Ring enlargement versus selenoetherification on the reaction of allenyl oxindoles with selenenylating reagents

Article abstract of DOI:10.1021/jo202495z

Lactam-tethered allenols, readily prepared from α-oxolactams, were used as starting materials for divergent reactivity with selenenylating reagents. Either oxycyclization (spirocyclic selenolactams) or ring expansion (selenoquinolones) can be achieved through the choice of both reagents and substrates. The biological activity of some of the synthesized heterocycles has additionally been evaluated in four human cancer cell lines.

Full text of DOI:10.1021/jo202495z

Note
pubs.acs.org/joc
Ring Enlargement versus Selenoetherification on the Reaction of
Allenyl Oxindoles with Selenenylating Reagents
Benito Alcaide,*,† Pedro Almendros,*,‡ Amparo Luna,† Gonzalo Gomez-Campillos,†
́
and M. Rosario Torres§
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organ
de Rayos X, Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid, Spain
‡Instituto de Química Organ
ica General, IQOG, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
́ ́
ica I, Unidad Asociada al CSIC and §CAI Difraccion
́
S
* Supporting Information
ABSTRACT: Lactam-tethered allenols, readily prepared from α-oxolactams, were used as starting materials for divergent
reactivity with selenenylating reagents. Either oxycyclization (spirocyclic selenolactams) or ring expansion (selenoquinolones)
can be achieved through the choice of both reagents and substrates. The biological activity of some of the synthesized
heterocycles has additionally been evaluated in four human cancer cell lines.
he carbon−carbon double bond of allenes, a class of
compounds with two π-orbitals perpendicular to each
Scheme 1. NPSP-Mediated Preparation of Spirocyclic Seleno
β-Lactams through Selenocyclization of Allenols
a
T
other, is around 10 kcal mol−1 less stable than that of simple
alkenes,1 rendering them significantly more reactive. Thus,
allenes have metamorphosed from a laboratory curiosity to a
versatile and uniquely reactive functional group, allowing
chemists to prepare a variety of compounds of chemical and
biological interest.2 In addition, interest in the chemistry of
organoselenium compounds has increased remarkably due to
their biological activities and pharmaceutical potential.3
Selenocyclizations are stereospecific anti addition reactions of
selenium electrophiles to olefins bearing internal nucleophiles
leading to cyclic products.4,5 The reaction of selenium
electrophiles with allenes has attracted much attention because
it provides functionalized derivatives.6 Following up on our
combined interest in the area of lactams and allenes,7 we have
recently communicated the preparation of spirocyclic seleno β-
lactams 2 from 2-azetidinone-tethered allenols 1 and N-
phenylselenophthalimide (Scheme 1).8 We wish to report
here an unprecedented behavior of selenium electrophilic
reagents, namely, the ring enlargement of 2-indolinone-tethered
allenols in preference to selenoetherification on reacting with
selenenylating reagents.
Starting allenols 3a−e were achieved via indium-mediated
Barbier-type allenylation reactions of isatins in aqueous media
following our previously described methodology.9 PhSeBr,
NPSS (N-phenylselenosuccinimide), or diphenyl diselenide in
the presence of (diacetoxyiodo)benzene were shown to serve as
donors of PhSe+ in reactions with 2-indolinone-tethered allenol
3a, affording exclusively the expected spirocyclic seleno-
oxindole 4a (Table 1, entries 1−3).10 To further test the
reactivity of 2-indolinone-tethered allenols 3, we examined the
a
PMP = 4-MeOC6H4. Az = (R)-3-methoxy-1-(4-methoxyphenyl)-
azetidinyl-2-one. Diox = (S)-2,2-dimethyl-1,3-dioxolan-4-yl. Tol = 4-
MeC6H4. NPSP = N-phenylselenophthalimide.
reaction of allenol 3a with NPSP (N-phenylselenophthalimide),
a well-known source of seleniranium ion.11 Interestingly, it was
found that the combined use of NPSP and catalytic amounts of
PTSA in dichloromethane at room temperature gave rise to
quinoline-2,3-dione 5a as major product; quinoline-2,4-dione
6a and spirocycle 4a were also isolated as minor components
(Table 1, entry 4). Worthy of note, the reaction of 2-
indolinone-tethered allenols 3 with NPSP exhibited a chemo-
selectivity different from that previously observed for 2-
azetidinone-tethered allenols 1, namely, ring enlargement
versus selenocycloetherification. The comparative studies of
quinolone formation with addition of PTSA demonstrated that
the presence of the Brønsted acid gives higher yields and that
the acid additive acts as an activator but not as a catalyst.12
brief optimization of the reaction conditions revealed that
A
Received: December 14, 2011
Published: March 15, 2012
© 2012 American Chemical Society
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Note
Table 1. Controlled Selenocycloetherification versus Ring Expansion Reactions of 2-Indolinone-Tethered Allenols 3 under
Modified Selenenylation Conditions
a
entry
reagent
solvent
time (h)
additive
T (°C)
R1, R2, R3
product
4a
yield 4/5/6/7 (%)
1
PhSeBr
PhSeSePh
NPSS
CH2Cl2
DCE
1
72
96
24
5
20
40
Me, H, H
Me, H, H
Me, H, H
Me, H, H
Me, H, H
Me, H, H
Ph, H, H
Ph, H, H
PMP, H, H
Me, Cl, H
Me, Cl, H
Me, H, Cl
Me, H, Cl
71/0/0/0
60/0/0/0
70/0/0/0
26/56/17/0
80/2/13/0
43/40/12/0
0/79/0/0
0/0/0/56
0/65/0/0
44/0/0/0
2
DIB
4a
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PTSA (15 mol %)
PTSA (15 mol %)
PTSA (15 mol %)
PTSA (15 mol %)
PTSA (15 mol %)
20
4a
4
NPSP
20
4a/5a/6a
4a/5a/6a
4a/5a/6a
5b
5
NPSP
110
−15
20
6
NPSP
240
24
1
7
NPSP
8
PhSeBr
NPSP
20
7b
9
24
1
PTSA (15 mol %)
PTSA (15 mol %)
20
5c
10
11
12
13
NPSP
20
4d
b
PhSeBr
NPSP
1
20
4d/7d
4e/5e/6e
4e/7e
55/0/0/9
72
0.5
PTSA (15 mol %)
20
25/10/5/0
b
PhSeBr
20
43/0/0/19
a
Yield of pure, isolated product with correct analytical and spectral data. NPSS = N-Phenylselenosuccinimide. NPSP = N-Phenylselenophthalimide.
b
DCE = 1,2-Dichloroethane. DIB = (Diacetoxyiodo)benzene. PMP = 4-MeOC6H4. PTSA = p-Toluenesulfonic acid. Compounds 4d/7d and 4e/7e
were obtained as unseparable mixtures.
Scheme 2. Rearrangement Reaction of NH-Indolinone-Tethered Allenols 8a−c to Quinoline-2,3-diones 9a−c by NPSP
a
Treatment
a
Conditions: (i) NPSP, 15 mol % PTSA, CH2Cl2, rt, 8a: 72 h; 8b: 72 h, 8c: 24 h. PMP = 4-MeOC6H4. NPSP = N-phenylselenophthalimide. PTSA
= p-toluenesulfonic acid.
employment of other solvents (acetonitrile, THF, or 1,4-
dioxane) did not improve the yield of 5a. The reaction of
allenol 3a with the binary system NPSP/PTSA in 1,2-
dichloroethane at 110 °C gave as the major product the
spirocyclic component 4a (Table 1, entry 5). A general trend
can be deduced on the basis of this result: the spirocycle 4a is
the thermodynamic control product, while the quinoline-2,3-
dione 5a is the kinetic control product. With the optimized
conditions in hand, the generality of this transformation was
examined (Table 1). Fortunately, compounds 4, 5, and 6 are
easily separated by flash chromatography. Happily, the ring
expansion products 5b and 5c were isolated in good yields as
the sole isomers from the skeletal reorganization of 2-
indolinone-tethered allenols 3b and 3c bearing an aromatic
substituent at the allenic moiety (Table 1, entries 7 and 9).
Despite that the presence of halide substituents at the aromatic
ring is anticipated to provide the same reactivity pattern, the 5-
chloroindolinone 3d led to spirocyclic selenooxindole 4d as the
sole product, while 7-chloroindolinone 3e afforded 4e as the
major product; the expected 1,2-dicarbonylic compound 5e was
the minor component (Table 1, entries 10 and 12). It should be
noted that the presence of a chlorine atom at the aromatic ring
as in chloroindolinones 3d and 3e encumbers or even avoids
the migration of the benzene nucleus toward ring expansion,
which makes spirocyclization more feasible. This interesting
change in the ratio of ring expansion products versus spirocyclic
products, with the introduction of a chlorine substituent in a
rather distant part of the molecule, may be explained invoking
the deactivating effect of the chlorine substituent toward the
aromatic ring. This deactivating effect may be related to the
decreased migration ability of the chlorobenzene moiety to
form quinolinediones. Surprisingly, the reaction of phenyl-
substituted allenol 3b with PhSeBr afforded the allene 1,2-
addition adduct 7b as exclusive reaction product (Table 1, entry
8). Despite that a priori NPSP and PhSeBr are similar sources
of PhSe+, different products, namely, 5b and 7b, were obtained
starting from the common precursor 3b (Table 1, entries 7 and
8). This different behavior for both selenenylating reagents may
be explained taking into account their different chemical nature.
The initial common addition of PhSe+ cation to the central sp
carbon atom of the allene group forms a carbocationic sp2
center, which induces an intramolecular oxycyclization for the
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Note
a
Scheme 3. Reaction of Indolinone-Tethered Allenols 3 and 8 with NPSP under Gold Catalysis
a
Conditions: (i) NPSP, 5 mol % AuCl3, CH2Cl2, rt, 3a: 1 h; 3b: 2 h, 3c: 1 h; 3d: 1 h, 3e: 2 h; 8a: 2 h; 8b: 1 h, 8c: 1 h. PMP = 4-MeOC6H4. NPSP =
N-phenylselenophthalimide.
Scheme 4. Mechanistic Explanation for the Ring Expansion of 2-Indolinone-Tethered Allenols through Reaction with NPSP
NPSP case, while an intermolecular attack of the bromide
counteranion is observed for PhSeBr.
conditions. In general, the lack of substitution at the indole
nitrogen gave both selectivity and yields very comparable to
those attained using N-methyl derivatives and could be
considered excellent in the context of constructing multiple
bonds in a selective manner. When using the methyl-
substituted allenol 8a, the ring enlargement/spirocyclization
ratio was 88:12. Gratifyingly, allenols 8b and 8c containing an
aromatic motif were completely and exclusively converted to
selenylquinoline-2,3-diones 9b and 9c, spirocycle formation
being suppressed (Scheme 2).
The structural assignments of selenylquinoline-2,3-dione 5a
and selenyloxindole 7b were confirmed by means of an X-ray
diffraction analysis (Supplementary Figures S1 and S2).13,14
The intermolecular contact O(1)···H(2) in compound 7b may
indicate hydrogen bonding; these contacts link the molecules
into dimers (Supplementary Figure S3).
Having established the feasibility of the reaction for N-methyl
oxindoles 3, we investigated the generality of the protocol for
allenic NH-oxindoles 8a−c under the optimized reaction
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Note
The use of gold salts has gained a lot of attention in the
recent times because of their powerful soft Lewis acidic
nature.15 In particular, gold activation of allenes toward attacks
by oxygen nucleophiles is an important C−O bond-forming
reaction.16 However, gold-catalyzed protocols for the reaction
of allenols in the presence of selenylated reagents have not yet
been available. Despite the anticipated difficulty, we decided to
test the reactivity of our allenic 2-indolinones 3 and 8 with
NPSP under gold-catalyzed conditions. The stage was thus set
for the Au(III)-catalyzed reaction of 2-indolinone-tethered
allenol 3a with NPSP. Preliminary studies demonstrated that
the combined use of NPSP and catalytic amounts of both
AuCl3 and PTSA gave rise to messy reactions. When allenol 3a
was treated with NPSP in dichloromethane at room temper-
ature using 5 mol % of AuCl3, a clean and fast reaction occurred
to give selenyloxindole 4a (major product) and selenylquino-
line-2,3-dione 5a (minor product). Similar results were
obtained for the rest of allenols 3 and 8 (Scheme 3); the
selenocycloetherification was the major or exclusive path in
most cases. Probably, the presence of the phenyl group (R1 =
Ph) at the allene moiety forms a benzylic-like carbocation that
is more prone to suffer rearrangement in the case of NH-
indolone 8b than for 3b, because the ring opening of NH-
indolones is normally easier than the cleavage of N-methyl
indolones. Interestingly, replacement of PTSA by AuCl3
resulted in a much faster reaction favoring spirocyclization,
with both the acceleration and the selectivity being interesting
issues.
For the NPSP-promoted ring expansion of indolinone-
tethered allenols 3 and 8, two regioisomeric reaction pathways
presenting a one-step mechanism may be considered. They are
related to the migration of the aryl group, path I, or the
migration of carbonyl group, path II, along the ring expansion
(Scheme 4). These NPSP-promoted ring expansions involve
two distinct processes: (i) addition of PhSe+ cation from NPSP
to the proximal allenic double bond and (ii) a ring expansion.
Therefore, two regioisomeric TSs for the reaction of oxindoles
3 and 8, TS-I and TS-II, and the corresponding products have
been depicted in Supplementary Scheme S4. The addition of
PhSe+ cation to the central sp carbon atom of the allene group
forms a carbocationic sp2 center, which induces the
concomitant ring expansion, the migration of the phenyl
group being favored over the migration of the carbonyl one.
A possible pathway for the achievement of spirocyclic
selenooxindoles 4 and 11 from allenols 3 and 8 may initially
involve the formation of the complexes 3-AuCl3 and 8-AuCl3
through coordination of the gold trichloride to the distal allenic
double bond. Next, regioselective 5-endo oxyauration forms
zwitterionic species 12. Loss of HCl generates neutral species
13, which followed by electrophilic capture of the σ-gold
species (selenolysis of the carbon−gold bond) affords spiro-
cycles 4 and 11 and regenerates the gold catalyst (Scheme 5).
The fact that related metal salts such as InCl3 or FeCl3 were not
effective for the selenoetherification sequence ruled out the
hypothesis of simple Lewis acid catalysis, with the gold salt
AuCl3 activating the allene group. With the aim of trapping the
organogold intermediate to confirm the mechanism of this
reaction, we performed studies with water. Under otherwise
identical conditions, but with the addition of 2 equiv of H2O,
selenoetherification reaction of 2-indolinone-tethered allenol
3d with NPSP catalyzed by AuCl3 in dichloromethane afforded
4d (50%) accompanied by 14 in 10% yield, indicating that a
hydrogen atom was incorporated at the alkenyl carbon
Scheme 5. Mechanistic Explanation for the Gold-Catalyzed
Selenoetherification of 2-Indolinone-Tethered Allenols
through Reaction with NPSP
(Supplementary Scheme S1). The fact that the AuCl3-catalyzed
conversion of allenol 3d into spirocycle 4d in the presence of 2
equiv of H2O afforded 14 suggests that protonolysis of the
carbon−gold in species 13 has occurred.
As the combination of two different heterocycles within the
same molecule is known to enhance biological activity,17
a
biological evaluation of representative compounds of types 2, 4,
and 5 (Supplementary Figure S4) was next planned . The
cytotoxicity of the mentioned compounds was examined in the
human cancer cell line HL-60. The results clearly show that
there is significant difference between the three series of
compounds. Interestingly, all compounds 2 showed higher
toxicity toward HL-60 cells than compounds 4a and 5a
(Supplementary Table S1). The cytotoxicity of the mentioned
compounds 2a−2d was examined in four different cancer cell
lines, namely, HL-60 (human promyelocytic leukemia), HT-
1080 (human fibrosarcoma), HT-29 (human colon adenocar-
cinoma), and MDA-MB-231 (human breast carcinoma). The
results of this investigation are summarized in Supplementart
Table S1. Compounds 2 showed typical dose−response curves
for all the cell lines assayed, with a sharp decrease of cell
survival at concentrations that are close to the IC50 values
(Supplementary Figures S5−S8, Tables S2−S5). Data indicate
that, in the seleno β-lactam group of compounds, 2a and 2c
exhibited the higher cytotoxic activity for all cell types. The best
results were obtained with 2a, which showed values of IC50
around 5 μg/mL for the leukemia, fibrosarcoma, and breast
carcinoma cell lines. On the contrary, compound 2d was the
least active compound for all cell lines tested. This could be due
to a lower solubility of this compound, since some crystals
appeared in the assay wells throughout the experiment
(Supplementary Figure S9).
In conclusion, an unprecedented and divergent preparation
of spirocyclic selenolactams and selenoquinolone derivatives by
reaction of lactam-tethered allenols with selenenylating
reagents has been developed. Chemoselectivity (oxycyclization
versus ring expansion) control in the reaction of lactam-
tethered allenols can be achieved through the choice of both
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Note
material disappeared as indicated by TLC. Saturated aqueous sodium
hydrogen carbonate (1.5 mL) was added to the reaction mixture,
before being partitioned between dichloromethane and water. The
organic extract was washed with brine, dried (MgSO4), concentrated
under vacuum, and purified by flash column chromatography eluting
with ethyl acetate/hexanes mixtures.
reagents and substrates. These selenofunctionalization reactions
have been developed experimentally, and the biological activity
of some of the synthesized heterocycles has additionally been
evaluated in four cancer cell lines (see Supporting Informa-
tion).
Procedure C. Reaction between Allenols 3 and Diphenyl
Diselenide. To a solution of the corresponding allenol 3 (0.18
mmol) in dichloroethane (1.5 mL) were sequentially added PhSeSePh
(0.18 mmol), (diacetoxy)iodobenzene (0.36 mmol), and water (0.18
mmol). The reaction mixture was stirred at 40 °C until the starting
material disappeared as indicated by TLC. The reaction was
concentrated under vacuum and purified by flash column chromatog-
raphy eluting with ethyl acetate/hexanes mixtures.
Procedure D. Gold-Catalyzed Reaction between Allenols 3 and
N-Phenylselenophthalimide. A solution of N-phenylselenophthali-
mide (0.20 mmol) and AuCl3 (0.008 mmol) in dichloromethane (4
mL) under argon was stirred for 5 min. Then, the appropriate allenol 3
(0.15 mmol) was added, and the resulting mixture was stirred at RT
until the starting material disappeared as indicated by TLC. Saturated
aqueous sodium hydrogen carbonate (1.5 mL) was added to the
reaction mixture, before it was partitioned between dichloromethane
and water. The organic extract was washed with brine, dried (MgSO4),
concentrated under vacuum, and purified by flash column chromatog-
raphy eluting with ethyl acetate/hexanes mixtures or dichloro-
methane/ethyl acetate mixtures.
Cyclization of Allenol 3a. Preparation of Spirocycle 4a,
Quinoline-2,3-dione 5a, and Quinoline-2,4-dione 6a. Procedure
A. From 193 mg (0.90 mmol) of allenol 3a and after chromatography
of the residue using dichloromethane/ethyl acetate (98:2) as eluent,
58 mg (17%) of the less polar compound 6a, 186 mg (56%) of
compound 5a (intermediate polarity), and 87 mg (26%) of the more
polar compound 4a were obtained.
Cyclization of Allenol 3a. Preparation of Spirocyclic Seleno
Indolone 4a. Procedure B. From 30 mg (0.14 mmol) of allenol 3a
and after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent, the procedure gave compound 4a (36 mg, 71%) as a
colorless solid: mp 163−165 °C; 1H NMR (300 MHz, CDCl3, 25 °C)
δ 7.50 (d, J = 7.7 Hz, 2H), 7.26 (m, 5H), 7.07 (t, J = 7.5 Hz, 1H), 6.81
(d, J = 7.7 Hz, 1H), 4.94 and 4.78 (dq, J = 11.8, 2.0 Hz, each 1H), 3.18
(s, 3H), 1.50 (t, J = 2.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 25 °C)
δ 174.9, 143.9, 139.0, 131.8, 130.3, 129.4, 128.1, 127.8, 127.3, 124.5,
124.4, 123.2, 108.4, 93.2, 79.9, 26.3, 11.3; IR (CH2Cl2) ν 1725 cm−1;
HRMS (ES) calcd for C19H17NO2Se [M + H]+ 372.0503, found
372.0508.
EXPERIMENTAL SECTION
■
General Methods. 1H NMR and 13C NMR spectra were recorded
on 700, 500, 300, or 200 MHz spectrometers. NMR spectra were
recorded in CDCl3 solutions, except when otherwise stated. Chemical
shifts are given in ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C,
76.9 ppm). Low and high resolution mass spectra were taken using the
electronic impact (EI) or electrospray modes (ES) unless otherwise
stated. Specific rotation [α]D is given in 10−1 deg cm2 g−1 at 20 °C, and
the concentration (c) is expressed in grams per 100 mL. All
commercially available compounds were used without further
purification.
Materials and Methods for the Biological Evaluation. Cell
Culture. Compounds 2, 4, and 5 were dissolved in
dimethylsufoxide (DMSO) and stored at −20 °C until use.
All cancer cell lines used in this study were obtained from the
American Type Culture Collection (ATCC). Human fibro-
sarcoma HT-1080 cells were maintained in Dulbecco’s
modified Eagle’s medium (DMEM) containing glucose (4.5
g/L), glutamine (2 mM), penicillin (50 IU/mL), streptomycin
(50 μg/mL), and amphotericin (1.25 μg/mL) supplemented
with 10% FBS. Human colon adenocarcinoma HT-29 cells
were maintained in McCoy’s 5A medium containing glutamine
(2 mM), penicillin (50 IU/mL), streptomycin (50 μg/mL),
and amphotericin (1.25 μg/mL) supplemented with 10% FBS.
Human breast cancer carcinoma MDA-MB-231 and human
promyelocytic leukemia HL-60 cells were maintained in
RPMI1640 medium containing glutamine (2 mM), penicillin
(50 IU/mL), streptomycin (50 μg/mL), and amphotericin
(1.25 μg/mL) supplemented with 10% and 20% FBS,
respectively.
Cytotoxicity Assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide dye reduction assay was performed in 96-well
microplates by using the Mosmann’s method [Mosmann, T. J.
Immunol. Methods 1983, 65, 55]. Here, 2 × 103 tumor cells in a total
volume of 100 μL of their respective growth media were incubated
with serial dilutions of the tested compounds. After 3 days of
incubation (37 °C, 5% CO2 in a humid atmosphere), 10 μL of MTT
(5 mg/mL in PBS) was added to each well, and the plate was
incubated for a further 4 h (37 °C). The resulting formazan was
dissolved in 150 μL of 0.04 N HCl-2 propanol and read at 550 nm. All
determinations were carried out in triplicate. IC50 values were
calculated from semilogarithmic dose−response plots as the
concentration of compound yielding 50% cell survival.
General Experimental Procedures for the Synthesis of
Organoselenium Compounds. Procedure A. Reaction between
Allenols 1 or 3 and N-Phenylselenophthalimide. To a solution of
the appropriate allenols 1 or 3 (0.15 mmol) in dichloromethane
were sequentially added N-phenylselenophthalimide (0.195
mmol) and p-toluenesulphonic acid monohydrate (0.0225
mmol) under argon. The reaction mixture was stirred at RT
until the starting material disappeared as indicated by TLC.
Saturated aqueous sodium hydrogen carbonate (1.5 mL) was
added to the reaction mixture, before being partitioned
between dichloromethane and water. The organic extract was
washed with brine, dried (MgSO4), concentrated under
vacuum, and purified by flash column chromatography eluting
with ethyl acetate/hexanes mixtures or dichloromethane/ethyl
acetate mixtures. Spectroscopic and analytical data for pure
forms of compounds 4, 5, 6, and 7 follow.
Cyclization of Allenol 3a. Procedure C. From 40 mg (0.18
mmol) of allenol 3a and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, the procedure gave gave
compound 4a (40 mg, 60%).
Cyclization of Allenol 3a. Preparation of Spirocycle 4a and
Quinoline-2,3-dione 5a. Procedure D. From 30 mg (0.14 mmol) of
allenol 3a and after chromatography of the residue using hexanes/ethyl
acetate (2:1) as eluent, 27 mg (52%) of the less polar compound 4a
and 10 mg (19%) of the more polar compound 5a were obtained.
1
Spirocycle 4a. Colorless solid; mp 163−165 °C; H NMR (300
MHz, CDCl3, 25 °C) δ 7.50 (d, J = 7.7 Hz, 2H), 7.26 (m, 5H), 7.07 (t,
J = 7.5 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 4.94 and 4.78 (dq, J = 11.8,
2.0 Hz, each 1H), 3.18 (s, 3H), 1.50 (t, J = 2.0 Hz, 3H); 13C NMR (75
MHz, CDCl3, 25 °C) δ 174.9, 143.9, 139.0, 131.8, 130.3, 129.4, 128.1,
127.8, 127.3, 124.5, 124.4, 123.2, 108.4, 93.2, 79.9, 26.3, 11.3; IR
(CH2Cl2) ν 1725 cm−1; HRMS (ES) calcd for C19H17NO2Se [M +
H]+ 372.0503, found 372.0508.
1
Quinoline-2,3-dione 5a. Colorless solid; mp 219−221 °C; H
NMR (300 MHz, CDCl3, 25 °C) δ 7.80 and 7.29 (m, each 4H), 7.01
(d, J = 8.8 Hz, 1H), 5.56 and 5.23 (d, J = 2.1 Hz, each 1H), 3.44 (s,
3H), 1.78 (s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 191.7, 167.8,
157.3, 143.7, 138.3, 135.5, 134.3, 132.6, 129.7, 129.4, 128.5, 128.0,
124.0, 123.5, 120.1, 115.4, 59.1, 30.0, 21.1; IR (CH2Cl2) ν 3202, 1774,
1746, 1370 cm−1; HRMS (ES) calcd for C19H17NO2Se [M + H]+
372.0503, found 372.0503.
Procedure B. Reaction between Allenols 3 and N-Phenylselenyl
Bromide. To a solution of the corresponding allenol 3 (0.14 mmol) in
dichloromethane (2.8 mL) was added PhSeBr (0.21 mmol) under
argon. The reaction mixture was stirred at RT until the starting
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Note
1
Quinoline-2,4-dione 6a. Pale yellow oil; H NMR (700 MHz,
CDCl3, 25 °C) δ 7.95 (d, J = 7.7 Hz, 1H), 7.62 (m, 1H), 7.45 (d, J =
7.7 Hz, 1H), 7.20 (m, 5H), 7.11 (d, J = 7.7 Hz, 1H), 5.93 and 5.55 (d,
J = 1.4 Hz, each 1H), 3.39 (s, 3H), 1.71 (s, 3H); 13C NMR (176 MHz,
CDCl3, 25 °C) δ 194.2, 170.9, 142.9, 139.3, 135.9, 134.3, 129.4, 129.0,
128.4, 127.9, 123.1, 122.7, 120.4, 114.7, 64.6, 29.9, 22.6; IR (CH2Cl2)
ν 2931, 1698, 1600, 1471 cm−1; HRMS (ES) calcd for C19H17NO2Se
[M + H]+ 372.0503, found 372.0501.
(CHCl3) ν 1725 cm−1; HRMS (ES) calcd for C25H21NO3Se [M + H]+
464.0765, found 464.0748.
Cyclization of Allenol 3d. Procedure A. From 27 mg (0.11
mmol) of allenol 3d and after chromatography of the residue using
dichloromethane/ethyl acetate (99:1) as eluent, the procedure gave
compound 4d (19 mg, 44%).
Cyclization of Allenol 3d. Preparation of Spirocycle 4d and
Selenooxindole 7d. Procedure B. From 30 mg (0.12 mmol) of
allenol 3d and after chromatography of the residue using dichloro-
methane/ethyl acetate (9:1) as eluent, the procedure gave an isomeric
mixture (90:10) of nonseparable compounds 4d and 7d (31.5 mg,
64%).
Cyclization of Allenol 3b. Procedure A. From 30 mg (0.11
mmol) of allenol 3b and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, the procedure gave compound
5b (37 mg, 79%).
Cyclization of allenol 3d. Procedure D. From 25 mg (0.10
mmol) of allenol 3d and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent, the procedure gave compound
4d (21.5 mg, 53%).
Cyclization of Allenol 3b. Procedure B. From 27 mg (0.09
mmol) of allenol 3b and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent, the procedure gave compound
7b (26 mg, 56%).
Cyclization of Allenol 3b. Preparation of Spirocycle 4b,
Quinoline-2,3-dione 5b, and Quinoline-2,4-dione 6b. Procedure
D. From 31 mg (0.11 mmol) of allenol 3b and after chromatography
of the residue using hexanes/ethyl acetate (5:1) as eluent, 1.8 mg (4%)
of the less polar compound 6b, 27 mg (57%) of compound 4b
(intermediate polarity), and 4 mg (9%) of the more polar compound
5b were obtained.
1
Spirocycle 4d. Colorless solid; mp 209−211 °C; H NMR (300
MHz, CDCl3, 25 °C) δ 7.54 (m, 2H), 7.26 (m, 5H), 6.77 (d, J = 8.4
Hz, 1H), 4.95 and 4.79 (dd, J = 11.9, 2.0 Hz, each 1H), 3.20 (s, 3H),
1.53 (t, J = 2.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 174.5,
142.4, 137.7, 134.3, 132.5, 132.2, 130.2, 129.4, 128.7, 127.5, 125.0,
123.6, 109.4, 93.1, 80.1, 26.5, 11.2; IR (CH2Cl2) ν 1748 cm−1; HRMS
(ES) calcd for C19H16ClNO2Se [M + H]+ 406.0113, found 406.0093.
Cyclization of Allenol 3e. Preparation of Spirocycle 4e,
Quinoline-2,3-dione 5e, and Quinoline-2,4-dione 6e. Procedure
A. From 30 mg (0.12 mmol) of allenol 3e and after chromatography of
the residue using hexanes/ethyl acetate (7:1) as eluent, 12 mg (25%)
of the less polar compound 4e, 2.5 mg (5%) of compound 6e
(intermediate polarity), and 5 mg (10%) of the more polar compound
5e were obtained.
Spirocycle 4b. Colorless oil; 1H NMR (300 MHz, CDCl3, 25 °C)
δ 7.65 (m, 2H), 7.33 (m, 5H), 7.18 (m, 3H), 7.07 (t, J = 7.9 Hz, 1H),
6.97 (m, 2H), 6.72 (d, J = 7.9 Hz, 1H), 5.01 and 4.83 (d, J = 12.5 Hz,
each 1H), 3.10 (s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 174.7,
143.9, 137.7, 134.3, 131.9, 130.4, 129.5, 129.3, 128.3, 128.2, 128.1,
128.0, 126.4, 124.9, 123.1, 108.4, 93.7, 79.9, 26.2; IR (CH2Cl2) ν 1725
cm−1; HRMS (ES) calcd for C24H19NO2Se [M + H]+ 434.0659, found
434.0644.
Cyclization of Allenol 3e. Preparation of Spirocycle 4e and
Selenooxindole 7e. Procedure B. From 30 mg (0.12 mmol) of
allenol 3e and after chromatography of the residue using dichloro-
methane/ethyl acetate (98:2) as eluent, the procedure gave an
isomeric mixture (70:30) of nonseparable compounds 4e and 7e (32.5
mg, 62%).
Cyclization of Allenol 3e. Procedure D. From 40 mg (0.16
mmol) of allenol 3e and after chromatography of the residue using
hexanes/ethyl acetate (5:1) as eluent, the procedure gave compound
4e (30.5 mg, 47%).
1
Quinoline-2,3-dione 5b. Colorless solid; mp 153−155 °C; H
NMR (300 MHz, CDCl3, 25 °C) δ 7.87, 7.77, and 7.65 (m, each 2H),
7.48 (t, J = 8.5 Hz, 1H), 7. Nineteen (m, 7H), 5.59 and 5.36 (d, J = 1.5
Hz, each 1H), 3.40 (s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ
189.2, 167.8, 156.5, 142.3, 138.2, 135.7, 135.2, 134.2, 132.6, 130.8,
129.9, 129.6, 129.3, 128.8, 128.7, 128.5, 125.2, 123.8, 123.5, 115.7,
70.8, 30.2; IR (CH2Cl2) ν 3205, 1747, 1686, 1371 cm−1; HRMS (ES)
calcd for C24H19NO2Se [M + H]+ 434.0659, found 434.0667.
Quinoline-2,4-dione 6b. Colorless oil; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 8.03 (d, J = 7.7 Hz, 1H), 7.77 (m, 1H), 7.56 (m, 1H),
7.30 (m, 7H), 7.14 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.70
and 5.23 (d, J = 1.0 Hz, each 1H), 3.55 (s, 3H); 13C NMR (175 MHz,
CDCl3, 25 °C) δ 192.8, 169.4, 142.5, 140.5, 135.8, 134.3, 133.8, 131.4,
129.1, 129.0, 128.9, 128.6, 128.3, 128.2, 127.7, 127.5, 127.2, 123.2,
121.5, 114.8, 53.4, 30.4; IR (CH2Cl2) ν 1698, 1660, 1351 cm−1;
HRMS (ES) calcd for C24H19NO2Se [M + H]+ 434.0644, found
434.0644.
Spirocycle 4e. Colorless solid; mp 85−87 °C; 1H NMR (300
MHz, CDCl3, 25 °C) δ 7.53 (m, 2H), 7.30 (m, 4H), 7.10 (dd, J = 7.3,
1.3 Hz, 1H), 7.00 (m, 1H), 4.95 and 4.79 (dq, J = 11.9, 2.0 Hz, each
1H), 3.58 (s, 3H), 1.53 (t, J = 2.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 175.2, 139.8, 138.2, 132.6, 132.1, 130.8, 129.4, 127.9,
127.5, 125.0, 124.0, 123.1, 115.9, 92.6, 80.0, 29.7, 11.2; IR (CH2Cl2) ν
1732 cm−1; HRMS (ES) calcd for C19H16ClNO2Se [M + H]+
406.0113, found 406.0102.
1
Quinoline-2,3-dione 5e. Pale yellow solid; mp 94−96 °C; H
Quinoline-2,3-dione 5c. Procedure A. From 23 mg (0.07 mmol)
of allenol 3c and after chromatography of the residue using hexanes/
ethyl acetate (2:1) as eluent, the procedure gave compound 5c (21
NMR (700 MHz, CDCl3, 25 °C) δ 7.45 (m, 3H), 7.32 (m, 4H), 7.20
(t, J = 7.9 Hz, 1H), 5.42 and 5.09 (d, J = 2.1 Hz, each 1H), 3.49 (s,
3H), 1.75 (s, 3H); 13C NMR (176 MHz, CDCl3, 25 °C) δ 191.8,
161.0, 144.0, 137.4, 136.3, 132.5, 130.6, 129.6, 129.0, 127.6, 126.1,
125.8, 125.3, 118.8, 58.9, 36.4, 19.7; IR (CH2Cl2) ν 3205, 1747, 1686,
1371 cm−1; HRMS (ES) calcd for C19H16ClNO2Se [M + H]+
406.0113, found 406.0105.
1
mg, 65%) as a pale yellow oil: H NMR (300 MHz, CDCl3, 25 °C) δ
7.81 (d, J = 9.0 Hz, 2H), 7.65 (m, 2H), 7.33 (m, 7H), 6.92 (d, J = 9.0
Hz, 2H), 6.13 and 5.66 (d, J = 1.1 Hz, each 1H), 5.30 (s, 3H), 3.87 (s,
3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 193.2, 165.7, 163.4, 159.5,
143.5, 137.9, 136.5, 132.0, 131.7, 131.4, 129.6, 129.1, 128.9, 127.7,
127.3, 124.6, 113.6, 77.1, 55.4, 25.6; IR (CH2Cl2) ν 3205, 1747, 1686,
1371 cm−1; HRMS (ES) calcd for C25H21NO3Se [M + H2O + K]+
520.0429, found 520.0443.
Quinoline-2,4-dione 6e. Colorless oil; 1H NMR (700 MHz,
CDCl3, 25 °C) δ 7.61 and 7.57 (dd, J = 8.1, 1.4 Hz, each 1H), 7.34 (d,
J = 8.1 Hz, 2H), 7.21 (m, 2H), 7.11 (m, 2H), 5.67 and 5.16 (d, J = 1.5
Hz, each 1H), 3.55 (s, 3H), 1.66 (s, 3H); 13C NMR (176 MHz,
CDCl3, 25 °C) δ 194.5, 170.6, 141.4, 140.6, 137.3, 134.6, 129.3, 128.8,
128.2, 126.8, 126.2, 125.2, 122.8, 120.9, 65.8, 36.9, 19.5; IR (CH2Cl2)
ν 3205 cm−1; HRMS (ES) calcd for C19H16ClNO2Se [M + H]+
406.0113, found 406.0120.
Selenyloxindole 7b. Procedure B. From 27 mg (0.09 mmol) of
allenol 3b and after chromatography of the residue using hexanes/
ethyl acetate (2:1) as eluent, the procedure gave compound 7b (26
mg, 56%) as a colorless solid: mp 166−168 °C; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 7.69 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H),
7.24 (m, 8H), 6.99 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 6.6 Hz, 1H), 6.32
Cyclization of Allenol 3c. Procedure D. From 31 mg (0.10
mmol) of allenol 3c and after chromatography of the residue using
dichloromethane/ethyl acetate (98:2) as eluent, the procedure gave
compound 4c (16 mg, 35%).
Spirocycle 4c. Colorless solid; mp 73−75 °C; 1H NMR (300
MHz, CDCl3, 25 °C) δ 7.88 (m, 2H), 7.77 (m, 2H), 7.63 (m, 2H),
7.33 (m, 3H), 7.08 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.71
(m, 2H), 5.00 and 4.82 (d, J = 12.4 Hz, each 1H), 3.75 (s, 3H), 3.13
(s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 174.8, 159.4, 143.9,
137.7, 134.3, 134.0, 132.6, 130.4, 129.3, 129.2, 128.4, 128.3, 128.2,
126.7, 124.8, 124.2, 123.6, 123.1, 113.7, 108.4, 93.4, 79.8, 55.0, 26.3; IR
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Note
(d, J = 7.8 Hz, 1H), 4.89 and 4.62 (d, J = 10.2 Hz, each 1H), 2.84 (s,
3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 178.2, 146.5, 144.4, 140.9,
139.0, 138.3, 133.4, 132.9, 132.2, 131.9, 131.6, 131.4, 131.3, 131.0,
130.9, 130.5, 127.9, 126.5, 111.4, 85.1, 34.2, 28.9; IR (CH2Cl2) ν 1701,
1579, 1434, 1376 cm−1; HRMS (ES) calcd for C24H20BrNO2Se [(M +
H) − H2O ]+ 495.9815, found 495.9818.
Cyclization of Allenol 8a. Preparation of Quinoline-2,3-
dione 9a, Quinoline-2,4-dione 10a, and Spirocycle 11a.
Procedure A. From 28 mg (0.13 mmol) of allenol 8a and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent, 4.5 mg (9%) of the less polar compound 11a, 12 mg (23%) of
compound 10a (intermediate polarity), and 21 mg (46%) of the more
polar compound 9a were obtained.
117.2, 117.1, 78.4; IR (CH2Cl2) ν 3202, 1748, 1379, 1306 cm−1;
HRMS (ES) calcd for C23H17NO2Se [M + H]+ 420.0503, found
420.0484.
1
Spirocycle 11b. Pale yellow oil; H NMR (300 MHz, CDCl3, 25
°C) δ 7.48 (m, 13H), 6.67 (d, J = 8.0 Hz, 1H), 4.94 and 4.71 (d, J =
11.3, Hz, each 1H); 13C NMR (175 MHz, CDCl3, 25 °C) δ 176.8,
140.8, 138.9, 138.5, 136.1, 131.5, 130.4, 129.8, 129.3, 129.1, 128.5,
128.2, 127.6, 126.2, 125.4, 123.5, 123.0, 110.3, 90.9, 76.0; IR (CH2Cl2)
ν 1720 cm−1; HRMS (ES) calcd for C23H17NO2Se [M + H]+
420.0510, found 420.0498.
Cyclization of Allenol 8c. Procedure A. From 26 mg (0.09 mmol)
of allenol 8c and after chromatography of the residue using hexanes/
ethyl acetate (2:1) as eluent, the procedure gave compound 9c (35
mg, 89%).
Cyclization of Allenol 8a. Preparation of Quinoline-2,3-
dione 9a, Quinoline-2,4-dione 10a, and Spirocycle 11a.
Procedure D. From 25 mg (0.12 mmol) of allenol 8a and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
eluent, 23 mg (54%) of the less polar compound 11a, 3.5 mg (8%) of
compound 10a (intermediate polarity), and 5 mg (12%) of the more
polar compound 9a, were obtained.
Cyclization of Allenol 8c. Preparation of Quinoline-2,3-
dione 9c and Spirocycle 11c. Procedure D. From 26 mg (0.09
mmol) of allenol 8c and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent, 15 mg (36%) of the less polar
compound 9c and 6 mg (15%) of the more polar compound 11c were
obtained.
1
1
Quinoline-2,3-dione 9a. Pale yellow solid; mp 159−161 °C; H
Quinoline-2,3-dione 9c. Pale yellow solid; mp 197−199 °C; H
NMR (700 MHz, CDCl3, 25 °C) δ 9.07 (s, 1H), 7.88 (m, 1H), 7.77
(m, 1H), 7.34 (m, 5H), 7.15 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.7 Hz,
1H), 5.72 (s, 1H), 5.33 (s, 1H), 1.77 (s, 3H); 13C NMR (176 MHz,
CDCl3, 25 °C) δ 192.2, 167.8, 155.8, 143.2, 135.5, 134.3, 129.6, 129.4,
128.7, 128.5, 128.4, 126.3, 124.3, 123.6, 119.8, 116.5, 60.1, 23.0; IR
(CH2Cl2) ν 3202, 1774, 1746, 1370 cm−1; HRMS (ES) calcd for
C18H15NO2Se [M + H]+ 358.0346, found 358.0336.
NMR (300 MHz, CDCl3, 25 °C) δ 8.85 (br s, 1H), 7.82 (m, 7H), 7.47
(t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.23 (m, 1H), 7.11 (t, J =
7.2 Hz, 1H), 6.85 (m, 2H), 5.75 and 5.38 (d, J = 1.0 Hz, each 1H),
3.75 (s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 192.5, 170.8,
167.9, 159.8, 139.9, 139.7, 135.8, 134.3, 133.7, 131.8, 130.2, 129.0,
128.3, 127.6, 127.5, 125.4, 123.7, 123.6, 115.9, 114.3, 77.3, 55.2; IR
(CH2Cl2) ν 3202, 1748, 1662, 1380 cm−1; HRMS (ES) calcd for
C24H19NO3Se [M + H]+ 450.0608, found 450.0605.
1
Quinoline-2,4-dione 10a. Colorless solid; mp 221−223 °C; H
Spirocycle 11c. Colorless oil; 1H NMR (300 MHz, CDCl3, 25 °C)
δ 7.64 (m, 2H), 7.28 (m, 6H), 7.07 (t, J = 7.2 Hz, 1H), 6.94 (m, 2H),
6.72 (m, 2H), 5.00 and 4.82 (d, J = 12.5 Hz, each 1H), 3.73 (s, 3H);
13C NMR (175 MHz, CDCl3, 25 °C) δ 176.5, 159.4, 140.7, 137.1,
135.6, 134.3, 134.2, 132.5, 131.4, 130.4, 129.3, 129.2, 129.1, 128.5,
128.3, 126.5, 125.4, 124.0, 123.3, 113.7, 110.2, 93.5, 79.9, 55.0; IR
(CH2Cl2) ν 1726 cm−1; HRMS (ES) calcd for C24H19NO3Se [M +
H]+ 450.0608, found 450.0620.
NMR (300 MHz, CDCl3, 25 °C) δ 8.97 (br s, 1H), 7.89 (m, 2H), 7.77
(m, 2H), 7.53 (m, 2H), 7.16 (m, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.05
and 5.65 (d, J = 1.5 Hz, each 1H), 1.73 (s, 3H); 13C NMR (75 MHz,
CDCl3, 25 °C) δ 194.0, 172.5, 168.0, 140.4, 138.4, 136.1, 134.3, 132.5,
129.0, 128.3, 127.9, 123.7, 123.6, 123.3, 116.1, 64.7, 22.7; IR (CH2Cl2)
ν 3202, 1748, 1379, 1306 cm−1; HRMS (ES) calcd for C18H15NO2Se
[M + H]+ 358.0346, found 358.0334.
1
Spirocycle 11a. Colorless oil; H NMR (300 MHz, CDCl3, 25
°C) δ 8.90 (br s, 1H), 7.88 (m, 1H), 7.77 (m, 2H), 7.53 (d, J = 6.9 Hz,
1H), 7.31 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H),
6.88 (d, J = 7.5 Hz, 1H),), 4.97 and 4.83 (dd, J = 12.0, 1.9 Hz, each
1H), 1.58 (s, 3H); 13C NMR (75 MHz, CDCl3, 25 °C) δ 176.8, 140.7,
138.6, 135.5, 134.3, 132.5, 132.0, 130.3, 129.4, 128.1, 127.4, 124.9,
124.7, 123.5, 110.2, 93.5, 80.0, 11.2; IR (CH2Cl2) ν 1725 cm−1;
HRMS (ES) calcd for C18H15NO2Se [M + H]+ 358.0346, found
358.0342.
1
Spirocycle 14. Pale yellow oil; H NMR (300 MHz, CDCl3, 25
°C) δ 7.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 6.75 (d,
J = 8.3 Hz,1H), 5.98 (m, 1H), 4.95 (ddm, J = 31.3, 12.4, 2.0 Hz, 2H),
3.18 (s, 3H), 1.44 (q, J = 2.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 25
°C) δ 175.1, 142.5, 135.2, 130.0, 129.9, 128.6, 125.3, 124.9, 109.2,
92.3, 76.5, 26.4, 11.1; IR (CH2Cl2) ν 1740 cm−1; HRMS (ES) calcd
for C13H13ClNO2 [M + H]+ 250.0635, found 250.0639.
Cyclization of Allenol 8b. Procedure A. From 26 mg (0.10
mmol) of allenol 8b and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent, the procedure gave compound
9b (31 mg, 74%).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H NMR and 13C NMR spectra for all new
Cyclization of Allenol 8b. Preparation of Quinoline-2,3-
dione 9b, Quinoline-2,4-dione 10b, and Spirocycle 11b.
Procedure D. From 30 mg (0.11 mmol) of allenol 8a and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as
eluent, 21 mg (46%) of the less polar compound 10b, 22 mg (48%) of
compound 9b (intermediate polarity), and 3 mg (6%) of the more
polar compound 11b were obtained.
compounds; ORTEP plots for compounds 5a and 7b; in vitro
dose−response curves of compounds 2a−d. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
1
Quinoline-2,3-dione 9b. Colorless solid; mp 177−179 °C; H
Corresponding Author
*E-mail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es.
NMR (300 MHz, acetone-d6, 25 °C) δ 10.14 (br s, 1H), 7.67 (m, 2H),
7.43 (m, 6H), 7.19 (m, 4H), 7.07 (m, 2H), 5.59 and 5.34 (d, J = 1.3
Hz, each 1H); 13C NMR (75 MHz, acetone-d6, 25 °C) δ 191.5, 169.4,
156.3, 144.0, 136.7, 136.3, 135.1, 134.1, 131.7, 131.3, 130.9, 130.8,
130.4, 129.8, 129.7, 129.6, 125.2, 124.2, 123.9, 117.8, 117.7, 72.9; IR
(CH2Cl2) ν 3203, 1746, 1698, 1376 cm−1; HRMS (ES) calcd for
C23H17NO2Se [M + H]+ 420.0498, found 420.0503.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
Quinoline-2,4-dione 10b. Pale yellow solid; mp 61−63 °C; H
Support for this work by the DGI-MICINN (Project
NMR (300 MHz, acetone-d6, 25 °C) δ 10.24 (br s, 1H), 7.90 (m, 2H),
7.76 (m, 2H), 7.61 (m, 2H), 7.35 (m, 6H), 7.15 (m, 2H), 5.65 and
5.26 (d, J = 1.0 Hz, each 1H); 13C NMR (75 MHz, acetone-d6, 25 °C)
δ 193.9, 170.4, 142.2, 137.2, 135.5, 135.1, 134.1, 133.9, 133.7, 132.1,
130.3, 130.0, 129.9, 129.8, 129.7, 128.5, 128.3, 128.1, 124.1, 123.9,
́
CTQ2009-09318), Comunidad Autonoma de Madrid (Project
S2009/PPQ-1752), and SANTANDER-UCM (Project GR35/
10) is gratefully acknowledged. G.G.C. thanks the MEC for a
predoctoral grant.
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The Journal of Organic Chemistry
Note
squares procedures on F2 (SHELXL-97). All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were included in
calculated positions and refined riding on the respective carbon atoms.
Final R(Rw) values were R1 = 0.0609, wR2 = 0.1495. CCDC-765453
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge via the www.ccdc.cam.ac.uk/data_
request/cif (or from The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, U.K.; Fax (+44)1223−336033; or
deposit@cccdc.cam.ac.uk).
REFERENCES
■
(1) Padwa, A.; Filipkowski, M. A.; Meske, M.; Murphree, S. S.;
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(14) X-ray data of 7b: crystallized from ethyl acetate/n-hexane at 20
°C; C24H20BrNO2Se (Mr = 513.28); triclinic; space group = P-1; a =
9.2292(13) Å, b = 13.5016(19) Å; c = 18.493(3) Å; α = 72.535(2)°; β
= 81.060(3)°; γ = 76.979(3)°; V = 2132.1(5) Å3; Z = 4; cd = 1.599 mg
m−3; μ = 3.655 mm−1; F(000) = 1024. A transparent crystal of 0.21 ×
0.10 × 0.07 mm3 was used. 9841 [R(int) = 0.1727] independent
reflections were collected on a Bruker Smart CCD difractomer using
graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) operating
at 50 Kv and 30 mA. Data were collected over a hemisphere of the
reciprocal space by combination of three exposure sets. Each exposure
of 20s covered 0.3 in ω. The cell parameter were determined and
refined by a least-squares fit of all reflections. The first 100 frames were
recollected at the end of the data collection to monitor crystal decay,
and no appreciable decay was observed. The structure was solved by
direct methods and Fourier synthesis. It was refined by full-matrix
least-squares procedures on F2 (SHELXL-97). All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were included
in calculated positions and refined riding on the respective carbon
atoms. Final R(Rw) values were R1 = 0.0785, wR2 = 0.1265. CCDC-
827677 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via the www.ccdc.
cam.ac.uk/data_request/cif (or from The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB21EZ, U.K.; Fax (+44)
1223−336033; or deposit@cccdc.cam.ac.uk).
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(12) The reaction of allenol 3a with NPSP in the absence of the
Brønsted acid additive (PTSA) proceeded to afford the corresponding
products 4a, 5a, and 6a in a slightly lower yield. The Brønsted acid
present in solution seems to act as a scavenger for the free phthalimide
from the NPSP.
(13) X-ray data of 5a: crystallized from ethyl acetate/n-hexane at 20
°C; C19H17NO2Se (Mr = 370.30); monoclinic; space group = P2(1)/n;
a = 12.360(2) Å, b = 12.862(3) Å; c = 22.211(4) Å; α = 90°; β =
104.886(4)°; γ = 90°; V = 3412.6(11) Å3; Z = 8; cd = 1.441 mg m−3; μ
= 2.209 mm−1; F(000) = 1504. A transparent crystal of 0.17 × 0.11 ×
0.09 mm3 was used. 6688 [R(int) = 0.0976] independent reflections
were collected on a Bruker Smart CCD difractomer using graphite-
monochromated Mo Kα radiation (λ = 0.71073 Å) operating at 50 Kv
and 30 mA. Data were collected over a hemisphere of the reciprocal
space by combination of three exposure sets. Each exposure of 20 s
covered 0.3 in ω. The cell parameters were determined and refined by
a least-squares fit of all reflections. The first 100 frames were
recollected at the end of the data collection to monitor crystal decay,
and no appreciable decay was observed. The structure was solved by
direct methods and Fourier synthesis and refined by full-matrix least-
3556
dx.doi.org/10.1021/jo202495z | J. Org. Chem. 2012, 77, 3549−3556