H-4Ј), 6.84 (1H, d, Jϭ8.8 Hz, H-8Ј). 13C-NMR (CDCl3, 50 MHz) d: 23.48,
38.29 (cyclopentane C), 85.97 (C-2Ј), 117.05 (C-4Јa), 117.82 (C-7Ј), 119.64
(C-4Ј), 123.98 (C-8Ј), 131.71 (C-3Ј, C-5Ј), 137.72 (C-6Ј), 145.22 (C-8Јa).
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.71;
H, 5.38; N, 11.22.
The following compounds were prepared according to the procedure de-
scribed for 16a.
5Ј-Nitrospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-amine (16b): Yield:
92%. mp: 116—117 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d: 1.3—1.9
(10H, m, cyclohexane H), 5.13 (2H, br s, NH2, D2O exchangeable), 5.75
(1H, d, Jϭ10.2 Hz, H-3Ј), 6.57 (1H, d, Jϭ8.8 Hz, H-7Ј), 6.70 (1H, d, Jϭ
10.2 Hz, H-4Ј), 6.89 (1H, d, Jϭ8.8 Hz, H-8Ј). 13C-NMR (CDCl3, 50 MHz) d:
5Ј-Nitrospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-acetamide (8c):

May 2003
527
provide 18a (119 mg, 60%). mp: 226 °C (EtOAc). 1H-NMR (CDCl3, 400
MHz) d: 1.6—2.2 (8H, m, cyclopentane H), 5.85 (1H, d, Jϭ10.2 Hz, H-3Љ),
6.26 (1H, d, Jϭ10.2 Hz, H-4Љ), 6.32 (1H, d, Jϭ15.7 Hz, H-2), 6.89 (1H, d,
Jϭ8.8 Hz, H-8Љ), 7.44 (1H, d, Jϭ8.8 Hz, H-7Љ), 7.58 (1H, d, Jϭ15.7 Hz, H-
3). 13C-NMR (CDCl3, 50 MHz) d: 23.64, 39.92 (cyclopentane C), 88.52 (C-
2Љ), 114.48 (C-4Љa), 116.26 (C-4Љ), 118.87 (C-6Љ), 119.18 (C-2), 119.38 (C-
8Љ), 127.55 (C-7Љ), 133.54 (C-3Љ), 139.30 (C-3), 147.54 (C-5Љ), 155.56 (C-
8Љa), 171.29 (C-1). Anal. Calcd for C16H15NO5: C, 63.78; H, 5.02; N, 4.65.
Found: C, 63.92; H, 5.33; N, 4.46.
21.34, 25.15, 34.94 (cyclohexane C), 75.61 (C-2Ј), 116.95 (C-4Јa), 117.99
(C-7Ј), 119.14 (C-4Ј), 124.01 (C-8Ј), 131.69 (C-5Ј), 132.11 (C-3Ј), 137.87
(C-6Ј), 144.85 (C-8Јa). Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N,
10.76. Found: C, 64.54; H, 6.28; N, 10.63.
5Ј-Nitrospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopyran]-6Ј-amine (16c): Yield:
1
88%. mp: 89 °C (Et2O). H-NMR (CDCl3, 400 MHz) d: 1.4—2.1 (12H, m,
cycloheptane H), 5.07 (2H, br s, NH2, D2O exchangeable), 5.71 (1H, d,
Jϭ10.2 Hz, H-3Ј), 6.56 (1H, d, Jϭ8.8 Hz, H-7Ј), 6.65 (1H, d, Jϭ10.2 Hz, H-
4Ј), 6.84 (1H, d, Jϭ8.8 Hz, H-8Ј). 13C-NMR (CDCl3, 50 MHz) d: 21.51,
29.29, 38.18 (cycloheptane C), 79.56 (C-2Ј), 116.62 (C-4Јa), 117.73 (C-4Ј),
117.92 (C-7Ј), 124.14 (C-8Ј), 131.61 (C-5Ј),133.16 (C-3Ј), 137.76 (C-6Ј),
144.80 (C-8Јa). Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.81; H, 6.76; N, 10.50.
The following compounds were prepared according to the procedure de-
scribed for 18a.
3-{5Љ-Nitrospiro[cyclohexane-1Ј,2Љ(2ЉH)[1]benzopyran-6Љ-yl]}propen-2-
oic Acid (18b): Yield: 63%. mp: 223 °C (EtOAc). 1H-NMR (CDCl3, 400
MHz) d: 1.2—2.0 (10H, m, cyclohexane H), 5.85 (1H, d, Jϭ10.2 Hz, H-3Љ),
6.25 (1H, d, Jϭ10.2 Hz, H-4Љ), 6.33 (1H, d, Jϭ15.7 Hz, H-2), 6.97 (1H, d,
Jϭ8.8 Hz, H-8Љ), 7.46 (1H, d, Jϭ8.8 Hz, H-7Љ), 7.58 (1H, d, Jϭ15.7 Hz, H-
3). 13C-NMR (CDCl3, 50 MHz) d: 21.11, 24.95, 36.05 (cyclohexane C),
78.58 (C-2Љ), 114.70 (C-4Љa), 116.07 (C-4Љ), 118.94 (C-6Љ), 119.34 (C-8Љ, C-
2), 127.67 (C-7Љ), 134.29 (C-3Љ), 139.30 (C-3), 147.59 (C-5Љ), 155.59 (C-
8Љa), 170.77 (C-1). Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43; N, 4.44.
Found: C, 64.63; H, 5.38; N, 4.31.
5Ј-Nitrospiro[tricyclo[3,3,1,13,7]decane-2,2Ј(2ЈH)[1]benzopyran]-6Ј-amine
(16d): Yield: 96%. mp: 196 °C (Et2O). 1H-NMR (CDCl3, 400 MHz) d: 1.4—
2.3 (14H, m, adamantane H), 5.19 (2H, br s, NH2, D2O exchangeable), 6.22
(1H, d, Jϭ10.2 Hz, H-3Ј), 6.61 (1H, d, Jϭ9.1 Hz, H-7Ј), 6.79 (1H, d,
Jϭ10.2 Hz, H-4Ј), 6.98 (1H, d, Jϭ9.1 Hz, H-8Ј). 13C-NMR (CDCl3,
50 MHz) d: 26.74, 27.14, 32.47, 33.54, 34.86, 37.62 (adamantane C), 78.86
(C-2Ј), 118.07 (C-4Јa, C-7Ј), 119.87 (C-4Ј), 124.43 (C-8Ј), 130.68 (C-3Ј),
131.50 (C-5Ј), 138.21 (C-6Ј), 144.64 (C-8Јa). Anal. Calcd for C18H20N2O3:
C, 69.21; H, 6.45; N, 8.97. Found: C, 69.00; H, 6.41; N, 9.06.
3-{5Љ-Nitrospiro[cycloheptane-1Ј,2Љ(2ЉH)[1]benzopyran-6Љ-yl]}propen-2-
oic Acid (18c): Yield: 55%. mp: 215 °C (EtOAc). 1H-NMR (CDCl3, 400
MHz) d: 1.4—2.1 (12H, m, cycloheptane H), 5.86 (1H, d, Jϭ10.2 Hz, H-3Љ),
6.20 (1H, d, Jϭ10.2 Hz, H-4Љ), 6.32 (1H, d, Jϭ15.7 Hz, H-2), 6.93 (1H, d,
Jϭ8.8 Hz, H-8Љ), 7.44 (1H, d, Jϭ8.8 Hz, H-7Љ), 7.63 (1H, d, Jϭ15.7 Hz, H-
3). 13C-NMR (CDCl3, 50 MHz) d: 21.52, 29.48, 39.53 (cycloheptane C),
82.55 (C-2Љ), 114.36 (C-4Љa), 114.56 (C-4Љ), 118.82 (C-6Љ), 119.41 (C-8Љ, C-
2), 127.54 (C-7Љ), 135.05 (C-3Љ), 139.09 (C-3), 147.49 (C-5Љ), 155.49 (C-
8Љa), 171.05 (C-1). Anal. Calcd for C18H19NO5: C, 65.64; H, 5.81; N, 4.25.
Found: C, 65.87; H, 5.99; N, 3.95.
6؅-Iodo-5؅-nitrospiro[cyclopentane-1,2؅(2؅H)[1]benzopyrane] (17a)
The nitroderivative 16a (370 mg, 1.5 mmol) was dissolved in a mixture of
concentrated H2SO4 (4.5 ml) and water (11 ml) with warming and then was
cooled to 0 °C. A solution of NaNO2 (116 mg, 1.68 mmol) in water (2 ml)
was added dropwise and the mixture was stirred at room temperature for 4 h,
followed by dropwise addition of a solution of KI (349 mg, 2.1 mmol) in
water (3 ml). The resulting mixture was stirred at room temperature for 12 h,
the product was extracted into dichloromethane, the organic phase was dried
(Na2SO4) and evaporated to dryness. The residue was purified by column
chromatography (silica gel) using a mixture of cyclohexane/EtOAc 12/1 as
3-{5Љ-Nitrospiro[tricyclo[3,3,1,13,7]decane-2Ј,2Љ(2ЉH)[1]benzopyran-6Љ-
1
1
yl]}propen-2-oic Acid (18d): Yield: 45%. mp: Ͼ250 °C (EtOAc). H-NMR
the eluent to give pure 17a as an oil (300 mg, 56%). H-NMR (CDCl3, 400
(CDCl3–CD3OD, 400 MHz) d: 1.2—2.1 (14H, m, adamantane H), 6.00 (1H,
d, Jϭ10.5 Hz, H-3Љ), 6.03 (1H, d, Jϭ15.8 Hz, H-2), 6.11 (1H, d, Jϭ10.5 Hz,
H-4Љ), 6.76 (1H, d, Jϭ8.8 Hz, H-8Љ), 7.16 (1H, d, Jϭ15.8 Hz, H-3), 7.23
(1H, d, Jϭ8.8 Hz, H-7Љ). 13C-NMR (CDCl3–CD3OD, 50 MHz) d: 26.09,
26.46, 31.68, 32.78, 35.43, 37.01 (adamantane C), 81.08 (C-2Љ), 114.93 (C-
4Љa), 115.96 (C-4Љ), 118.87 (C-6Љ), 119.05, 120.23 (C-2, C-8Љ), 127.10 (C-
7Љ), 132.39 (C-3Љ), 136.84 (C-3), 146.84 (C-5Љ), 154.48 (C-8Љa), 167.83 (C-
1). Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.38;
H, 5.82; N, 3.60.
3-{5؆-Aminospiro[cyclopentane-1؅,2؆(2؆H)[1]benzopyran-6؆-yl]}
propen-2-oic Acid (19a) To a solution of 18a (813 mg, 2.7 mmol) in ace-
tone (30 ml) was added SnCl2·2H2O (3 g, 13.5 mmol) and the mixture was
stirred at 70 °C for 24 h. The solvent was vacuum-evaporated, water was
added to the residue and it was made alkaline with a 28% ammonia solution.
The precipitate was filtered off through a layer of celite, washed with water
and the combined filtrate was acidified to pH 5 with concentrated HCl to
give a solid. The product was purified by reprecipitation from aqueous am-
monia to give pure 19a (417 mg, 57%). mp: Ͼ250 °C. 1H-NMR (DMSO-d6,
400 MHz) d: 1.6—2.0 (8H, m, cyclopentane H), 5.86 (1H, d, Jϭ9.9 Hz, H-
3Љ), 6.31 (1H, d, Jϭ14.1 Hz, H-2), 6.63 (1H, d, Jϭ8.1 Hz, H-8Љ), 7.19 (1H, d,
Jϭ9.9 Hz, H-4Љ), 7.42 (1H, d, Jϭ8.1 Hz, H-7Љ), 7.78 (1H, d, Jϭ14.1 Hz, H-
3). 13C-NMR (DMSO-d6, 50 MHz) d: 23.27, 38.74 (cyclopentane C), 87.19
(C-2Љ), 107.28 (C-4Љa), 108.36 (C-2), 112.20 (C-8Љ), 114.25 (C-6Љ), 116.71
(C-4Љ), 129.15 (C-3Љ), 129.22 (C-7Љ), 135.11 (C-5Љ), 141.21 (C-3), 154.51
(C-8Љa), 163.07 (C-1). Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N,
5.16. Found: C, 71.05; H, 6.44; N, 5.22.
MHz) d: 1.6—2.2 (8H, m, cyclopentane H), 5.80 (1H, d, Jϭ10.2 Hz, H-3Ј),
6.17 (1H, d, Jϭ10.2 Hz, H-4Ј), 6.62 (1H, d, Jϭ8.4 Hz, H-8Ј), 7.49 (1H, d,
Jϭ8.4 Hz, H-7Ј). 13C-NMR (CDCl3, 50 MHz) d: 23.55, 39.56 (cyclopentane
C), 72.99 (C-6Ј), 87.99 (C-2Ј), 116.09 (C-4Јa), 116.37 (C-4Ј), 120.12 (C-8Ј),
133.79 (C-3Ј), 138.97 (C-7Ј), 151.54 (C-5Ј), 153.73 (C-8Јa). Anal. Calcd for
C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 43.33; H, 3.48; N, 4.16.
The following compounds were prepared according to the procedure de-
scribed for 17a.
6Ј-Iodo-5Ј-nitrospiro[cyclohexane-1,2Ј(2ЈH)[1]benzopyrane] (17b): Yield:
1
53%. Oil. H-NMR (CDCl3, 400 MHz) d: 1.1—2.0 (10H, m, cyclohexane
H), 5.78 (1H, d, Jϭ10.2 Hz, H-3Ј), 6.14 (1H, d, Jϭ10.2 Hz, H-4Ј), 6.68 (1H,
d, Jϭ8.8 Hz, H-8Ј), 7.49 (1H, d, Jϭ8.8 Hz, H-7Ј). 13C-NMR (CDCl3, 50
MHz) d: 20.93, 24.81, 35.60 (cyclohexane C), 72.94 (C-6Ј), 77.84 (C-2Ј),
115.92 (C-4Ј), 116.11 (C-4Јa), 120.15 (C-8Ј), 134.48 (C-3Ј), 138.98 (C-7Ј),
151.42 (C-5Ј), 153.56 (C-8Јa). Anal. Calcd for C14H14INO3: C, 45.30; H,
3.80; N, 3.77. Found: C, 45.54; H, 3.67; N, 3.79.
6Ј-Iodo-5Ј-nitrospiro[cycloheptane-1,2Ј(2ЈH)[1]benzopyrane] (17c): Yield:
1
71%. Oil. H-NMR (CDCl3, 400 MHz) d: 1.4—2.1 (12H, m, cycloheptane
H), 5.81 (1H, d, Jϭ10.2 Hz, H-3Ј), 6.12 (1H, d, Jϭ10.2 Hz, H-4Ј), 6.66 (1H,
d, Jϭ8.8 Hz, H-8Ј), 7.50 (1H, d, Jϭ8.8 Hz, H-7Ј). 13C-NMR (CDCl3, 50
MHz) d: 21.50, 29.46, 39.25 (cycloheptane C), 72.92 (C-6Ј), 82.02 (C-2Ј),
114.69 (C-4Ј), 116.01 (C-4Јa), 120.35 (C-8Ј), 135.33 (C-3Ј), 139.04 (C-7Ј),
151.55 (C-5Ј), 153.70 (C-8Јa). Anal. Calcd for C15H16INO3: C, 46.77; H,
4.19; N, 3.64. Found: C, 46.72; H, 4.09; N, 3.81.
6Ј-Iodo-5Ј-nitrospiro[tricyclo[3,3,1,13,7]decane-2,2Ј(2ЈH)[1]benzopyrane]
1
(17d): Yield: 68%. mp: 217—219 °C (Et2O). H-NMR (CDCl3, 400 MHz)
The following compounds were prepared according to the procedure de-
scribed for 19a.
d: 1.5—2.3 (14H, m, adamantane H), 6.25 (1H, d, Jϭ10.2 Hz, H-3Ј), 6.32
(1H, d, Jϭ10.2 Hz, H-4Ј), 6.77 (1H, d, Jϭ8.8 Hz, H-8Ј), 7.55 (1H, d,
Jϭ8.8 Hz, H-7Ј). 13C-NMR (CDCl3, 50 MHz) d: 26.56, 26.92, 32.27, 32.39,
35.69, 37.58 (adamantane C), 73.32 (C-6Ј), 81.15 (C-2Ј), 116.71 (C-4Ј),
117.19 (C-4Јa), 120.48 (C-8Ј), 133.08 (C-3Ј), 139.20 (C-7Ј), 151.57 (C-5Ј),
153.54 (C-8Јa). Anal. Calcd for C18H18INO3: C, 51.08; H, 4.29; N, 3.31.
Found: C, 51.10; H, 4.18; N, 3.43.
3-{5؆-Nitrospiro[cyclopentane-1؅,2؆(2؆H)[1]benzopyran-6؆-yl]}propen-
2-oic Acid (18a) A mixture of 17a (236 mg, 0.66 mmol), Pd(OAc)2 (4.3
mg, 0.02 mmol), PPh3 (10.1 mg, 0.039 mmol), K2CO3 (457 mg, 3.30 mmol)
and acrylic acid (0.08 ml, 1.20 mmol) in DMF (5 ml) and water (1 ml) was
stirred at 100 °C for 12 h, then cooled, diluted with water and extracted with
diethyl ether. The aqueous layer was acidified under cooling and the result-
ing precipitate was filtered. The product was purified by column chromatog-
raphy (silica gel) using a mixture of cyclohexane/EtOAc 8/2 as the eluent, to
3-{5Љ-Aminospiro[cyclohexane-1Ј,2Љ(2ЉH)[1]benzopyran-6Љ-yl]}propen-
2-oic Acid (19b): Yield: 60%. mp: Ͼ250 °C. 1H-NMR (DMSO-d6, 400 MHz)
1
d: H-NMR (CDCl3, 400 MHz) d: 1.2—1.9 (10H, m, cyclohexane H), 5.65
(1H, d, Jϭ10.0 Hz, H-3Љ), 6.08 (2H, m, H-2, H-8Љ), 6.73 (1H, d, Jϭ10.0 Hz,
H-4Љ), 7.27 (1H, d, Jϭ8.6 Hz, H-7Љ), 7.81 (1H, d, Jϭ15.6 Hz, H-3). 13C-
NMR (DMSO-d6, 50 MHz) d: 20.33, 24.18, 35.67 (cyclohexane C), 76.18
(C-2Љ), 106.50 (C-2), 107.00 (C-4Љa), 112.06 (C-6Љ), 115.12 (C-8Љ), 117.82
(C-4Љ), 128.51 (C-7Љ), 129.08 (C-3Љ), 140.40 (C-3), 144.14 (C-5Љ), 153.69
(C-8Љa), 168.16 (C-1). Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N,
4.91. Found: C, 71.61; H, 6.59; N, 4.85.
3-{5Љ-Aminospiro[cycloheptane-1Ј,2Љ(2ЉH)[1]benzopyran-6Љ-yl]}propen-
2-oic Acid (19c): Yield: 52%. mp: Ͼ250 °C. 1H-NMR (DMSO-d6, 400 MHz)
d: 1.3—2.0 (12H, m, cycloheptane H), 5.65 (1H, d, Jϭ9.9 Hz, H-3Љ), 6.05

528
Vol. 51, No. 5
to give 21a (221 mg, 65%). mp: 229—230 °C (EtOH). 1H-NMR (DMSO-d6,
400 MHz) d: 1.5—2.0 (8H, m, cyclopentane H), 3.71 (1H, dd, Jϭ4.7, 5.1
Hz, H-9Ј), 5.03 (1H, dd, Jϭ4.7, 7.8 Hz, H-10Ј), 5.34 (1H, d, Jϭ5.1 Hz, 9Ј-
OH, D2O exchangeable), 5.74 (1H, d, Jϭ7.8 Hz, 10Ј-OH, D2O exchange-
able), 6.30 (1H, d, Jϭ9.4 Hz, H-4Ј), 6.60 (1H, d, Jϭ8.6 Hz, H-6Ј), 7.44 (1H,
d, Jϭ8.6 Hz, H-5Ј), 7.81 (1H, d, Jϭ9.4 Hz, H-3Ј), 10.63 (1H, br s, NH). 13C-
NMR (DMSO-d6, 50 MHz) d: 23.64, 23.86, 34.59, 34.85 (cyclopentane C),
63.89 (C-10Ј), 69.47 (C-9Ј), 89.94 (C-8Ј), 107.48 (C-10Јa), 112.44 (C-6Ј),
113.21 (C-4Јa), 117.44 (C-3Ј), 128.42 (C-5Ј), 139.78 (C-10Јb), 140.92 (C-
4Ј), 154.89 (C-6Јa), 161.50 (C-2Ј). Anal. Calcd for C16H17NO4: C, 66.89; H,
5.96; N, 4.87. Found: C, 66.84; H, 6.08; N, 4.93.
(1H, d, Jϭ8.4 Hz, H-8Љ), 6.10 (1H, d, Jϭ15.4 Hz, H-2), 6.68 (1H, d, Jϭ9.9
Hz, H-4Љ), 7.26 (1H, d, Jϭ8.4 Hz, H-7Љ), 7.80 (1H, d, Jϭ15.4 Hz, H-3). 13C-
NMR (DMSO-d6, 50 MHz) d: 20.97, 28.75, 38.54 (cycloheptane C), 79.56
(C-2Љ), 106.08 (C-2), 107.10 (C-4Љa), 111.93 (C-6Љ), 113.97 (C-4Љ), 116.75
(C-8Љ), 128.11 (C-3Љ), 128.23 (C-7Љ), 140.26 (C-3), 144.09 (C-5Љ), 155.06
(C-8Љa), 168.21 (C-1). Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N,
4.68. Found: C, 72.56; H, 6.82; N, 4.50.
3-{5Љ-Aminospiro[tricyclo[3,3,1,13,7]decane-2Ј,2Љ(2ЉH)[1]benzopyran-6Љ-
1
yl]}propen-2-oic Acid (19d): Yield: 49%. mp: Ͼ250 °C. H-NMR (DMSO-
d6, 400 MHz) d: 1.45—2.30 (14H, m, adamantane H), 6.31 (1H, d, Jϭ9.7
Hz, H-3Љ), 6.58 (1H, d, Jϭ15 Hz, H-2), 6.60 (1H, d, Jϭ8.3 Hz, H-8Љ), 7.21
(1H, d, Jϭ9.7 Hz, H-4Љ), 7.28 (1H, d, Jϭ8.3 Hz, H-7Љ), 7.84 (1H, d, Jϭ15
Hz, H-3). 13C-NMR (DMSO-d6, 50 MHz) d: 26.01, 26.38, 31.70, 32.62,
35.34, 37.00 (adamantane C), 81.15 (C-2Љ), 107.32 (C-4Љa), 112.82 (C-6Љ),
114.81 (C-2), 116.06 (C-4Љ), 119.88 (C-8Љ), 128.56 (C-3Љ), 128.67 (C-7Љ),
133.71 (C-3), 146.65 (C-5Љ), 154.07 (C-8Љa), 167.20 (C-1). Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.67; H, 6.81; N, 3.94.
Spiro[cyclopentane-1,8؅(8؅H)-pyran[2,3-h]quinolin]-2؅(1؅H)-one (20a)
A mixture of 19a (35.2 mg, 0.13 mmol) and 4% HCl solution was heated at
reflux for 2 h, After cooling the precipitate was filtered and the crude prod-
uct was purified by column chromatography (silica gel) using a mixture of
cyclohexane/EtOAc 3/1 as the eluent to give 20a (26.3 mg, 80%). mp: 200—
202 °C (EtOAc). 1H-NMR (CDCl3, 400 MHz) d: 1.5—2.3 (8H, m, cyclopen-
tane H), 5.82 (1H, d, Jϭ10.2 Hz, H-9Ј), 6.50 (1H, d, Jϭ9.5 Hz, H-4Ј), 6.68
(1H, d, Jϭ8.4 Hz, H-6Ј), 7.21 (1H, d, Jϭ10.2 Hz, H-10Ј), 7.26 (1H, d,
Jϭ8.4 Hz, H-5Ј), 7.64 (1H, d, Jϭ9.5 Hz, H-3Ј), 11.54 (1H, br s, NH, D2O
exchangeable). 13C-NMR (CDCl3, 50 MHz) d: 23.52, 39.32 (cyclopentane
C), 87.48 (C-8Ј), 107.99 (C-10Јa), 113.02 (C-6Ј), 114.60 (C-4Јa), 116.33 (C-
10Ј), 117.91 (C-3Ј), 128.39 (C-5Ј), 129.45 (C-9Ј), 134.86 (C-10Јb), 141.36
(C-4Ј), 155.22 (C-6Јa), 164.67 (C-2Ј). Anal. Calcd for C16H15NO2: C, 75.87;
H, 5.97; N, 5.53. Found: C, 75.99; H, 5.70; N, 5.18.
The following compounds were prepared according to the procedure de-
scribed for 21a.
(Ϯ)-cis-9Ј,10Ј-Dihydro-9Ј,10Ј-dihydroxyspiro[cyclohexane-1,8Ј(8ЈH)-
pyran[2,3-h]quinolin]-2Ј(1ЈH)-one (21b): Yield: 84%. mp: 230 °C (EtOH).
1H-NMR (DMSO-d6, 400 MHz) d: 1.2—1.7 (9H, m, cyclohexane H), 2.04
(1H, m, cyclohexane H), 3.67 (1H, t, Jϭ5.0 Hz, H-9Ј), 5.06 (1H, d, Jϭ5.0
Hz, H-10Ј), 5.26 (1H, d, Jϭ5.0 Hz, 9Ј-OH, D2O exchangeable), 5.70 (1H,
brs, 10Ј-OH, D2O exchangeable), 6.30 (1H, d, Jϭ9.5 Hz, H-4Ј), 6.65 (1H, d,
Jϭ8.8 Hz, H-6Ј), 7.46 (1H, d, Jϭ8.8 Hz, H-5Ј), 7.81 (1H, d, Jϭ9.5 Hz, H-
3Ј), 10.59 (1H, br s, NH, D2O exchangeable). 13C-NMR (DMSO-d6, 50
MHz) d: 20.76, 20.88, 24.97, 31.04, 31.14 (cyclohexane C), 63.08 (C-10Ј),
69.24 (C-9Ј), 79.16 (C-8Ј), 107.15 (C-10Јa), 112.32 (C-6Ј), 113.21 (C-4Јa),
117.33 (C-3Ј), 128.48 (C-5Ј), 139.84 (C-10Јb), 140.89 (C-4Ј), 154.56 (C-
6Јa), 161.48 (C-2Ј). Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.99; H, 6.20; N, 4.57.
(Ϯ)-cis-9Ј,10Ј-Dihydro-9Ј,10Ј-dihydroxyspiro[cycloheptane-1,8Ј(8ЈH)-
pyran[2,3-h]quinolin]-2Ј(1ЈH)-one (21c): Yield: 59%. mp: Ͼ250 °C (EtOH).
1H-NMR (DMSO-d6, 400 MHz) d: 1.3—1.8 (11H, m, cycloheptane H), 2.26
(1H, m, cycloheptane H), 3.70 (1H, d, Jϭ4.0 Hz, H-9Ј), 5.04 (1H, d, Jϭ4.0
Hz, H-10Ј), 5.45 (2H, br s 2ϫOH, D2O exchangeable), 6.30 (1H, d, Jϭ9.5
Hz, H-4Ј), 6.61 (1H, d, Jϭ8.8 Hz, H-6Ј), 7.44 (1H, d, Jϭ8.8 Hz, H-5Ј), 7.81
(1H, d, Jϭ9.5 Hz, H-3Ј), 10.37 (1H, br s, NH, D2O exchangeable). 13C-NMR
(DMSO-d6, 50 MHz) d: 21.74, 21.88, 30.05, 35.27 (cycloheptane C), 63.69
(C-10Ј), 69.18 (C-9Ј), 84.20 (C-8Ј), 107.38 (C-10Јa), 112.84 (C-6Ј), 113.51
(C-4Јa), 117.66 (C-3Ј), 128.74 (C-5Ј), 140.24 (C-10Јb), 141.21 (C-4Ј),
155.05 (C-6Јa), 161.77 (C-2Ј). Anal. Calcd for C18H21NO4: C, 68.55; H,
6.71; N, 4.44. Found: C, 68.81; H, 6.59; N, 4.48.
The following compounds were prepared according to the procedure de-
scribed for 20a.
Spiro[cyclohexane-1,8Ј(8ЈH)-pyran[2,3-h]quinolin]-2Ј(1ЈH)-one (20b):
1
Yield: 75%. mp: 218 °C (EtOAc). H-NMR (CDCl3, 400 MHz) d: 1.2—2.1
(10H, m, cyclohexane H), 5.80 (1H, d, Jϭ10.1 Hz, H-9Ј), 6.50 (1H, d,
Jϭ9.2 Hz, H-4Ј), 6.73 (1H, d, Jϭ8.5 Hz, H-6Ј), 7.18 (1H, d, Jϭ10.1 Hz, H-
10Ј), 7.28 (1H, d, Jϭ8.5 Hz, H-5Ј), 7.65 (1H, d, Jϭ9.2 Hz, H-3Ј), 11.14 (1H,
br s, NH, D2O exchangeable). 13C-NMR (CDCl3, 50 MHz) d: 21.16, 25.22,
35.76 (cyclohexane C), 77.37 (C-2Ј), 108.06 (C-10Јa), 113.07 (C-6Ј), 114.64
(C-4Јa), 115.90 (C-10Ј), 117.87 (C-3Ј), 128.51 (C-5Ј), 130.18 (C-9Ј), 134.89
(C-10Јb), 141.41 (C-4Ј), 155.16 (C-6Јa), 164.64 (C-2Ј). Anal. Calcd for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.40; H, 6.20; N, 5.41.
Spiro[cycloheptane-1,8Ј(8ЈH)-pyran[2,3-h]quinolin]-2Ј(1ЈH)-one (20c):
(Ϯ)-cis-9Ј,10Ј-Dihydro-9Ј,10Ј-dihydroxyspiro[tricyclo[3,3,1,13,7]decane-
2,8Ј(8ЈH)-pyran[2,3-h]quinolin]-2Ј(1ЈH)-one (21d): Yield: 72%. mp: Ͼ250 °C
1
(EtOH). H-NMR (DMSO-d6, 400 MHz) d: 1.5—2.3 (14H, m, adamantane
H), 3.74 (1H, m, H-9Ј), 4.93 (1H, m, H-10Ј), 5.55 (1H, d, Jϭ5.1 Hz, 9Ј-OH,
D2O exchangeable), 5.68 (1H, br s, 10Ј-OH, D2O exchangeable), 6.26 (1H,
d, Jϭ9.5 Hz, H-4Ј), 6.72 (1H, d, Jϭ8.8 Hz, H-6Ј), 7.39 (1H, d, Jϭ8.8 Hz, H-
5Ј), 7.73 (1H, d, Jϭ9.5 Hz, H-3Ј), 10.43 (1H, br s, NH, D2O exchangeable).
13C-NMR (DMSO-d6, 50 MHz) d: 26.31, 27.10, 32.28, 33.62, 35.21, 37.90
(adamantane C), 63.20 (C-10Ј), 69.33 (C-9Ј), 80.05 (C-8Ј), 108.05 (C-10Јa),
112.83 (C-6Ј), 114.11 (C-4Јa), 117.56 (C-3Ј), 128.96 (C-5Ј), 137.34 (C-
10Јb), 141.12 (C-4Ј), 154.23 (C-6Јa), 162.63 (C-2Ј). Anal. Calcd for
C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.46; H, 6.51; N, 4.19.
NMR Spectra and Molecular Calculations COSY and NOESY spec-
tra were acquired with 1024 complex points for 256 experiments with 2 s re-
cycling delay, TPPI phase cycle and 1 s mixing time for NOESY. The het-
eronuclear single quantum coherence (HSQC) spectrum was obtained using
B0 gradient pulses, 128 FIDs in the t1 domain and 1 K in the t2 domain, 8
transients for each t1 experiment and recycling delay of 1.5 s. Molecular sim-
ulations were performed with Macromodel 6.522) using MM2* as force field
implemented in Macromodel.
1
Yield: 83%. mp: Ͼ250 °C (EtOAc). H-NMR (CDCl3, 400 MHz) d: 1.4—
2.1 (12H, m, cycloheptane H), 5.80 (1H, d, Jϭ10.2 Hz, H-9Ј), 6.48 (1H, d,
Jϭ9.2 Hz, H-4Ј), 6.70 (1H, d, Jϭ8.4 Hz, H-6Ј), 7.02 (1H, d, Jϭ10.2 Hz, H-
10Ј), 7.33 (1H, d, Jϭ8.4 Hz, H-5Ј), 7.63 (1H, d, Jϭ9.2 Hz, H-3Ј), 11.16 (1H,
br s, NH, D2O exchangeable). 13C-NMR (CDCl3, 50 MHz) d: 21.54, 29.50,
39.20 (cycloheptane C), 81.39 (C-8Ј), 107.63 (C-10Јa), 113.26 (C-6Ј),
114.25 (C-4Јa), 114.52 (C-10Ј), 117.76 (C-3Ј), 128.47 (C-5Ј), 131.27 (C-9Ј),
134.67 (C-10Јb), 141.46 (C-4Ј), 155.14 (C-6Јa), 164.46 (C-2Ј). Anal. Calcd
for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.98; H, 6.53; N,
5.22.
Spiro[tricyclo[3,3,1,13,7]decane-2,8Ј(8ЈH)-pyran[2,3-h]quinolin]-2Ј(1ЈH)-
one (20d): Yield: 88%. mp: Ͼ250 °C (EtOAc). 1H-NMR (CDCl3, 400 MHz)
d: 1.5—2.4 (14H, m, adamantane H), 6.29 (1H, d, Jϭ10.2 Hz, H-9Ј), 6.48
(1H, d, Jϭ9.1 Hz, H-4Ј), 6.81 (1H, d, Jϭ8.8 Hz, H-6Ј), 6.92 (1H, d, Jϭ10.2
Hz, H-10Ј), 7.32 (1H, d, Jϭ8.8 Hz, H-5Ј), 7.65 (1H, d, Jϭ9.1 Hz, H-3Ј),
10.22 (1H, br s, NH, D2O exchangeable). 13C-NMR (CDCl3, 50 MHz) d:
26.74, 27.07, 32.31, 33.54, 35.42, 37.71 (adamantane C), 80.68 (C-8Ј),
108.52 (C-10Јa), 113.07 (C-6Ј), 114.51 (C-4Јa), 115.79 (C-10Ј), 118.05 (C-
3Ј), 128.66 (C-5Ј), 129.08 (C-9Ј), 134.63 (C-10Јb), 141.37 (C-4Ј), 154.50
(C-6Јa), 163.83 (C-2Ј). Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N,
4.39. Found: C, 78.80; H, 6.61; N, 4.27.
(؎)-cis-9؅,10؅-Dihydro-9؅,10؅-dihydroxyspiro[cyclopentane-1,8؅(8؅H)-
pyran[2,3-h]quinolin]-2؅(1؅H)-one (21a) Compound 20a (300 mg, 1.18
mmol) was added to a solution of OsO4 (1.3 ml, 0.012 mmol, 2.5% in tert-
butanol) and N-methylmorpholine-N-oxide (192 mg, 1.64 mmol) in a 10 :
3 : 1 mixture of tert-BuOH : THF : H2O (15 ml) and the reaction mixture was
stirred at room temperature for 3 d. A saturated NaHSO3 solution (3 ml) was
then added and the mixture was stirred at room temperature for 2 h. The sol-
vents vacuum-evaporated and the residue was purified by column chro-
matography (silica gel) using a mixture of CH2Cl2/MeOH 95/5 as the eluent
Measurement of DPPH Radical Scavenging The method has been
previously described in detail.27) Briefly, to a solution of DPPH (final con-
centration 200 mM) in absolute ethanol, an equal volume of the compound
dissolved in ethanol was added at various concentrations (5—400 mM).
Ethanol was added to the control solution. Absorbance was recorded at
517 nm after 20, 30, 45 and 60 min of incubation at room temperature.28)
Each experiment was performed at least in triplicate and the standard devia-
tion in absorbance values was less than Ϯ10%.
Acknowledgments The present study was supported by a grant from
the Greek General Secretariat for Research and Technology (YPER 3971).
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