Oxidative Cleavage of Indole δ-Lactones with m-Chloroperbenzoic Acid: First Synthesis of Spiroindolin-2-one γ-Lactones

Full text of DOI:10.1021/jo000694u

J . Org. Chem. 2000, 65, 6773-6776
6773
Sch em e 1
Oxid a tive Clea va ge of In d ole δ-La cton es
w ith m -Ch lor op er ben zoic Acid : F ir st
Syn th esis of Sp ir oin d olin -2-on e γ-La cton es
Christophe Tratrat, Sylviane Giorgi-Renault,* and
Henri-Philippe Husson*
Laboratoire de Chimie The´rapeutique associe´ au CNRS et a`
l'Universite´ Rene´ Descartes (UMR 8638), Faculte´ des
Sciences Pharmaceutiques et Biologiques, 4 avenue de
l'Observatoire, 75270 Paris Cedex 06, France
S.Giorgi-Renault@pharmacie.univ-paris5.fr
Received May 5, 2000
Sch em e 2
In a previous study dealing with the preparation of
quinolones annelated at the 2,3-positions to a γ-lactam
and a γ-imide, we described the one-pot synthesis of
pyrrolo[3,4-b]quinoline-3,9-diones (quinolone γ-lactams)
3a ,b from 2,3,4,9-tetrahydropyrido[3,4-b]indol-1-ones (in-
dole δ-lactams) 1a ,b via nonisolated ketoamides 2a ,b
(Scheme 1).1 Under the same conditions (O2, tert-BuOK),
the corresponding quinolone γ-lactone 3c could not be
obtained from the 3,4-dihydropyrano[3,4-b]indol-1(9H)-
one (indole δ-lactone) 1c.
Another possible route to prepare such unknown
quinolone γ-lactones is a two-step procedure, i.e., oxida-
tion of 1 to a nine-membered ring ketoamide 2 and
subsequent cyclization in alkaline medium. Various
methods of oxidative cleavage of the 2,3-double bond of
the indole nucleus such as ozonolysis2 or oxidation by
sodium periodate3 or by O2/Pt4 were attempted without
success using indole δ-lactones 1c and 4a as starting
material.
In this paper, we report the unexpected results ob-
tained in the course of this project by oxidation of
N-substituted indole δ-lactones 4 with m-chloroperben-
zoic acid (m-CPBA).
was performed at 25 °C, the hydroxyindolenine was
obtained as the major product (57%) beside 21% of
ketoamide and two spiro derivatives as byproducts (9%
7
of spiroindolin-3-one and 3% of spiroindolin-2-one).
Moreover, ketoamides have been prepared by m-CPBA
oxidation of a tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-
8
9
one and of N-methylazetopyridoindoles.
In light of these results, we have attempted the
oxidative cleavage of the indole 2,3 double bond according
Oxidation of 2,3-disubstituted indoles with peracids is
9
to Kurihara’s experimental conditions (m-CPBA, room
5
well-known.
Hino has reported that treatment of
temperature in CH2Cl2) with N-substituted indole δ-lac-
tones 4a -c. The expected ketoamides were not obtained,
but instead new heterocycles were formed to which the
structures of 4,5-dihydrospiro[furan-3(2H),3′-indole]-2,2′-
(1′H)-diones (spiroindolin-2-one γ-lactones) 5a -c were
attributed (Scheme 2). The reaction proceeded in the
same manner but faster when performed in 1,2-dichlo-
roethane at reflux instead of using CH2Cl2 at room
temperature (1 h instead of 2 days in the case of 5a ).
The formation of two spiro structures 5 and 9 could be
considered (Scheme 3). The presence in the 13C NMR
spectra of a new quaternary carbon (≈56 ppm) in addition
to two carbonyl signals (172-174 ppm) are in agreement
with mass spectrometry data. The two carbonyl absorp-
tions in the IR spectra at 1757-1781 cm-1 and 1720-
1727 cm-1 are typical of γ-lactone and lactam, respec-
tively. This hypothesis is also corroborated by a complex
ABXY pattern in the1H NMR spectra accounting for the
lactone ring ethano protons (2.70, 2.90, 4.65, and 4.80
tetrahydrocarbazole with m-CPBA (1 equiv, -60 °C in
CH2Cl2) afforded hydroxy-4aH-carbazole as the major
product. 6 The latter hydroxyindolenine could be oxidized
in good yield to the corresponding ketoamide by either
4
perbenzoic acid or m-CPBA in the presence of a small
amount of H2SO4.6 Protonated hydroxyindoline facilitates
the addition of peracid to the CdN double bond, and the
6
ketoamide is obtained by subsequent cleavage. On the
other hand, m-CPBA oxidation at -40 °C of aristoteline,
a piperidino-indole alkaloid, gave the corresponding
hydroxyindolenine in 94% yield. When the same reaction
* To whom correspondence should be addressed.S. Giorgi-Renault
or H.-P. Husson: husson@pharmacie.univ-paris5.fr, Fax: 33 + 143 291
403.
(1) Tratrat, C.; Giorgi-Renault, S.; Husson, H.-P. Synlett. 1998, 1071.
(2) Witkop, B.; Goodwin, S. J . Am. Chem. Soc. 1953, 75, 3371.
(3) (a) Beisler, J . A. J . Med. Chem. 1971, 14, 1116. (b) Gatta, F.;
Misiti, D. J . Heterocycl. Chem. 1989, 26, 537.
(4) Witkop, B.; Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 2196.
(5) (a) Witkop, B.; Fiedler, H. Ann. Chim. 1947, 558, 91. (b) Witkop,
B. Ibid. 1947, 558, 98. (c) Hutchison, A. J .; Kishi, Y. Tetrahedron Lett.
1978, 539. (d) Sundberg, R. J ., Ed. The Chemistry of Indoles; Academic
Press: New York, 1970.
(6) Hino, T.; Yamaguchi, H.; Matsuki, K.; Nakano, K.; Sodeoka, S.;
Nakagawa, M. J . Chem. Soc., Perkin Trans. 1 1983, 141.
(7) Gu¨ller, R.; Borschberg, H. J . Helv. Chim. Acta 1993, 76, 1847.
(8) Friary, R. J .; Schwerdt, J . H. Tetrahedron 1991, 47, 9981.
(9) Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa,
S.; Yoneda, R.Chem. Pharm. Bull. 1995, 43, 1089.
10.1021/jo000694u CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

6774 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Sch em e 3
10
ppm for 5a ). According to Gu¨ller,
spiroindolin-3-one
cordingly, indoliminium salt 7 (Scheme 3) should be in
equilibrium with the hydrated form 8, the resulting diol
could undergo a pinacol type rearrangement to give 5 and
9. On the other hand, Zhang17 has demonstrated that the
first step of the dimethyldioxirane oxidation of N-acetyl-
2,3-dialkylindoles is the formation of 2,3-epoxides which
rearrange to indolinones. The ratio of indolin-2-one and
-3-one is interpreted in terms of ring opening via a
carbocation intermediate. A stabilized benzylic carbocat-
ion leads to the pinacol-rearranged indolin-2-one as the
major product. According to Hino,6 the products obtained
by m-CPBA oxidation of 2,3-disubstituted indole might
derive from 2,3-epoxide or 3-hydroxyindolenine as the
first intermediate.
Although the formation of epoxide was not proven for
m-CPBA oxidation, the mechanism described for the
transformation of the indole-lactones 4 in pathway B
(Scheme 3) may be the more probable one. Indeed, the
other process (pathway A) would led to a mixture of
indolinones 5 and 9 as published in other series. Benzylic
carbocation 10 is more stable than indolinium 7 which
is destabilized by the presence of the lactone function.
Consequently, the carbocation 10 is exclusively formed
and the transposition occurred at the benzylic position
to give the indolin-2-one 5.
and -2-one can be distinguished because the former shows
a benzylic carbonyl near 200 ppm in the 13C NMR and a
quaternary C-2 near 80 ppm, but the latter shows a
lactam carbonyl near 180 ppm and a quaternary C-3 near
60 ppm. Moreover, compounds 9a and 9c are known11
and their melting points are significantly different from
those of our N-methyl and N-acetyl spiro derivatives.
Thus, the spiro-2,2′ structure 9 could be disregarded. The
spiro 3,3′ structure 5 was definitely assigned by the
chemical transformation of 5a into the known 3-(2-
hydroxyethyl)-1-methyloxindole 6 12 by heating in KOH-
MeOH (Scheme 2). The opening of the lactone ring is
followed by a facile decarboxylation of the â-amido acid.
To our knowledge, no 4,5-dihydrospiro[furan-3(2H),3′-
indole]-2,2′(1′H)-dione has been previously described in
the literature. Despite the absence of subsequent acidic
or alkaline medium and workup in neutral conditions,
the yields in 5a -c are moderate on account of the
instability of their lactone rings. The presence of other
derivatives was not detected by TLC in the reaction
medium.
This spiroannelation is rather surprising since car-
bocyclic spiroindolin-2-ones are usually obtained either
15
by action of tert-butyl hypochlorite,13 NBS,14 and OsO4
and subsequent acidic treatment or by Pb(OAc)4 oxidation
followed by an akaline treatment.
The rearrangement of hydroxyindolenine in acidic
medium to spiroindolin-2-one as the minor derivative
besides spiroindolin-3-one was interpreted by Gu¨ller10 in
terms of hydratation of the protonated indolenine. Ac-
It is noteworthy that the indole-lactone 1c is not
oxidized in the above conditions. The difference in
reactivity between N-substituted and unsubstituted in-
doles can be interpreted in terms of tautomerism that
leads to a decreasing enamine character of the indole
(Figure 1).
16
It should also be noted that m-CPBA oxidation of the
N-(4-methoxyphenyl) substituted indole-lactam 11 did
not furnish a spiro derivative but a mixture of the two
oxindoles 12 and 13 which were easily separated by
column chromatography (Scheme 4). Two possibilities can
be considered for the formation of 12: either the reaction
starts by oxidation, transposition into spirolactone, hy-
drolysis of the lactone, and then decarboxylation or the
first step is the hydrolysis of the δ-lactone ring of 11, and
then oxidation, transposition, and decarboxylation. Diol
13 probably results from further oxidation of the enol
form of 12 and subsequent deshydratation.
(10) Gu¨ller, R.; Borschberg, H. J . Tetrahedron: Asymmetry 1992,
3, 1197.
(11) Kawada, M.; Kawano, Y.; Sugihara, H.; Takei, S.; Imada, I.
Chem. Pharm. Bull. 1981, 29, 1900.
(12) Nozoye, T.; Shibanuma, Y.; Nakai, T.; Hatori, Y. Chem. Pharm.
Bull. 1988, 36, 4980.
(13) (a) Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai,
S. I. Tetrahedron 1989, 45, 1327. (b) Martin, S. F.; Mortimore, M.
Tetrahedron Lett. 1990, 31, 4557. (c) Yu, P.; Cook, J . M. Ibid. 1997,
38, 8799.
(14) (a) Hiemstra, H. C.; Biera¨ugel, H.; Wijnberg, M.; Pandit, U.K.
Tetrahedron 1983, 39, 3981. (b) Pellegrini, C.; Stra¨ssler, C.; Weber,
M.; Borschberg, H. J . Tetrahedron: Asymmetry 1994, 5, 1979. (c)
Pellegrini, C.; Weber, M.; Borschberg, H. J . Helv. Chim. Acta 1996,
79, 151.
The difference in reactivity between derivatives 4 and
11 may be interpreted in terms of difference in the
(15) (a) Takayama, H.; Odaka, H.; Aimi, N.; Sakai, S. I. Tetrahedron
Lett. 1990, 31, 5483. (b) Peterson, A. C.; Cook; J . M. J . Org. Chem.
1995, 60, 120.
(16) Takayama, H.; Kurihara, M.; Subhadhirasakul, S.; Kitajima,
M.; Aimi, N.; Sakai, S. I. Heterocycles 1996, 42, 87.
(17) Zhang, X.; Foote, C. S. J . Am. Chem. Soc. 1993, 115, 8867.

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6775
Hz), 7.40 (t, 1H, J ) 8 Hz), 7.55 (d, 1H, J ) 8 Hz), 7.60 (d, 1H,
J ) 8 Hz); 13C NMR (DMSO-d6) δ: 22.0, 32.1, 69.9, 108.1, 112.1,
121.4, 122.2, 123.1, 123.8, 124.0, 127.2, 149.2. Anal. Calcd for
C
12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.94; H, 5.50;
N, 6.65.
9-(2,4-Din it r op h e n yl)-3,4-d ih yd r op yr a n o[3,4-b]in d ol-
1(9H)-on e 4b. A mixture of indole-lactone 1c (187 mg, 1 mmol),
K2CO3 (138 mg, 1 mmol), and 2,4-dinitrofluorobenzene (0.5 mL)
was heated at 140 °C for 6 h. After being cooled to room
temperature, the reaction mixture was diluted with CH2Cl2 and
washed with water. The crude product was purified by chroma-
tography on silica gel (ligroin/AcOEt 8.5:1.5) and then recrys-
tallization from ethanol to give 310 mg (88%) of pure 4b: mp
208 °C (EtOH); 1H NMR (CDCl3) δ: 3.20 (t, 2H, J ) 8 Hz), 4.65
(t, 2H, J ) 8 Hz), 7.05 (d, 1H, J ) 8 Hz), 7.25 (t, 1H, J ) 8 Hz),
7.35 (t, 1H, J ) 8 Hz), 7.65 (d, 1H, J ) 8 Hz), 7.75 (d, 1H, J )
F igu r e 1.
Sch em e 4
8 Hz), 8.55 (dd, 1H, J ) 8 and 2 Hz), 9.00 (d, 1H, J ) 2 Hz); 13
C
NMR (CDCl3) δ: 21.5, 68.8, 110.5, 121.6, 122.8, 125.0, 127.1,
128.0, 128.3, 132.1, 136.8, 138.4, 139.3, 145.9, 146.8, 159.5. Anal.
Calcd for C17H11N3O6: C, 57.80; H, 3.14; N, 11.89. Found: C,
57.50; H, 2.99; N, 11.49.
9-Acetyl-3,4-d ih yd r op yr a n o[3,4-b]in d ol-1(9H)-on e 4c. To
a solution of indole-lactone 1c (500 mg, 2.67 mmol) in THF (5
mL) were added tert-BuOK (448 mg, 4 mmol) and Ac2O (0.38
mL, 4 mmol). The reaction mixture was stirred for 30 min at
room temperature and then poured into water. After extraction
with CH2Cl2, the crude product was purified by chromatography
on silica gel (CH2Cl2) to yield 400 mg (65%) of 4c: mp 144 °C
(EtOH); 1H NMR (CDCl3) δ: 2.65 (s, 3H), 3.10 (t, 2H, J ) 6 Hz),
4.60 (t, 2H, J ) 6 Hz), 7.25 (t, 1H, J ) 8 Hz), 7.45 (d, 1H, J )
8 Hz), 7.50 (t, 1H, J ) 8 Hz), 8.35 (d, 1H, J ) 8 Hz). Anal. Calcd
for C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C, 68.03; H,
4.96; N, 6.01.
P r ep a r a tion of Sp ir oin d olin -2-on e γ-La cton es 5 fr om
In d ole La cton es 4. A solution of m-CPBA (1.5 g) in 1,2-
dichloroethane (20 mL), which had been previously dried over
Na2SO4, was added to a solution of indole lactone 4 (2.5 mmol)
in 1,2-dichloroethane (30 mL). The reaction mixture was refluxed
either for 1 h (compound 4a ,c) or for 5 h (compound 4b). After
being cooled to room temperature, the reaction mixture was
filtered off, and the resulting solution was purified by chro-
matographies on alumina (CH2Cl2) and then on silica gel (CH2-
Cl2). A recrystallization from methanol afforded pure indole
lactones 5.
stability of their lactone functions under the reaction
conditions. Contrary to the N-methyl derivative 4a (no
reaction after 1 h), lactone 11 is a quite labile compound
which is hydrolyzed in 10 min in refluxing 1,2-dichloro-
ethane in the presence of a small amount of H2SO4. The
resulting acid-alcohol 14, treated with m-CPBA, provided
the two derivatives 12 and 13. The instability of 11 in
acidic medium could justify the occurrence of the pathway
via 14. When the reaction was carried out for an ad-
ditional 18 h, it was possible to isolate 13 as a single
product in 58% yield. Consequently, the m-CPBA oxida-
tion of N-substituted-3-(2-hydroxyethyl)indole-2-carbox-
ylic acids may be an interesting route for the synthesis
of N-substituted-3-hydroxy-3-(2-hydroxyethyl)oxindoles.
To our knowledge, only the N-unsubstituted derivative
1′-Met h yl-4,5-d ih yd r osp ir o[fu r a n -3(2H ),3′-in d ole]-2,2′-
(1′H)-d ion e 5a : yield: 52%; mp 141 °C (MeOH); IR (KBr) 1757,
1720 cm-1; 1H NMR (CDCl3) δ: 2.70 (m, 1H), 2.90 (m, 1H); 3.25
(s, 3H), 4.65 (m, 1H), 4.80 (m, 1H), 6.90 (d, 1H, J ) 8 Hz), 7.15
(t, 1H, J ) 8 Hz), 7.25 (d, 1H, J ) 8 Hz), 7.40 (t, 1H, J ) 8 Hz);
13C NMR (CDCl3) δ: 26.6, 33.4, 55.5, 66.7, 108.8, 122.8, 123.3,
127.6, 129.6, 144.2, 172.9, 173.2; MS (CI): m/z 218 [MH]+, 235
[MNH4]+. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45.
Found: C, 66.71; H, 5.44; N, 6.08.
has been prepared from isatin in six steps and in 50%
18
overall yield.
However, the utility of this method is
limited by the availability of isatins.
1′-(2,4-Din it r op h en yl)-4,5-d ih yd r osp ir o[fu r a n -3(2H ),3′-
in d ole]-2,2′(1′H)-d ion e 5b: yield: 50%; mp 210 °C dec (MeOH);
In conclusion, we have described the first synthesis of
4,5-dihydrospiro[fura n-3(2H),3′-indole]-2,2′(1′H)-di-
ones. Moreover, a new synthesis of 3-hydroxy-3-(2-
hydroxyethyl)oxindoles has been achieved.
IR (KBr) 1769, 1727 cm-1 1H NMR (CDCl3) δ: 2.80 (m, 1H),
;
3.05 (m, 1H), 4.65 (m, 1H), 4.85 (m, 1H), 6.80 (d, 1H, J ) 8 Hz),
7.25-7.40 (m, 3H), 7.95 (d, 1H, J ) 9 Hz), 8.65 (dd, 1H, J ) 9
and 2 Hz), 9.05 (d, 1H, J ) 2 Hz); 13C NMR (CDCl3) δ: 34.1,
55.9, 66.8, 109.2, 121.9, 124.1, 125.3, 127.6, 128.7, 129.9, 130.9,
132.8, 142.0, 145.5, 147.1, 171.8, 172.0; MS (CI): m/z 387
[MNH4]+. Anal. Calcd for C17H11N3O7: C, 55.29; H, 3.00; N,
11.38. Found: C, 55.54; H, 3.14; N, 11.22.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively. m-CPBA (70-75%
purity) was purchased from Acros and used without further
purification.
9-Meth yl-3,4-d ih yd r op yr a n o[3,4-b]in d ol-1(9H)-on e 4a . To
a solution of indole-lactone 1c19 (187 mg, 1 mmol) in THF (10
mL) were added tert-BuOK (123 mg, 1.1 mmol) and then methyl
iodide (0.125 mL, 2 mmol). The reaction mixture was stirred for
1 h at room temperature. After the solvent has been removed
by evaporation, the residue was triturated with water, filtered
off, dried, and recrystallized from ethanol to give 4a (191 mg,
95%). mp 104 °C (EtOH); 1H NMR (DMSO-d6) δ: 3.10 (t, 2H, J
) 5 Hz), 4.00 (s, 3H), 4.55 (t, 2H, J ) 5 Hz), 7.15 (t, 1H, J ) 8
1′-Acet yl-4,5-d ih yd r osp ir o[fu r a n -3(2H ),3′-in d ole]-2,2′-
(1′H)-d ion e 5c: yield: 52%; mp 138 °C (MeOH); IR (KBr) 1781,
1
1745, 1720 cm-1; H NMR (CDCl3) δ: 2.60-2.75 (m, 4H), 3.00
(m, 1H), 4.65 (m, 1H), 4.85 (m, 1H), 7.25 (m, 2H), 7.40 (t, 1H, J
) 8 Hz), 8.30 (d, 1H, J ) 8 Hz); 13C NMR (CDCl3) δ: 26.5, 34.4,
56.4, 66.7, 117.0, 122.4, 125.9, 126.6, 130.0, 140.7, 170.2, 171.8,
174.2; MS (CI): m/z 246 [MH]+, 263 [MNH4]+. Anal. Calcd for
C
13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.48; H, 4.63;
N, 5.55.
3-(2-H yd r oxye t h yl)-1-m e´t h yl-1,3-d ih yd r o-2H -in d ol-2-
on e 6. A mixture of compound 5a (100 mg, 0.46 mmol) and
NaOH (37 mg, 0.92 mmol) in methanol (5 mL) was refluxed for
5 min. After being cooled to room temperature, the reaction
mixture was diluted with CH2Cl2 and washed with water. The
(18) Rasmussen, H. B.; MacLeod, J . K. J . Nat. Prod. 1997, 60, 1152.
(19) Plieninger, H. Chem. Ber. 1950, 83, 271.

6776 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
crude product was purified by chromatography on silica gel (CH2-
Cl2/CH3OH 9.8: 0.2) to yield 72 mg (82%) of 6 as oil. The
spectroscopic data were consistent with the structure of the
product.12
3-Hyd r oxy-3-(2-h yd r oxyeth yl)-1-(4-m eth oxyp h en yl)-1,3-
d ih yd r oin d ol-2-on e 13: IR (film) 3386, 1710 cm-1 1H NMR
;
(CDCl3) δ: 2.05 (m, 1H), 2.25 (m, 1H), 3.15 (bs, 1H, D2O exch),
3.75 (s, 3H), 3.85 (t, 2H, J ) 5 Hz), 4.70 (bs, 1H, D2O exch), 6.75
(d, 1H, J ) 8 Hz), 6.90 (d, 2H, J ) 8 Hz), 7.00 (t, 1H, J ) 8 Hz),
7.15 (t, 1H, J ) 8 Hz), 7.20 (d, 2H, J ) 8 Hz), 7.35 (d, 1H, J )
8 Hz); 13C NMR (CDCl3) δ: 39.6, 55.4, 58.4, 76.1, 109.6, 114.8,
123.5, 124.1, 126.4, 127.8, 129.5, 130.1, 143.3, 159.2, 178.1; MS
(EI): m/z 299 [M]+; HRMS calcd for C17H17NO4 299.115 758,
found 299.114 954.
3-(2-H yd r oxyet h yl)-1-(4-m et h oxyp h en yl)in d ole-2-ca r -
boxylic a cid 14. A solution of indole lactone 11 (100 mg, 0.34
mmol) in 1,2-dichloroethane (10 mL) was refluxed for 10 min in
the presence of a small amount of concd H2SO4 . After the solvent
has been removed by evaporation, the residue was triturated
with water, filtered off, dried, and recrystallized from DMF to
give 14 (82 mg, 78%): mp 208 °C (DMF); IR (KBr) 3404, 1677
cm-1; 1H NMR (DMSO-d6) δ: 3.25 (t, 2H, J ) 7 Hz), 3.65 (t, 2H,
J ) 7 Hz), 3.85 (s, 3H), 6.95 (d, 1H, J ) 8 Hz), 7.02 (d, 2H, J )
8 Hz), 7.15 (t, 1H, J ) 8 Hz), 7.20 (m, 3H), 7.75 (d, 1H, J ) 8
Hz); 13C NMR (DMSO-d6) δ: 29.8, 56.4, 62.8, 112.0, 115.3, 121.5,
121.8, 122.6, 126.7, 128.0, 128.2, 129.6, 132.7, 140.1, 163.7. Anal.
Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.26;
H, 5.64; N, 4.40.
9-(4-Me t h oxyp h e n yl)-3,4-d ih yd r op yr a n o[3,4-b]in d ol-
1(9H)-on e 11. A mixture of indole lactone 1c (500 mg, 2.67
mmol), 4-bromoanisole (0.4 mL, 3.2 mmol), K2CO3 (400 mg, 3.6
mmol), and CuO (13 mg, 0.16 mmol) in DMF (4 mL) was refluxed
for 24 h. After being cooled to room temperature, the reaction
mixture was diluted with CH2Cl2 and washed with water. The
crude product was purified by chromatography on silica gel (CH2-
Cl2) to yield 525 mg (67%) of pure oily 11: 1H NMR (CDCl3) δ:
3.05 (t, 2H, J ) 8 Hz), 3.82 (s, 3H), 3.95 (t, 2H, J ) 8 Hz), 6.95
(d, 2H, J ) 8 Hz), 7.10-7.20 (m, 2H), 7.35 (d, 2H, J ) 8 Hz),
7.40 (d, 1H, J ) 8 Hz), 7.62 (d, 1H, J ) 8 Hz); 13C NMR (CDCl3)
δ: 28.6, 55.5, 62.5, 110.4, 112.6, 114.6, 119.0, 119.7, 122.3, 125.6,
126.5, 128.4, 132.6, 136.5, 158.0.
m -CP BA Oxid a tion of th e In d ole La cton e 11. Indole
lactone 11 (500 mg, 1.7 mmol) was oxidized in the same manner
as described for 4, except that the mixture was refluxed for 30
min. After workup, purification of the crude product by flash
chromatographies on alumina (CH2Cl2) and then on silica gel
(CH2Cl2/ MeOH 9.8:0.2) provided 12 (70 mg, 15%) and 13 (180
mg, 35%) as oils.
3-(2-Hyd r oxyeth yl)-1-(4-m eth oxyp h en yl)-1,3-d ih yd r oin -
d ol-2-on e 12: IR (film) 3380, 1708 cm-1 1H NMR (CDCl3) δ:
;
Ack n ow led gm en t. C. Tratrat was supported by a
2.35 (m, 1H), 2.45 (m, 1H), 3.85 (dd, 1H, J ) 5 and 8 Hz), 3.95
(s, 3H), 4.05 (t, 2H, J ) 5 Hz), 6.85 (d, 1H, J ) 8 Hz), 7.15 (d,
2H, J ) 8 Hz), 7.20 (t, 1H, J ) 8 Hz), 7.30 (t, 1H, J ) 8 Hz),
7.45 (m, 3H); 13C NMR (CDCl3) δ: 33.3, 44.3, 55.4, 60.6, 109.3,
114.8, 122.8, 123.8, 126.7, 127.8, 128.3, 144.3, 159.1, 178.6; MS
(EI): m/z 283 [M]+; HRMS calcd for C17H17NO3 283.120 844,
found 283.120 104.
fellowship from La Ligue Nationale contre le Cancer.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 5a -c, 12, 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O000694U