New diastereoselective synthesis of 3-alkylidene-1-methyloxindoles

Article abstract of DOI:10.1055/s-2002-19299

Addition of alkyl or aryl α-substituted acetophenones to N-methylisatin in basic media gives diastereomeric mixtures of the corresponding α-substituted 3-benzoylmethyl-3-hydroxy-1-methyloxindole in good yields. Under anhydrous conditions (concentrated sul

Full text of DOI:10.1055/s-2002-19299

1
04
PAPER
New Diastereoselective Synthesis of 3-Alkylidene-1-methyloxindoles
D
P
iastereoselec
i
tive Sy
l
nthesis
a
of 3-Alkyl
r
idene-1-methy
L
loxindole
s
ópez-Alvarado, Carmen Avendaño*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: avendano@eucmax.sim.ucm.es
Received 12 June 2001; revised 26 September 2001
Ring A
Abstract: Addition of alkyl or aryl -substituted acetophenones to
N-methylisatin in basic media gives diastereomeric mixtures of the
4
H
4
H
corresponding -substituted 3-benzoylmethyl-3-hydroxy-1-methy-
loxindole in good yields. Under anhydrous conditions (concentrated
sulfuric acid at 0 °C) these adducts eliminate benzoic acid, instead
of water, to give pure (E)-3-alkylidene derivatives in quantitative
yield. Applying the same treatment to the -unsubstituted analogue,
dehydration took place to give pure (Z)-3-benzoylmethylen-1-me-
thyloxindole.
Ph
H
O
O
O
O
H
H
3
3
3α
3α
H
Ph
N
N
3
H C
3
H C
O
O
Key words: indoles, addition reactions, eliminations, rearrange-
ments, isatinylidenes
Ring B
2 (3S*,3αS*) threo-isomer
1
13 (3S*,3αR*) erythro-isomer
Figure Conformations of threo-isomer 12 and erythro-isomer 13
Some 3-alkylidenoxindole derivatives have recently at-
tracted pharmacological interest in preventing, treating
and relieving proliferative vascular lesions such as vascu-
lar reconstriction after percutaneous transluminal coro-
nary recanalization, arterial sclerosis, peripheral
carbonyl and the C(3)-OH groups (Figure). Thus, spectro-
scopic data of threo-isomers 12 and 15 (Tables 3 and 4)
showed the indole H-4 signal more shielded ( > 1 ppm)
than their diastereomers 13 and 14, indicating that the H-
4 proton is close to the benzene ring A in the first case. In
fact, irradiation of the H-4 proton in compounds 12 and 15
produced a NOE enhancement of the protons H-2’’, 6’’
1
embolism and angiitis. Their synthesis by base-catalyzed
2
3
condensation of aldehydes or ketones with oxindoles, or
by Wittig reaction of aldehydes with 3-indolyltriphe-
4
nylphosphoranylidene derivatives usually requires rather
(
ring A). On the other hand, compounds 13 and 14 showed
drastic conditions and gives mixtures of E/Z-diastere-
omers. The same mixtures are normally formed in the al-
ternative condensations of isatin derivatives and
methylene active reagents, either in the presence of base
NOEs between H-2’, 6’ (ring B) and H-2’’, 6’’-protons,
indicating the proximity of rings A and B. In a model
where the benzene indole ring is located in the pseudocy-
5
or in Wittig reactions.
Addition of acetophenone (1a) to N-methylisatin in basic
medium to give 3-benzoylmethyl-3-hydroxy-1-methylox-
indole (2), followed by dehydration in acid to the (E)-ole-
7.86 ppm
fin 3 (Table 1 and Scheme 1), was first described in
6
1
932. However, we have not found any literature prece-
O
H
dent of this protocol involving -substituted acetophe-
nones. This work comprises some of these adducts and
their subsequent acid treatment.
HCl/EtOH
O
r. t. or reflux
N
CH3
With the exception of compound 12 (Tables 1 and 2),
which precipitated in ethanol as a single diastereoisomer,
addition of phenones 1b–e to N-methylisatin gave diaste-
reomeric mixtures in which the erythro isomers were the
major products (Tables 1 and 2).
H
O
H
E-3 (96 %)
OH
O
N
CH3
±)-2
Assignment of the relative configuration of the two stere-
ocenters by extensive NMR experiments (HETCOR,
COSY and NOE) was possible thanks to the conforma-
tional restriction imposed by a hydrogen-bonded six-
membered pseudocyclic structure involving the C(3 )=O
7.17 ppm
(
H SO ,
2
4
H
0 °C
O
O
N
CH3
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
Z-3 (100 %)
1
437-210X,E;2002,0,01,0104,0110,ftx,en;T04501SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
©
Scheme 1

PAPER
Diastereoselective Synthesis of 3-Alkylidene-1-methyloxindoles
105
Table 1 Addition of Acetophenones to N-Methylisatin
Ar
3β R
O
O
Hα
3α
4
base, r. t.
OH
O
Ar
CH2-R
+
3
N
EtOH or THF
O
O
CH3
N
R = H, CH3, C2H5, C3H7,
C4H9, C6H5, C6H4-(p-OMe)
CH3
2, 4-15
1a-e
Compound Ar
R
Base
Configuration
3S + 3R
erythro
threo
Diasteromeric Ratio Isolation
Yield (%)
84
(
(
(
(
(
(
(
(
(
(
(
(
(
)-2a
)-4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
piperidine
KOH
–
precipitation
Me
Me
Et
4:5 = 3:1
chromatography
chromatography
chromatography
chromatography
chromatography
chromatography
chromatography
chromatography
precipitation
71
)-5
KOH
24
)-6
KOH
erythro
threo
6:7 = 2:1
8:9 = 4:1
10:11 = 7:2
60b
30b
65b
17b
73b
21b
80
)-7
Et
KOH
)-8
Pr
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
erythro
threo
)-9
Pr
)-10
)-11
)-12
)-13
)-14
Bu
Bu
Ph
Ph
erythro
threo
threo
–c
erythro
erythro
threo
–d
–
–
4-MeOC H
4-MeOC H
14:15 = 3:1
chromatography
chromatography
65b
22b
6
4
4
6
4
4
)-15
4-MeOC H
4-MeOC H
6
6
a
b
c
d
Ref.6
Overall yield calculated for converted starting material.
Isolated as a single diastereomer.
Formed by epimerization of ( )-12 in DMSO-d and observed by H NMR.
1
6
cle equatorially, the (3S*, 3 R*)-erythro-isomers 13 and
4 have ring A also equatorial and far away from the H-4-
1
H3C
PhOC
COPh
CH3
O
HCl/EtOH
reflux
H
4
proton, while the (3S*, 3 S*)-threo-isomers 12 and 157
have this ring upon the H(4)-proton in an axial position.
(R = Me)
O
+
Because of the acidity of benzylic 3 -protons, both iso-
mers of compounds with R = aryl are soon equilibrated in
solution and decompose in a retroaldol reaction.
-
H2O
N
N
CH3
CH3
O
R
Z-16 (49 %)
E-16 (29 %)
1H NMR data of adducts where R is Me, Et, Pr or Bu, did
not allow a conclusive assignment and the stereochemisty
of both diastereomers was proposed by assuming that
their relative stability was also in favor of the erythro-iso-
mers. Because of the lower reactivity of the H-3 proton,
these adducts are stable in deuterated chloroform. The ad-
dition reaction failed with isobutyrophenone, indicating
that the active mehylene must not be disubstituted.
OH
O
N
R
H
CH3
R = Me, Et,
H2SO4
0 °C
n
n
O
Pr, Bu, Ph
erythro-isomer
and/or threo-isomer)
-
BzOH
(
N
CH3
R = Me, E-17 (100 %)
R = Et, E-18 (100 %)
6
According to the literature, compound 2 was dehydrated
n
R = nPr, E-19 (89 %)
in HCl/EtOH at room temperature to give (E)-3 as the
only product, but when we treated 2 with concentrated
R = Bu, E-20 (93 %)
R = Ph, E-21 (85 %)
8
sulfuric acid at 0 °C for 5 minutes (Z)-3 was quantitative-
9
Scheme 2
ly obtained (Scheme 1). This unprecedented result must
be a consequence of the anhydrous conditions.10
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York

1
06
P. López-Alvarado, C. Avendaño
PAPER
When we studied the -substituted adducts, we observed actions were monitored by thin layer chromatography, on alumini-
um plates coated with silica gel with fluorescent indicator (Scharlau
Cf 530), which were visualized with a UV lamp (Camag UV-II, 254
that dehydration of the mixture of isomers 4 and 5 (de-
rived from propiophenone) with HCl/EtOH required their
and 366 nm). Separations by flash chromatography were performed
treatment under reflux and gave a 5:3 mixture of (Z)-16/
on silica gel (SDS 60 ACC, 230–400 mesh). All reagents were of
(
E)-16 together with a considerable amount of 1-methyli-
commercial quality (Aldrich, Merck, SDS, Probus, Panreac, Schar-
lau, Fluka) and were used as received. Petroleum ether refers to the
1
1
satin, which is formed in a retroaldol reaction. However,
treatment of the same mixture with sulfuric acid at 0 °C fraction boiling at 40–60 °C.
gave quantitatively (E)-17 by elimination of benzoic acid.
The same behavior was observed in compounds 6–12,
which gave (E)-18–(E)-21 as products (Scheme 2).
Addition of Acetophenones 1a–e to N-Methylisatin; General
Procedure
Compounds 2, 8–15: N-Methylisatin (10 g, 6.21 mmol) and an
The elimination of benzoic acid does not occur during the equimolecular amount of the corresponding acetophenone were dis-
quenching with water, since the treatment of adducts with solved in absolute ethanol (200 mL) (or THF for compounds 14 and
1
5) and piperidine (2 mL) was added. The mixture was allowed to
dilute sulfuric acid reverted them near quantitatively to
the starting materials.
stand overnight at r.t. In the case of compounds 2 and 12, the off-
white precipitates formed were separated by filtration and for com-
It can be concluded that, since most of the methods so far pounds 8–11, 14 and 15, the mixture was concentrated under re-
described for the synthesis of 3-alkylidenoxindole deriva- duced pressure to give an orange oil which was purified by flash
chromatography on silica gel (CHCl to 90% CHCl –Et O).
tives gave mixtures of E/Z-isomers, the debenzoylation in
3
3
2
sulfuric acid of adducts of N-methylisatin and -substitut- Compounds 4-7: Equimolecular amounts of N-methylisatin and the
ed acetophenones here described, can be proposed as an corresponding acetophenone were dissolved in 60% aq EtOH (15
mL) containing 0.16% of KOH per gram of isatin. The mixture was
allowed to stand overnight at r.t. and then isolated following the
method for compounds 8–11, 14 and 15.
alternative method for the synthesis of pure (E)-isomers.
IR spectra were recorded on a Perkin Elmer Paragon 1000 spectro-
photometer, for solids as KBr pellets and liquids as films between
NaCl paltes. NMR spectra were obtained on Bruker AC-250 (250
Dehydration of Compounds 4 and/or 5
A solution of 4 and/or 5 (2.5 g, 8.47 mmol) in a mixture of HCl–
EtOH (15/8 mL) was refluxed for 14 h. Then, the mixture was
quenched with H O (50 mL), extracted with Et O (2 100 mL),
1
13
MHz for H, 63 MHz for C) and Bruker AC-200 spectrometers
Servicio de Espectroscopía, Universidad Complutense). The sol-
(
2
2
vents used were CDCl and DMSO-d . Interchangeable chemical
washed with aq NaHCO solution (50 mL), dried (Na SO ), and
3
6
3
2
4
shifts are marked with the symbol *.
concentrated under reduced pressure to give an orange oil. Flash
chromatography (80% petroleum ether–Et O) yielded 1.150 g
2
Elemental analyses were determined by the Servicio de Microanáli-
sis, Universidad Complutense. Melting points were measured on a
(
0
49%) of (Z)-3-(1-benzoylethylidene)-1-methyloxindole [(Z)-16],
.680 g (29%) of (E)-3-(1-benzoylethylidene)-1-methyloxindole
'
Reichert' hot stage microscope model 723, and are uncorrected. Re-
[
(E)-16], and 0.286 g (21%) of isatin.
(
Z)-16
Table 2 Melting Points and IR Data of Compounds 2,4–15
Yellow solid; mp 169–171 °C.
–
1
IR (KBr): 1699, 1665 cm–1.
Com-
IR (cm )
Mp (°C) (solvent)
pounda
1
H NMR (CDCl , 250 MHz): = 7.93 (dd, 2 H, J = 7.0, 1.5 Hz, H-
3
b
2’,6’), 7.63 (d, 1 H, J = 7.6 Hz, H-4), 7.55 (tt, 1 H, J = 7.1, 1.2 Hz,
H-4’), 7.46 (tt, 2 H, J = 7.0, 1.2 Hz, H-3’,5’), 7.34 (td, 1 H, J = 7.8,
1.1 Hz, H-6), 7.09 (td, 1 H, J = 7.6, 0.9 Hz, H-5), 6.83 (d, 1 H, J =
(
(
(
(
)-2
)-4
)-5
)-6
3370 (OH), 1686 (C=O)
166–167 (EtOH)
3388 (OH), 1693 (C=O)
128–130 (EtOH)
134–136 (EtOH)
103–105 (EtOH)
7
.8 Hz, H-7), 3.10 (s, 3 H, NCH ), 2.48 (s, 3 H, C -CH ).
3 3a 3
3328 (OH), 1700, 1677 (C=O)
13C NMR (CDCl3,
63 MHz): = 198.77 (C-3 ), 165.82 (C-2),
1
47.46 (C-3a), 144.40 (C-7a), 134.59 (C-1’), 134.57 (C-4’), 129.55
3592, 3519, 3294 (OH), 1697,
(
(
C-6), 128.75 (C-3’,5’), 128.57 (C-2’,6’), 125.54* (C-3 ), 123.74
C-4), 122.17 (C-5), 121.50* (C-3), 108.30 (C-7), 25.75 (NCH3)
1665 (C=O)
(
(
(
(
(
(
(
(
)-7
3334 (OH), 1698, 1663 (C=O)
3379 (OH), 1715, 1681 (C=O)
3380 (OH), 1703, 1680 (C=O)
3380 (OH), 1715, 1682 (C=O)
3378 (OH), 1704, 1679 (C=O)
3338 (OH), 1682 (C=O)
156–158 (EtOH)
18.62 (C -CH ).
3a 3
Anal. Calcd for C H NO : C 77.96; H 5.45; N 5.05. Found: C
1
8
15
2
)-8
110–111 (Et O)
2
7
7.77; H 5.13; N 5.00.
)-9
152–154 (Et O)
2
(
E)-16
)-10
)-11
)-12
)-14
)-15
107–109 (Et O)
Yellow solid; mp 179–181 °C.
2
–
1
IR (KBr): 1703, 1670 cm .
135–137 (Et O)
2
1
H NMR (CDCl , 250 MHz): = 7.96 (d, 2 H, J = 7.5 Hz, H-2’6’),
3
127–129 (EtOH)
7
7
6
.60 (t, 1 H, J = 7.0 Hz, H-4’), 7.46 (t, 2 H, J = 7.7, 1.2 Hz, H-3’,5’),
.14 (t, 1 H, J = 7.7 Hz, H-6), 6.84 (d, 1 H, J = 7.6 Hz, H-4), 6.76–
.68 (m, 2 H, H-5 and H-7), 3.23 (s, 3 H, NCH ), 2.68 (s, 3 H, C -
3326 (OH), 1719, 1648 (C=O)
3378 (OH), 1717, 1673 (C=O)
160–162 (Et O)
2
3
3a
CH3).
Oil
a
Satisfactory microanalyses obtained: C 0.37, H 0.33, N 0.21.
Lit. mp 168–170 °C.
b
6
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of 3-Alkylidene-1-methyloxindoles
107
1
Table 3a H NMR Data of Compounds 2, 4–15 [CDCl , , J (Hz)]
3
Ar
3β
R
O
R
1
4
Hα
3α
'
4
7
OH
3'
5
6
3
Ar =
O
2'
N
1
'
CH
3
Com-
pound
R
NCH3
3.22
H4
H5
H6
H7
H
(
(
(
(
)-2 3.51 (d, 1 H, J = 17.4)
)-4 1.24 (d, 3 H, J = 7.2, CH3)
)-5 1.54 (d, 3 H, J = 7.2, CH3)
7.42 (d, 1 H,
J = 7.4)
7.01 (td, 1 H,
J = 7.4, 0.8)
7.30 (td, 1 H, J 6.84 (d, 1 H,
= 7.8, 1.2)
3.80 (d, 1 H,
J = 17.4)
(
s, 3 H)
J = 7.8)
3.17
7.56 (d, 1 H,
J = 7.4)
7.06 (td, 1 H,
J = 7.4, 0.7)
7.32 (td, 1 H,
J = 7.8, 1.2)
6.82 (d, 1 H,
J = 7.8)
3.99 (q, 1 H,
J = 7.2)
(
s, 3 H)
2.95
7.30 (d, 1 H,
J = 7.5)
6.95 (t, 1 H,
J = 7.5)
7.24 (t, 1 H,
J = 7.7)
6.74 (d, 1 H,
J = 7.7)
4.06 (q, 1 H,
J = 7.2)
(
s, 3 H)
)-6 0.67 (t, 3 H, J = 7.4, CH ), 1.55– 3.03
7.50 (d, 1 H,
6.98 (t, 1 H,
7.32 (td, 1 H, J 6.73 (d, 1 H,
4.02 (dd, 1 H,
3
1
.40 (m, 1 H, CH ), 1.78–1.62 (m, (s, 3 H)
J = 7.5)
J = 7.5)
= 7.7, 0.9)
J = 7.7)
J = 4.0, 10.5)
2
1
H, CH2)
(
(
)-7 0.83 (t, 3 H, J = 7.4, CH ), 2.14– 2.98
7.30 (d, 1 H,
J = 7.5)
6.94 (td, 1 H,
J = 7.5, 0.8)
7.32 (td, 1 H,
J = 7.8, 1.2)
6.74 (d, 1 H,
J = 7.7)
3.84 (dd, 1 H,
J = 3.3, 10.5)
3
2
.00 (m, 1H, CH ), 2.44–2.31 (m, (s, 3 H)
2
1
H, CH2)
)-8 0.70 (t, 3 H, J = 7.4, CH ), 1.14– 3.05
7.51 (d, 1 H,
7.02 (td, 1 H,
7.25 (td, 1 H,
6.74 (d, 1 H,
4.15 (dd, 1 H,
3
0
.99 (m, 2 H, CH CH ), 1.42–1.29 (s, 3 H)
J = 7.4)
J = 7.4, 0.8)
J = 7.7, 1.2)
J = 7.7)
J = 3.5, 10.8)
2
3
(
(
m, 1 H, CH CH CH ), 1.75–1.63
2 2 3
m, 1 H, CH CH CH )
2
2
3
(
(
)-9 0.88 (t, 3 H, J = 7.1, CH ), 1.34– 2.75
7.57–7.51
(overlapped m) J = 7.5)
6.96 (t, 1 H,
7.28 (td, 1 H, J 6.78 (d, 1 H,
3.91 (dd, 1 H,
J = 3.3, 10.7)
3
1
.13 (m, 2 H, CH CH ), 2.18–2.00 (s, 3 H)
= 7.7, 1.2)
J = 7.7)
2
3
(
(
m, 1 H, CH CH CH ), 2.42–2.28
2 2 3
m, 1 H, CH CH CH )
2
2
3
)-10 0.69 (t, 3 H, J = 7.1, CH ), 1.18– 3.09
7.55–7.49
7.03 (t, 1 H,
7.28 (t, 1 H,
6.77 (d, 1 H,
4.11 (dd, 1 H,
3
1
1
1
.08 [m, 4 H, (CH ) CH ] 1.50–
(s, 3 H)
(overlapped m) J = 7.6)
J = 7.7)
J = 7.8)
J = 3.3, 10.7)
2
2
3
.37 [m, 1 H, CH (CH ) CH ],
2
2 2
3
.83–1.68 [m, 1 H,
CH (CH ) CH ]
2
2 2
3
(
)-11 0.81 (t, 3 H, J = 7.3, CH ), 1.25– 2.80
7.54 (d, 1 H,
6.98 (td, 1 H, J 7.28 (td, 1 H, J 6.76 (d, 1 H,
3.95 (dd, 1 H,
3
1
2
2
.02 [m, 4 H, (CH ) CH ], 2.19– (s, 3 H)
J = 7.4)
= 7.5, 0.8)
= 7.7, 1.3)
J = 7.7)
J = 3.3, 10.7)
2
2
3
.00 [m, 1 H, CH (CH ) CH ],
2
2 2
3
.42–2.25 [m, 1 H,
CH (CH ) CH ]
2
2 2
3
(
)-12 7.29–7.23 (m, 5 H, C H )
3.15
s, 3 H)
6.43 (d, 1 H,
J = 7.4)
6.87 (t, 1 H,
J = 7.4)
7.29 (t, 1 H,
J = 7.7)
6.83 (d, 1 H,
J = 7.7)
5.32
(s, 1 H)
6
5
(
(
1
)-
2
7.24 (m, 2 H, H-2’’,6’’), 7.41–7.29 3.10
(m, 3 H, C H ) (s, 3 H)
5.92 (d, 1 H,
J = 7.4)
6.75 (t, 1 H,
J = 7.4)
7.25 (t, 1 H,
J = 7.7)
7.02 (d, 1 H,
J = 7.7)
5.51
(s, 1 H)
a
6
5
(
1
)-
3
7.70–7.10 (m, 5 H, C H )
2.87
(s, 3 H)
7.83 (d, 1 H,
J = 7.3)
7.70–7.10
7.70–7.10
7.70–7.10
5.48
6
5
a
(overlapped m) (overlapped m) (overlapped m) (s, 1 H)
(
(
)-14 3.58 (s, 3 H, OCH ), 6.93 (d, 2 H, 2.95
7.89 (d, 1 H,
J = 7.2)
6.99 (t, 1 H,
J = 7.5)
7.13 (t, 1 H,
J = 7.5)
6.56–6.51(m,1 5.11
3
J = 8.5, H-2’’,6’’), 6.56–6.51 (m, 2 (s, 3 H)
H, H-3’’,5’’)
H)
(s, 1 H)
)-15 3.74 (s, 3 H, OCH ), 7.16 (d, 2 H, 3.21
6.40 (d, 1 H,
6.90–6.70
7.27 (t, 1 H,
6.90–6.70
5.02
3
J = 8.5, H-2’’,6’’), 6.90–6.70
overlapped m)
(s, 3 H)
J = 7.3)
(overlapped m) J = 7.7)
(overlapped m) (s, 1 H)
(
a
Recorded in DMSO
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York

1
08
P. López-Alvarado, C. Avendaño
PAPER
1
Table 3b H NMR Data of Compounds 2, 4–15 [CDCl , , J (Hz)] (continued)
3
Com-
pound
H-2’,6’
H-3’,5’
H-4’
OH
R (4-CH OC H )
3 6 4
(
(
(
(
(
(
(
(
(
(
(
(
(
(
)-2
7.85 (dd, 2 H, J = 7.2, 1.3) 7.41 (t, 2 H, J = 7.4)
7.93 (dd, 2 H, J = 7.2, 1.3) 7.42 (t, 2 H, J = 7.7)
7.54 (tt, 1 H, J = 7.4, 1.3)
7.54 (tt, 1 H, J = 7.3, 1.3)
7.45 (t, 1 H, J = 7.5)
7.48 (t, 1 H, J = 7.5)
7.51 (tt, 1 H, J = 7.3, 1.4)
7.49 (tt, 1 H, J = 7.3, 1.2)
7.57–7.51 (overlapped m)
7.55–7.49 (overlapped m)
7.59–7.53 (overlapped m)
7.39 (t, 1 H, J = 7.2)
7.51 (t, 1 H, J = 7.3)
7.70–7.10 (m, 1 H)
–
4.55 (s, 1 H)
4.33 (s, 1 H)
4.80 (s, 1 H)
4.25 (br s, 1 H)
4.09 (br s, 1 H)
4.50 (br s, 1 H)
4.74 (br s, 1 H)
4.32 (br s, 1 H)
4.56 ( br s, 1 H)
3.43 (s, 1 H)
6.27(s, 1 H)
–
–
–
–
–
–
–
–
–
–
–
–
)-4
)-5
7.73 (d, 2 H, J = 7.3)
7.96 (d, 2 H, J = 7.3)
7.75 (d, 2 H, J = 7.3)
7.32 (t, 2 H, J = 7.3)
7.36 (t, 2 H, J = 7.2)
7.37 (t, 2 H, J = 7.3)
)-6
)-7
)-8
8.01 (dd, 2 H, J = 7.2, 1.3) 7.37 (t, 2 H, J = 7.7)
)-9
7.76 (d, 2 H, J = 7.4)
8.00 (d, 2 H, J = 7.8)
7.40 (t, 2 H, J = 7.8)
7.40 (t, 2 H, J = 7.8)
)-10
)-11
)-12
7.75 (dd, 2 H, J = 7.2, 1.4) 7.38 (t, 2 H, J = 7.8)
7.76 (d, 2 H, J = 7.9) 7.25 (t, 2 H, J = 7.3)
)-12a 7.76 (dd, 2 H, J = 7.2, 1.0) 7.41–7.29 (m, 2 H)
)-13a 7.95 (d, 2 H, J = 7.2)
7.70–7.10 (m, 2 H)
6.73 (d, 2 H, J = 8.0)
6.72 (d, 2 H, J = 8.9)
6.31 (s, 1 H)
2.13 (br s,1 H)
n. o.
)-14
)-15
7.85 (d, 2 H, J = 8.0)
7.72 (d, 2 H, J = 8.9)
3.70 (s, 3 H, OCH3)
3.78 (s, 3 H, OCH3)
–
a
Recorded in DMSO
1
3
C NMR Data of Compounds 2, 4–15 (CDCl , )a
Table 4a
3
Compound NCH3
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
C-3
C-3
(
(
(
(
(
(
(
(
(
(
(
(
)-2
26.48
26.17
26.00
26.11
26.21
26.62
26.55
26.63
26.46
27.75
25.85
26.38
176.28
176.79
176.74
177.08
176.16
177.62
176.53
177.58
176.86
179.15
178.21
176.87
74.61
77.64
76.53
77.77
77.06
78.20
77.60
78.26
77.57
76.94
63.92
76.86
130.13
128.19
129.68
128.14
129.39
128.66
129.84
128.59
128.74
131.28
126.38
125.90
124.14
125.74
124.53
126.03
124.51
126.50
124.97
126.51
125.08
126.86
125.41
125.15
123.20
122.85
122.72
122.77
122.76
123.26
123.24
123.28
123.25
122.93
122.41
122.30
130.08
129.85
129.48
129.76
129.56
130.22
130.08
130.26
130.05
129.54
128.70
129.66
108.49
108.32
108.38
108.23
108.47
108.73
108.77
108.73
108.75
110.09
107.67
108.01
143.79
143.69
143.39
143.43
142.81
143.88
143.10
143.92
143.28
146.50
143.33
144.52
44.55
45.19
47.60
51.92
53.74
50.92
52.24
50.87
52.62
61.51
60.03
59.53
198.60
203.37
202.33
203.10
203.04
203.50
203.37
203.60
203.32
199.54
196.42
196.88
)-4
)-5
)-6
)-7
)-8
)-9
)-10
)-11
)-12b
)-14
)-15
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Table 4b
Diastereoselective Synthesis of 3-Alkylidene-1-methyloxindoles
C NMR Data of Compounds 2, 4–15 (CDCl , ) (continued)
109
1
3
3
Com-
pound
R
Ar
C-1’
C-2’,6’
C-3’,5’
C-4’
R
–
–
–
–
–
–
(
(
(
(
(
(
)-2
)-4
)-5
)-6
)-7
)-8
-
136.44
136.50
136.06
138.95
138.05
139.36
128.28
128.41
128.33
128.44
128.25
128.92*
128.82
128.61
128.48
128.44
128.45
128.95*
133.97
133.39
133.24
133.08
133.38
133.54
12.85 (CH3)
12.26 (CH3)
21.28 (CH ), 12.01(CH )
2
3
20.40 (CH ), 12.76(CH )
2
3
30.62 (CH ), 21.33 (CH ),
2
2
1
4.61 (CH3)
(
(
)-9
29.54 (CH ), 21.83
138.37
139.32
128.74*
128.92*
128.97*
128.94*
133.92
133.57
–
–
2
(
CH ), 14.69 (CH )
2 3
)-10
30.15 (CH ), 28.24
2
(
CH ), 23.16 (CH ),
2
2
1
4.15 (CH3)
(
(
)-11
30.67 (CH ), 27.10 (CH ),
138.38
137.35
129.02*
130.27
129.76*
130.54
133.84
135.06
–
–
2
2
2
3.30 (CH ), 14.26 (CH )
2 3
)-12b
135.79 (C-4’’), 132.52
C-3’’,5’’), 130.65 (C-2’’,6’’),
29.82 (C-1)
(
1
(
(
)-14
)-15
54.98 (OCH ), 130.74
129.52
131.03
131.82
113.52
113.91
163.16
163.42
55.25 (OCH3)
55.28 (OCH3)
3
(
1
C-2’’,6’’), 113.27 (C-3’’,5’’),
58.77 (C-4’’)
55.45 (OCH), 113.68 (C-3’’,5’’), 129.47
1
1
28.93 (C-1’’), 131.43 (C-2’’,6’’),
59.40 (C-4’’)
a
The chemical shifts marked with an * are interchangeable.
Recorded in DMSO
b
13C NMR (CDCl3,
48.80 (C-3a), 142.54 (C-7a), 134.57 (C-4’), 133.40 (C-1’), 129.43
63 MHz): = 198.17 (C-3b), 167.31 (C-2),
Treatment of 3-Benzoylmethyl-3-hydroxy-1-methyloxindole
Derivatives 2, 4–12 with Sulfuric Acid; (Z)-3-Benzoylmethylen-
1-methyloxindole [(Z)-3] and (E)-3-Alkyliden-1-methyloxindole
Derivatives 17–21; General Procedure
1
(
(
C-3’,5’), 129.19 (C-2’6’), 129.12 (C-6), 123.43* (C-3a), 122.90
C-4), 121.94 (C-5), 120.36* (C-3), 107.85 (C-7), 25.71 (NCH3),
1
7.19 (C -CH ).
A solution of the corresponding 3-benzoylmethyl-3-hydroxy-1-me-
thyloxindole 2, 4–12 (0.100–0.050 g, 0.356–0.140 mmol) in 96%
H SO (2–3 mL) was stirred at r.t. for 5–10 min, and was then
3a
3
Anal. Calcd for C H NO : C 77.96; H 5.45; N 5.05. Found: C
7
18
15
2
2
4
7.68; H 5.29; N 4.89.
quenched with ice and extracted with CHCl (3 25–50 mL). The
3
combined organic layers were washed with aq NaHCO solution
3
(
25–50 mL), dried (Na SO ) and concentrated under reduced pres-
2 4
sure to give 3 ( 100% from 2), 17 ( 100% from 4 or 5), 18 ( 100%
from 6 or 7), 19 (89% from 8 or 9), 20 (93% from 10 or 11), and 21
(85% from 12) as yellow compounds (Table 5).
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York

1
10
P. López-Alvarado, C. Avendaño
PAPER
1
Table 5 H NMR [CDCl , , J (Hz)] of Compounds Z-3 and E-17–21
3
R
Z-3 (R = PhCO)
H
E-17 (R = Me)
E-18 (R = Et)
n
E-19 (R = Pr)
O
n
E-20 (R = Bu)
N
E-21 (R = Ph)
CH3
Com-
pound
NCH3
H-4
H-5
H-6
H-7
H
R
a
(Z)-3
3.11
7.49 (d, 1 H, 7.07 (td, 1
J = 7.7) H, J = 7.5,
.6)
7.34 (td, 1
H, J = 7.8,
1.1)
6.79 (d, 1 H, 7.17 (s, 1 H) 7.99 (dd, 2 H, J = 7.1, 1.5, H-2’,6'), 7.45
(s, 3 H)
J = 7.8)
(tt, 2 H, J = 7.1, 1.3, H-3’,5’), 7.57 (tt, 1
H, J = 7.3, 1.3, H-4’)
0
(
(
(
(
E)-17
E)-18
E)-19b
E)-20b
3.21
s, 3 H)
7.54 (d, 1 H, 7.02 (t, 1 H, 7.26 (t, 1 H, 6.80 (d, 1 H, 7.09 (q, 1 H, 2.25 (d, 3 H, J = 7.6,
J = 7.5) J = 7.5) J = 7.8) J = 7.8) J = 7.6) CH3)
(
3.20
s, 3 H)
7.49 (d, 1 H, 7.01 (t, 1 H, 7.24 (t, 1 H, 6.79 (d, 1 H, 7.00 (t, 1 H, 2.67 (m, 2 H, CH ), 1.22 (t, 3 H, J = 7.5,
2
(
J = 7.5)
J = 7.5)
J = 7.8)
J = 7.8)
J = 7.5)
CH3)
3.23
s, 3 H)
7.54 (d, 1 H, 7.04 (t, 1 H, 7.26 (t, 1 H, 6.81 (d, 1 H, 7.03 (t, 1 H, 2.64 (q, 2 H, J = 7.4, CH ), 1.67 (m, 2
2
(
J = 7.5)
J = 7.5)
J = 7.8)
J = 7.8)
J = 7.5)
H, CH ), 1.03 (t, 3 H, J = 7.4, CH )
2 3
3.24
s, 3 H)
7.55 (d, 1 H, 7.04 (t, 1 H, 7.26 (t, 1 H, 6.82 (d, 1 H, 7.03 (t, 1 H, 2.68 (q, 2 H, J = 7.4, CH ), 1.68–1.52
2
(
J = 7.5)
J = 7.5)
J = 7.8)
J = 7.8)
J = 7.5)
(m, 2 H, CH ), 1.50–1.38 (m, 2 H, CH ),
2
2
0
.95 (t, 3 H, J = 7.3, CH3)
(
E)-21b
3.25
s, 3 H)
7.63–7.36
(over-
lapped m)
6.86 (td, 1
H, J = 7.6,
0.8)
7.25 (td,
1 H, J = 7.8, J = 7.8)
1.0)
6.82 (d, 1 H, 7.83 (s, 1 H) 7.63–7.36 (overlapped m,
(
5 H, C H )
6 5
a
Compounds (E)-20 and (E)-21 are yellow oils. (E)-3: mp 155–156 °C (EtOH) (Lit. mp 156–158 °C); (E)-17: mp 76–78 °C (Lit.2a mp 78–
9 °C); (E)-18 mp 55–57 °C (Lit. mp 53–54 °C); (E)-19 mp 36–38 °C.
Satisfactory microanalyses obtained: C 0.25, H 0.33, N 0.20.
5c
2
a
7
b
A.; Mohamed, Y. S.; Abdel-Latif, F. F. J. Heterocycl. Chem.
1984, 22, 1233. (e) Faita, G.; Mella, M.; Righetti, P. P.;
Tacconi, G. Tetrahedron 1994, 50, 10955. (f) Kozminykh,
E. N.; Berezina, E. S.; Kozminykh, V. O. Zh. Obshch. Khim.
Acknowledgement
We thank CICYT for financial support of this research through
grant SAF-2000-0130.
1
996, 66, 1128; Chem. Abstr. 1996, 126, 7942.
6) Lindwall, H. G.; Maclennan, J. S. J. Am. Chem. Soc. 1932,
4, 4739.
(
(
5
References
7) In the case of compounds 9, 11, and 15 we observed slight
variations in the positions of the NMe, C(2)=O and
(1) (a) Sato, A.; Asao, T.; Hagiwara, Y.; Kitade, M.; Yamazaki,
Y. PCT Int. Appl. WO 9726242 A1., 1997; Chem. Abstr.
C(3)NMR signals, which may be a new example of the
known concentration dependence of NMR data that has been
found in other indole derivatives. For other examples, see:
(a) Jardine, R. V.; Brown, R. K. Can. J. Chem. 1963, 41,
2067. (b) Reinecke, M. G.; Johnson, H. W.; Sebastian, J. F.
J. Am. Chem. Soc. 1969, 91, 3817. (c) Avendaño, C.; De
Diego, C.; Elguero, J. Bull. Soc. Chim. Belg. 1989, 98, 73.
1
997, 127, 161696. (b) Sato, A.; Asao, T.; Hagiwara, Y.;
Kitade, M.; Yamazaki, Y. PCT Int. Appl. WO 9725986A1,
997; Chem. Abstr. 1997, 127, 190643.
1
(
2) (a) Tacconi, G.; Maggi, L. D.; Righetti, P.; Desimoni, G.;
Azzolina, O.; Ghislandi, V. J. Chem. Soc., Perkin Trans. 2
1976, 150. (b) Sumpter, W. E.; Miller, F. M. Heterocyclic
5
e
Compounds with Indole and Carbazole Systems;
Interscience: New York, 1954.
(8) Compound (Z)-3 has been obtained in Ref. by
isomerization of (E)-3 in the presence of AlCl3.
(9) Both isomers are clearly distinguished by the chemical shift
of their H(3 )-protons.
(
(
(
3) (a) Wahl, A.; Livovschi, V. Bull. Soc. Chim. Fr. 1938, 5,
653. (b) Anthony, W. C. J. Org. Chem. 1966, 31, 77.
4) Lathourakis, G. E.; Litinas, K. E. J. Chem. Soc., Perkin
Trans. 1 1996, 491.
5) (a) Pietra, S.; Tacconi, G. Il Farmaco 1958, 13, 893.
(10) For other acid-catalyzed dehydrations of 3-hydroxy
analogues, see: (a) Autrey, R. L.; Tahk, F. C. Tetrahedron
1967, 23, 901. (b) Beccalli, E. M.; Marchesini, A.; Pilati, T.
J. Chem. Soc., Perkin Trans. 1 1994, 579.
(11) A mutual NOE between H-4 and (3 )-methyl protons
characterized the Z-isomer.
(
b) Tacconi, G.; Gamba, A.; Marinone, F.; Desimoni, G.
Tetrahedron 1971, 27, 561.
c) Tacconi, G.; Marinone, F.; Gamba, A.; Desimoni, G.
Tetrahedron 1972, 28, 1517. (d) Fahmy, A. M.; Badr, M. Z.
(
Synthesis 2002, No. 1, 104–110 ISSN 0039-7881 © Thieme Stuttgart · New York