Directed ortho-lithiation of the 2-(N,N-dimethylhydrazinecarbonyl)-1-methylindole. Efficient preparation of tricyclic lactones

Article abstract of DOI:10.1055/s-2003-36786

N-Methyl indole-2-hydrazide 1 was lithiated at the 3-position using t-BuLi in the presence of TMEDA in THF. The generated ortho-lithiated intermediate is reacted with a variety of electrophiles to give regioselectively 2,3-disubstituted indoles in good yields. The hydroxyhydrazides were converted to the corresponding lactones after oxidation with MnO₂.

Full text of DOI:10.1055/s-2003-36786

LETTER
173
Directed ortho-Lithiation of the 2-(N,N-Dimethylhydrazinecarbonyl)-
1-methylindole. Efficient Preparation of Tricyclic Lactones
Efficient
Preparation
o
.
f
T
ricyclic
L
R
a
ctones omero, M. D. Pujol*
Laboratori de Química Farmacèutica (Unitat associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643,
08028-Barcelona, Spain
E-mail: mdpujol@farmacia.far.ub.es
Received 26 November 2002
In an earlier study,12 we obtained the alkylation of indole-
2-amides in excellent yield by metalation, but contrary to
our expectations, the hydrolysis step was not straightfor-
ward and gave multiple products depending on the reac-
Abstract: N-Methyl indole-2-hydrazide 1 was lithiated at the 3-po-
sition using t-BuLi in the presence of TMEDA in THF. The gener-
ated ortho-lithiated intermediate is reacted with a variety of
electrophiles to give regioselectively 2,3-disubstituted indoles in
good yields. The hydroxyhydrazides were converted to the corre- tion conditions. We examined several additional variables
sponding lactones after oxidation with MnO2.
in order to increase the yield, but without success. This
problem with the hydrolysis of the amide function led us
to consider the use of hydrazides as ortho-directing
function, which seems to be more activating than the
carboxylic acid group. The hydrazide function has been
introduced into synthetic practice in the DoM process on
the benzene ring by Wuts et al.13 but their application on
indole ring is not reported up till now.
Key words: indole-hydrazide, directed ortho-metalation (DoM),
3-oxofuroindole, 2,3-disubstituted indole, hydrazide cleavage
The process of directed ortho-metalation (DoM)1 of car-
boxamides,2 carbamates,3 carboxylic acids4 and hy-
drazides,5 is one of the better known methods for
appending a wide range of substituents onto the aromatic
nucleus. Amides, carbamates and oxazolines are excellent
substrates for the directed ortho-metalation reaction;
however, they require harsh conditions for their hydroly-
sis.6
Dimethylhydrazides are shown to be excellent substrates
for the DoM reaction, and the major interest is the suc-
cessful oxidative cleavage under relatively mild condi-
tions. This work can be considered an extension of the
previous work reported by Wuts et al.13 about the directed
ortho-metalation of the N,N-dimethylhydrazide of benzo-
ic acid.
The great majority of studies of ortho-metalation have
been carried out on the benzene ring, while heterocyclic
nuclei have received comparatively less attention. Recent-
ly Quéguiner et al.7 reported studies of metalation of azine
rings, whereas Fukuda et al.8 reported the lithiation of 1-
(2,2-diethylbutanoyl)indole and Matsuzomo9 the directed
lithiation at C-3 of 1-(triisopropylsilyl)indole. Previously,
Gribble et al.10 described new indole lithiation methods
that allowed the preparation of several substituted indole
derivatives, which are not readily available by conven-
tional methodologies.
Based on this aforementioned work, we are interested in
the preparation of the 2,3-disubstituted indoles via the
ortho-lithiated intermediate indole-2-hydrazide. The
compounds obtained will be of value for the synthesis of
indole alkaloids and also as intermediates in the synthesis
of compounds of interest in medicinal chemistry.
We report the lithiation of N-methyl-2-(N′,N′-dimethyl-
hydrazide)indole prepared from the corresponding car-
boxylic acid under conventional conditions. The N-
methylindole-2-hydrazide reacts selectively with t-butyl-
lithium-TMEDA complex at the 3-position, and forms the
corresponding carbanion, which behaves as excellent nu-
cleophile in the presence of electrophilic reagents
(Scheme 1). Table 1 depicts an overview of the scope di-
versity of electrophiles that may be used.
In general, the directed lithiation at C-3 of the indole-2-
carboxylic acids or indole-2-carboxamides presents diffi-
culties. Whereas, the treatment of the secondary amides
with s-BuLi and subsequent addition of acetaldehyde
gives the corresponding alcohol in acceptable yield, the
metalation of N,N-dimethylindole-2-carboxamide using
butyllithium suffers ring-opening to an alkyne.10b
The N-methylindole-2-hydrazide 1 is deprotonated at
–78 ºC with 3 equivalents of t-butyllithium in THF. The
reaction works well in THF and TMEDA improves the
yield. Normally, the solution of the ortho-lithiated inter-
mediate species is reacted with the appropriate electro-
phile in excess (3 equiv) at –78 ºC and the mixture
obtained is allowed to warm to room temperature. The
general conditions used were chosen on the basis of pre-
liminary experiments.12
The directed lithiation of indole-2-carboxylic acids does
not appear to be an efficient procedure for preparing the
corresponding 2,3-disubstituted indoles. Only few acylat-
ed indoles via C-3 lithiation directed by the C-2 carbonyl
group are reported.11
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0173,0178,ftx,en;D23902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

174
M. Romero, M. D. Pujol
LETTER
The lithiation of 1 leads to an ortho-lithiated intermediate,
which upon treatment with alkylaldehydes affords racem-
ic alcohols in good yield (entries 1–4, Table 1).
Steric hindrance of the alkyl group could be taken into ac-
count on the study of the experimental obtained results
(see entry 3, Table 1). The alkylation with aryl or α,β un-
saturated aldehydes can be achieved in acceptable yield
(entries 5 and 7, Table 1). The condensation with p-meth-
oxybenzaldehyde leads to the corresponding ketone in-
stead of the expected alcohol. The alcohol was observed
in small amounts when the p-methoxybenzaldehyde was
used as electrophile due to fast oxidation to the corre-
sponding ketone (entry 6, Table 1). The obtained result
suggests that, nucleophilic attack of the ortho-lithiated in-
termediate on the aldehyde occurs and the alcohol formed
Scheme 1 Lithiation of indole derivatives
Table 1 Directed ortho-Lithiation of Indole-2-hydrazide
Entry
Electrophile
R1
R2
H
H
H
H
H
R3
–
Compound
Yield (%)
1
2
3
4
5
CH3CHO
CH3
2
3
4
5
6
78
77
69
74
61
CH3(CH2)5CHO
(CH3)3CCHO
C6H5CH2OCH2CHO
CH3(CH2)5
(CH3)3C
C6H5CH2OCH2
–
–
–
–
6
–
–
7a
75
7
8
9
C6H5CH=CH
H
–
–
–
8
9
59
63
66
–(CH2)5–
–(CH2)2-NBn-(CH2)2–
10
10
11
12
13
(CH3)3SiCl
CH3I
–
–
–
–
–
–
–
–
–Si(CH3)3
CH3
11
12
13
14
85
81
83
61
CH3CH2I
CH3CH2
–CO(CH2)2CO2H
14
15
–
–
–
–
15
16
69
65
a Accompanied by trace of the corresponding alcohol.
Synlett 2003, No. 2, 173–178 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Preparation of Tricyclic Lactones
175
under the reaction presumably by aerial oxidation under
workup conditions, is rapidly oxidized to the correspond-
ing diarylketone. Condensation of the ortho-lithiated in-
termediate with cyclohexanone followed by acid
hydrolysis gave the alcohol 9 in acceptable yield as a sole
product (entry 8, Table 1). Among the derivatives avail-
able by this procedure is the functionalized amine 10 (en-
try 9, Table 1) obtained using N-benzyl-4-piperidone as
the electrophilic reagent. The obtained carbinols (2–10)
were proved to be labile, and the crude products were
quickly and carefully purified by chromatography and
then used directly in the next step.
Table 2 Oxidation and Cyclization of Hydrazides
Entry R1
R2
X
Com-
pound
Yield
(%)
92
95
79
83
55
1
2
3
4
5
CH3
H
H
H
H
H
O
O
O
O
O
17
18
19
20
21
CH3(CH2)5
(CH3)3C
C6H5CH2OCH2
The addition of trimethylsilyl chloride to the ortho-lithiat-
ed intermediate gave the desired 3-trimethylsilyl hy-
drazide in excellent yield (entry 10, Table 1). Moreover,
we found that the treatment of the metalated hydrazide
with allyl chloroformate led to the corresponding hy-
drazide acylated in the 3-position (entry 14, Table 1).
Alkylations with simple alkyl halides gave the expected
alkylhydrazide indoles (entries 11, 12, Table 1). The
ortho-lithiated hydrazide has proven to be efficient inter-
mediate for the synthesis of diverse acylderivatives (en-
tries 13–15, Table 1). The route involving the use of
hydrazide-indole proved to be efficient for the preparation
of 2,3-disubstituted indoles, and the obtained compounds
may be easily converted to the corresponding lactones or
acids by oxidative cleavage (Scheme 2 and Scheme 3).
6
7
8
–(CH2)5–
–(CH2)2-NBn-(CH2)2–
C6H5CH=CH
O
O
22
23
81
85
H
N–N(CH3)2 24
45a
a Isolated compound instead of the lactone.
Scheme 3 Oxidation of hydrazides to carboxylic acids
Directed ortho-lithiation of indole-2-hydrazides allows
easy generation of 2,3-disubstituted indole derivatives
which are of general synthetic interest.
Scheme 2 Oxidation and cyclization of hydrazides
The structural assignments of these prepared compounds
were based on their analytical data: NMR spectra, IR, MS,
and elemental analyses.
The alcohols obtained from the condensation of ortho-
lithiated intermediate with aldehydes (entries 1–5 and 7,
Table 1) or ketones (entry 8, 9, Table 1) were oxidized by
treatment with activated MnO2 in dichloromethane con-
taining excess acetic acid.5a It is interesting to note that the
use of CuCl213 as oxidizing agent leads to the correspond-
ing keto-hydrazides, whereas MnO2 by oxidative cleav-
age gives the expected lactone in good yields (Table 2).
Preparation of Indole-hydrazide. The N-methylindole-2-carbon-
yl chloride (obtained from the corresponding acid by treatment with
SOCl2 in toluene) was treated with the N,N-dimethylhydrazine (1.5
mmol) in CH2Cl2 and the mixture was stirred overnight at room
temperature. The solvent was removed and the residue was purified
by column chromatography giving the hydrazide 1 as a white solid
(98% yield).
The condensed lactones (entries 1–7, Table 2) can be con-
sidered efficient intermediates for the preparation of poly-
cyclic aromatic systems. All attempts to obtain the lactone
from the alcohol 8 were unsuccessful, the main product
formed was the cyclic hydrazide 24 (entry 8, Table 2).
Under the same conditions (MnO2, HOAc) the hydrazide
1 and the keto-hydrazide 7 were oxidized successfully to
the expected indole carboxylic acids 2514 and 26 respec-
tively (Scheme 3).
General Procedure for the Introduction of a Substituent at the
C-3 of the Hydrazide 1 (2–16).15 A 25 mL, 3 necked flask, provid-
ed with a septum, argon inlet and outlet, and a stirrer, is charged
with a solution of 1 (1 mmol) in anhyd THF (5 mL). The solution
was cooled to –78 ºC (acetone–solid CO2 bath) and a 1.6 M solution
(3 mmol) of t-BuLi in hexane and TMEDA (3 mmol) was added by
means of a syringe. The mixture turned brown. Stirring was contin-
ued for 3 h at –78 ºC, the corresponding electrophile (3 mmol) add-
ed by syringe and the mixture is allowed to warm to r.t. After 8 h,
water (ca. 2 mL) was added, and the mixture acidified with HCl 2
N (2 mL). Extraction with Et2O (3 × 15 mL), washing the combined
ether extracts with sat. NaHCO3 solution (15 mL) and with H2O (15
mL), drying with Na2SO4, removal of the Et2O on the rotary
Synlett 2003, No. 2, 173–178 ISSN 0936-5214 © Thieme Stuttgart · New York

176
M. Romero, M. D. Pujol
LETTER
(ppm) = 31.4 (CH3, NCH3), 47.5 [CH3, N(CH3)2], 103.6
(CH, C3H), 109.9 (CH, C7H), 120.3 (CH, C6H), 121.6 (CH,
C4H), 123.9 (CH, C5H), 125.8 (C, C3a), 130.5 (C, C2),
138.8 (C, C7a), 160.5 (C, C=O). MS: m/z = 218 [M+ + 1].
Anal. Calcd for C12H15N3O: C, 66.3; H, 7.0; N, 19.3%.
Found: C, 66.2; H, 6.9; N, 19.2%. 2-(N,N-
evaporator and silica gel chromatography of the crude product
(SiO2, 70–230 mesh, hexane–ethyl acetate) gave the products. Oils
were isolated directly by column chromatography, and solids were
purified by column chromatography, followed by recrystallization
(hexane–ethyl acetate). The yields of the pure compounds are indi-
cated on the Table 1.
Dimethylhydrazinecarbonyl)-1-methyl-3-(4-methoxy-
phenylcarbonyl)indole (7): Mp: 129–132 ºC (hexane–ethyl
acetate 3:7). IR (KBr): ν (cm–1) = 3196 (N-H), 1674
General Procedure for the Oxidation and Cyclization (17–26).15
A 50 mL, 1 necked flask, provided with a septum and argon inlet
and outlet, and a stirrer was charged with a solution of the hydroxy-
hydrazide (1 mmol) in dry CH2Cl2 (10 mL). The solution was stirred
vigorously, and then, activated MnO2 (10 mmol) and glacial acetic
acid (10 mmol) were added sequentially. After stirring for 8 h at r.t.
H2O was added. The reaction mixture was filtered and the solution
obtained was further diluted with H2O (10 mL) and CH2Cl2 (10
mL). The organic layer was separated and washed with H2O and
NaHCO3 solution, dried over Na2SO4 and concentrated. The prod-
ucts were purified by column chromatrography (SiO2, 70–230
mesh) using hexane–ethyl acetate as eluant. The yields of the pre-
pared compounds are indicated in the Table 2.
(ArCOAr), 1610 [CONHN(CH3)2]. 1H NMR (CDCl3, 200
MHz): δ (ppm) = 2.49 [s, 6 H, N(CH3)2], 3.53 (s, 3 H,
NCH3), 3.87 (s, 3 H, OCH3), 6.97 (d, J = 8.8, 2 H, C3′H, and
C5′H), 7.01–7.30 (m, 3 H, H-4, H-5, H-6), 7.49 (d, J = 8, 1
H, H-7), 7.80 (d, J = 8.8, 2 H, H-2′ and H-6′), 9.97 (br s, 1 H,
NH). 13C NMR (CDCl3, 50.3 MHz): δ (ppm): 31.2 (CH3,
NCH3), 46.5 [CH3, N(CH3)2], 55.4 (CH3, OCH3), 109.9 (CH,
C7H), 113.6 (CH, C3′H and C5′H), 121.3 (C, C2), 121.0,
121.3 and 123.4 (CH, C4H, C5H and C6H), 125.3 (C, C3),
131.8 (CH, C2′H and C6′H), 132.5 (C, C3a), 136.2 (C, C7a
and C1′), 159.0 (C, C4′), 163.4 [C, CONHN(CH3)2], 190.8
(C, C=O). MS: m/z = 352 [M+ + 1]. Anal. Calcd for
C20H21N3O3: C, 68.4; H, 6.0; N, 12.0%. Found: C, 68.5; H,
5.7; N, 12.1%. 2-(N,N-Dimethylhydrazinecarbonyl)-1-
methyl-3-trimethyl-silylindole (11): Mp: 148–149 ºC
(hexane–ethyl acetate 4:6). IR (KBr): ν (cm–1) = 3181 (N-
H), 1650 (C=O). 1H NMR (CDCl3, 200 MHz): δ (ppm) =
0.07 [s, 9 H, Si(CH3)3], 2.36 [s, 6 H, N(CH3)2], 3.35 (s, 3 H,
NCH3), 6.66 (br s, 1 H, NH), 6.70–6.96 (m, 3 H, H-4, H-5,
H-6), 7.41 (d, J = 7.8, 1 H, H-7). 13C NMR (CDCl3, 50.3
MHz): δ (ppm) = 0.73 [CH3, Si(CH3)3], 30.4 (CH3, NCH3),
46.9 [CH3, N(CH3)2], 109.6 (CH, C7H), 119.8 (CH, C6H),
121.9 (C, C3), 122.4 and 122.6 (CH, C4H and C5H), 131.8
(C, C2), 137.8 (C, C3a), 139.0 (C, C7a), 162.3 (C, C=O).
MS: m/z = 290 [M+ + 1]. Anal. Calcd for C15H23N3OSi: C,
62.2; H, 8.0; N, 14.5%. Found: C, 62.0; H, 7.7; N, 14.4%.
1,3-Dimethyl-2-(N,N-dimethylhydrazinecarbonyl)indole
(12): Mp: 161–163 ºC (hexane–ethyl acetate 2:8). IR (KBr):
ν (cm–1): 3242 (N-H), 1651 (C=O). 1H NMR (CDCl3, 200
MHz): δ (ppm) = 2,43 (2, 3 H, C3-CH3), 2.73 [s, 6 H,
N(CH3)2], 3.80 (s, 3 H, NCH3), 6.71–6.79 (br s, 1 H, NH),
7.07–7.39 (m, 3 H, H-4, H-5, H-6), 7.56 (d, J = 8, 1 H, H-7).
13C NMR (CDCl3, 50.3 MHz): δ (ppm) = 10.1 (CH3, C3-
CH3), 31.0 (CH3, NCH3), 47.7 [CH3, N(CH3)2], 109.6 (CH,
C7H),), 111.8 (C, C3), 119.4 (CH, C6H), 119.8 (CH, C4H),
123.8 (CH, C5H), 127.0 (C, C3a), 128.9 (C, C2), 137.7 (C,
C7a), 160.8 (C, C=O). MS: m/z = 232 [M+ + 1]. Anal. Calcd
for C13H17N3O: C, 67.5; H, 7.4; N, 18.2%. Found: C, 67.4;
H, 7.6; N, 18.3%. 3-Ethyl-2-(N,N-dimethylhydrazine-
carbonyl)-1-methylindole (13): Mp: 146–149 ºC (hexane–
ethyl acetate 2:8). IR (KBr): ν (cm–1) = 3202 (N-H), 1651
(C=O). 1H NMR (CDCl3, 200 MHz): δ (ppm) = 1.32 (t,
J = 7.6, 3 H, CH2CH3), 2.76 [s, 6 H, N(CH3)2], 2.93 (q,
J = 7.6, 2 H, CH2CH3), 3.85 (s, 3 H, NCH3), 6.58–6.60 (br s,
1 H, NH), 7.05–7.37 (m, 3 H, H-4, H-5, H-6), 7.63 (d,
J = 8.2, 1 H, H-7). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) =
16.1 (CH3, CH2CH3), 18.3 (CH2, CH2CH3), 31.0 (CH3,
NCH3), 47.6 [CH3, N(CH3)2], 109.7 (CH, C7H), 111.8 (C,
C3), 119.4 (CH, C6H), 119.9 (CH, C4H), 123.7 (CH, C5H),
126.1 (C, C3a), 128.5 (C, C2), 137.7 (C, C7a), 160.9 (C,
C=O). MS: m/z = 246 [M+ + 1]. Anal. Calcd for C14H19N3O:
C, 68.5; H, 7.8; N, 17.1. Found: C, 68.4; H, 7.6; N, 17.3.
3-(2-Carboxyethyl-1-carbonyl)-2-(N,N-dimethylhydra-
zinecarbonyl)-1-methylindole (14): Mp: 120–123 ºC (ethyl
acetate–methanol 9:1). IR (KBr): ν (cm–1): 3483 (O-H),
3201 (N-H), 1725 (C=O), 1649 (C=O, CONHNMe2). 1H
NMR (CDCl3, 200 MHz): δ (ppm) = 2.74 (t, J = 5.6, 2 H,
CH2CO2H), 2.83 [s, 6 H, N(CH3)2], 3.20 (t, J = 5.6, 2 H,
Ackowledgment
The authors express their gratitude to 01-SGR-00085 (Generalitat
de Catalunya, Spain).
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(14) The analytical data of 25 are identical to the analytical data
of the commercial carboxylic acid purchased from Sigma-
Aldrich Co.
(15) Analytical data of some representative synthesized
compounds: 2-(N,N-Dimethylhydrazinecarbonyl)-1-
methylindole (1): Mp: 168–170 ºC (hexane–ethyl acetate
2:8). IR (KBr): ν (cm–1) = 3218 (N-H), 1648
[CONHN(CH3)2]. 1H NMR (CDCl3, 200 MHz): δ (ppm) =
2.71 [s, 6 H, N(CH3)2], 4.01 (s, 3 H, NCH3), 6.81 (br s, 1 H,
NH), 7.08–7.39 (m, 3 H, H-4, H-5, H-6), 7.35 (s, 1 H, C3H),
7.61 (d, J = 7, 1 H, H-7). 13C NMR (CDCl3, 50.3 MHz): δ
Synlett 2003, No. 2, 173–178 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
CH2CO), 3.66 (s, 3 H, NCH3), 7.05–7.39 (m, 4 H, H-4, H-5,
Efficient Preparation of Tricyclic Lactones
177
(hexane–ethyl acetate 9:1). IR (KBr): ν (cm–1) = 2963 (C-H),
1749 (C=O). 1H NMR (CDCl3, 200 MHz): δ (ppm) = 1.11 [s,
9 H, C(CH3)3], 3.97 (s, 3 H, NCH3), 5.26 (s, 1 H, H-1), 7.21–
7.28 (m, 1 H, H-7), 7.39–7.45 (m, 2 H, H-6, H-8), 7.68 (d,
J = 8, 1 H, H-5). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) =
25.5 [CH3, C(CH3)3], 30.0 (CH3, NCH3), 35.4 [C, C(CH3)3],
87.6 (CH, C1H), 111.2 (CH, C5H), 120.8 (C, C8b), 120.9
and 122.2 (CH, C6H and C8H), 125.9 (CH, C6H), 129.9 (C,
C3a), 134.7 (C, C8a), 144.0 (C, C4a), 163.6 (C, C=O). MS:
m/z = 244 [M+ + 1]. Anal. Calcd for C15H17NO2: C, 74.0; H,
7.0; N, 5.8. Found: C, 74.3; H, 6.9; N, 5.8. 1-Benzyl-
oxymethyl-4-methyl-3-oxo-(1H)-furo[3,4-b]indole (20):
Mp: 116–118 ºC (hexane–ethyl acetate 9:1). IR (KBr): ν
(cm–1) = 2932 (C-H), 1748 (C=O). 1H NMR (CDCl3, 200
MHz): δ (ppm) = 3.90 (d, J = 6, 2 H, CH2O), 3.91 (s, 3 H,
NCH3), 4.65 (s, 2 H, CH2O), 5.70 (q, J = 6, 1 H, C1H), 7.24
(m, 1 H, Ar), 7.42 (m, 5 H, Ar), 7.46 (m, 2 H, Ar), 7.64 (d,
J = 8, 1 H, H-5). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) =
30.0 (CH3, NCH3), 71.4 (CH2, CH2O), 73.8 (CH2, CH2O),
77.8 (CH, C1H), 111.1 (CH, C5H), 120.4 (C, C8b), 121.0
and 121.6 (CH, C6H and C8H), 126.0 (CH, C4′H), 127.6
(CH, C7H), 127.7 (CH, C2′H and C6′H), 128.3 (CH, C3′H
and C5′H), 128.9 (C, C3a), 134.7 (C, C8a), 137.3 (C, C1′),
144.0 (C, C4a), 162.9 (C, C=O). MS: m/z = 308 [M+ + 1].
Anal. Calcd for C19H17NO3: C, 74.3; H, 5.6; N, 4.6. Found:
C, 74.0; H, 5.7; N, 4.4. 1-(3′-(Trifluoromethane)phenyl)-
4-methyl-3-oxo-(1H)-furo[3,4-b]indole (21): Hexane–
ethyl acetate 8:2. IR (NaCl): ν (cm–1) = 2919 (C-H), 1759
(C=O), 1331 (C-F). 1H NMR (CDCl3, 200 MHz): δ (ppm) =
4.02 (s, 3 H, NCH3), 6.59 (s, 1 H, H-1), 7.19–7.60 (m, 6 H,
H-4′, H-5′, H-6′, H-6, H-7, H-8), 7.64 (d, J = 7, 1 H, H-5),
7.71 (s, 1 H, H-2′). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) =
30.0 (CH3, NCH3), 79.2 (CH, C1H), 111.5 (CH, C5H), 120.2
(C, C8b), 120.8 and 121.5 (CH, C6H and C8H), 125.6 (C,
J = 288, CF3), 125.9 (CH, J = 3.6, C4′H), 126.4 (CH, C7H),
128.5 (CH, J = 3.6, C2′H), 128.9 (C, C3a), 129.4 (CH,
C5′H), 130.3 (CH, C6′H), 130.6 (C, J = 32, C3′), 131.9 (C,
J = 1, C1′), 141.0 (C, C8a), 144.4 (C, C4a), 162.7 (C, C=O).
MS: m/z = 332 [M+ + 1]. Anal. Calcd for C18H12F3NO2: C,
65.3; H, 3.7; N, 4.2. Found: C, 65.5; H, 3.9; N, 4.4. 4′-
Methyl-3-oxo-(1H)spiro{cyclo-hexyl[1,1′]furo[3,4-
b]indole} (22): Mp: 152–154 ºC (hexane–ethyl acetate 9:1).
IR (KBr): ν (cm–1): 2921 (C-H), 1749 (C=O). 1H NMR
(CDCl3, 200 MHz): δ (ppm) = 1.50–2.08 (m, 10 H, CH2),
3.93 (s, 3 H, NCH3), 7.18–7.27 (m, 1 H, H-7), 7.39–7.44 (m,
2 H, H-6, H-8), 7.68 (d, J = 8, 1 H, H-5). 13C NMR (CDCl3,
50.3 MHz):
H-6, CO2H), 7.89 (d, J = 8, 1 H, H-7), 8.43 (br s, 1 H, NH).
13C NMR (CDCl3, 50.3 MHz): δ (ppm) = 28.5 (CH2,
CH2CO), 31.4 (CH3, NCH3), 36.5 (CH2, CH2CO2H), 46.7
[CH3, N(CH3)2], 110.5 (CH, C7H), 115.0 (C, C3), 121.3
(CH, C6H), 121.4 (CH, C4H), 124.1 (CH, C5H), 121.3 (C,
C2), 124.3 (C, C3a), 136.6 (C, C7a), 160.6 (C,
CONHNMe2), 177.1 (C, CO2H), 195.5 (C, C=O). MS: m/z =
318 [M+ + 1]. Anal. Calcd for C16H19N3O4: C, 60.6; H, 6.0;
N, 13.2. Found: C, 60.3; H, 6.2; N, 13.2. 3-
(Allyloxycarbonyl)-2-(N,N-dimethylhydrazine-
carbonyl)indole (15): Hexane–ethyl acetate 2:8. IR (NaCl):
ν (cm–1) = 3200 (N-H), 1693 (COOR), 1670
[CONHN(CH3)2]. 1H NMR (CDCl3, 200 MHz): δ (ppm) =
2.77 [s, 6 H, N(CH3)2], 4.01 (s, 3 H, NCH3), 4.89 (d, J = 6, 2
H, CH2O), 5.37 (m, 2 H, CH2=CH), 6.10 (m, 1 H, CH2=CH),
6.80 (br s, 1 H, NH), 7.32 (m, 3 H, H-4, H-5, H-6), 8.15 (d,
J = 7, 1 H, H-7). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) =
32.4 (CH3, NCH3), 47.3 [CH3, N(CH3)2], 65.5 (CH2, CH2O),
113.3 (CH, C7H), 118.6 (CH2, CH2=CH), 121.2 (C, C3),
122.8 (CH, C6H), 122.9 (CH, C4H), 124.4 (CH, C5H),
125.3 (C, C2), 132.1 (CH, CH2=CH), 136.8 (C, C7a), 137.2
(C, C3a), 159.6 (C, COO-), 165.8 (C, CON-). MS: m/z = 302
[M+ + 1]. Anal. Calcd for C16H19N3O3: C, 63.8; H, 6.4; N,
13.9. Found: C, 63.5; H, 6.7; N, 13.8. 3-(t-Butylcarbonyl)-
2-(N,N-dimethylhydrazinecarbonyl)-1-methylindole
(16): Mp: 149–150 ºC (hexane–ethyl acetate 3:7). IR (KBr):
ν (cm–1) = 3226 (N-H), 1662 (C=O, CONHNMe2). 1H NMR
(CDCl3, 200 MHz): δ (ppm) = 1.28 [s, 9 H, C(CH3)3], 2.67
[s, 6 H, N(CH3)2], 3.93 (s, 3 H, NCH3), 7.05–7.38 (m, 3 H,
H-4, H-5, H-6), 7.51 (d, J = 8, 1 H, H-7), 7.52 (br s, 1 H,
NH). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) = 27.1 [CH3,
C(CH3)3], 31.3 (CH3, NCH3), 45.9 [C, C(CH3)3], 47.5 [CH3,
N(CH3)2], 110.2 (CH, C7H), 116.8 (C, C3), 121.0 (CH,
C6H), 121.4 (CH, C4H), 124.1 (CH, C5H), 124.2 (C, C3a),
129.6 (C, C2), 136.7 (C, C7a), 159.7 (C, CONHNMe2),
213.7 (C, C=O). MS: m/z = 302 [M+ + 1]. Anal. Calcd for
C17H23N3O2: C, 67.7; H, 7.7; N, 13.9. Found: C, 67.5; H, 7.9;
N, 13.6. 1,4-Dimethyl-3-oxo-(1H)-furo[3,4-b]indole (17):
Mp: 84–85 ºC (hexane–ethyl acetate 8:2). IR (KBr): ν
(cm–1) = 2932 (C-H), 1751 (C=O). 1H NMR (CDCl3, 200
MHz): δ (ppm) = 1.70 (d, J = 6.6, 3 H, CHCH3), 3.91 (s, 3
H, NCH3), 5.64 (q, J = 6.6, 1 H, CHCH3), 7.20–7.27 (m, 1 H,
H-7), 7.41–7.60 (m, 2 H, H-6, H-8), 7.61 (d, J = 8, 1 H, H-
5). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) = 20.7 (CH3,
CHCH3), 30.0 (CH3, NCH3), 75.4 (CH, CHCH3), 111.2 (CH,
C5H), 119.8 (C, C8b), 120.6 and 120.8 (CH, C6H and C8H),
125.9 (CH, C7H), 128.5 (C, C3a), 138.2 (C, C8a), 143.9 (C,
C4a), 163.2 (C, C=O). MS: m/z = 202 [M+ + 1]. Anal. Calcd
for C12H11NO2: C, 71.6; H, 5.5; N, 7.0. Found: C, 71.5; H,
5.7; N, 6.8. 1-Hexyl-4-methyl-3-oxo-(1H)-furo[3,4-
b]indole (18): Hexane–ethyl acetate 9:1. IR (NaCl): ν
(cm–1) = 2928 (C-H), 1752 (C=O). 1H NMR (CDCl3, 200
MHz): δ (ppm) = 0.91 [d, J = 6, 3 H, (CH2)5CH3], 1.21–1.63
[m, 8 H, CH2(CH2)4CH3], 1.82–2.10 [m, 2 H,
δ (ppm) = 22.5 (CH2, C3′H and C5′H), 24.6 (CH2, C4′H),
30.0 (CH3, NCH3), 36.7 (CH2, C2′H and C6′H), 86.0 (C,
C1), 111.2 (CH, C5H), 119.8 (C, C8b), 120.7 and 121.1
(CH, C6H and C8H), 125.7 (CH, C7H), 128.2 (C, C3a),
138.2 (C, C8a), 143.9 (C, C4a), 163.2 (C, C=O). MS: m/z =
256 [M+ + 1]. Anal. Calcd for C16H17NO2: C, 75.3; H, 6.7;
N, 5.5. Found: C, 75.2%, H, 6.9; N, 5.2. 1′-Benzyl-4-
methyl-3-oxo-(1H)-spiro{furo[3,4-b]indole-1,4′-
CH2(CH2)4CH3], 3.94 (s, 3 H, NCH3), 5.58 (q, J = 6, 1 H,
C1H), 7.23–7.46 (m, 3 H, H-6, H-7, H-8), 7.62 (d, J = 8, 1
H, H-5). 13C NMR (CDCl3, 50.3 MHz): δ (ppm) = 14.0
[CH3, (CH2)5CH3], 22.5 [CH2, (CH2)5CH3], 24.8 [CH2,
(CH2)5CH3], 29.0 [CH2, (CH2)5CH3], 30.0 (CH3, NCH3),
31.6 [CH2, (CH2)5CH3], 34.6 [CH2, (CH2)5CH3], 79.4 (CH,
C1H), 111.2 (CH, C5H), 120.1 (C, C8b), 120.8 and 121.0
(CH, C6H and C8H), 125.8 (CH, C7H), 128.8 (C, C3a),
137.0 (C, C8a), 144.0 (C, C4a), 163.4 (C, C=O). MS: m/z =
272 [M+ + 1]. Anal. Calcd for C17H21NO2: C, 75.2; H, 7.8;
N, 5.2. Found: C, 75.1; H, 7.7; N, 4.9. 1-t-Butyl-4-methyl-
3-oxo-(1H)-furo[3,4-b]indole (19): Mp: 171–173 ºC
piperidine} (23): Hexane–ethyl acetate 8:2. IR (NaCl): ν
(cm–1) = 1755 (C=O). 1H NMR (CDCl3, 200 MHz): δ (ppm)
= 1.87 (d, J = 12.8, 2 H, Hax-3′ and Hax-5′), 2.47 (dt,
J = 11.8, J′ = 4.4, 2 H, Heq-3′ and Heq-5′), 2.70 (dt, J = 11.6,
J′ = 2, 2 H, Hax-2′ and Hax-6′), 3.01 (d, J = 11.2, 2 H, Heq-2′
and Heq-6′), 3.74 (s, 2 H, CH2Ar), 3.92 (s, 3 H, NCH3), 7.11–
7.42 (m, 8 H, H-6, H-7, H-8, H-2′′, H-3′′, H-4′′, H-5′′ and H-
6′′), 7.63 (d, J = 8, 1 H, H-5). 13C NMR (CDCl3, 50.3 MHz):
δ (ppm) = 30.1 (CH3, NCH3), 35.7 (CH2, C3′ and C5′), 49.2
(CH2, C2′ and C6′), 62.5 (CH2, CH2Ar), 82.9 (C, C1), 111.2
(CH, C5H), 119.6 (C, C8b), 120.8 and 121.0 (CH, C6H and
C8H), 126.0 (CH, C7H), 127.5 (CH, C4′′H), 128.1 (C, C3a),
Synlett 2003, No. 2, 173–178 ISSN 0936-5214 © Thieme Stuttgart · New York

178
M. Romero, M. D. Pujol
LETTER
128.3 (CH, C2′′H and C6′′H), 129.6 (CH, C3′′H and C5′′H),
136.4 (C, C1′′), 140.4 (C, C8a), 143.9 (C, C4a), 162.5 (C,
C=O). MS: m/z = 347 [M+ + 1]. Anal. Calcd for C22H22N2O2:
C, 76.3; H, 6.4; N, 8.1. Found: C, 76.1; H, 6.6; N, 8.3. 1-
(Cynnamyl)-2-(N,N-dimethylamino)-4-methyl-3-oxo-
(1H)-pirrolo[3,4-b]indole (24): Mp: 170–172 ºC (hexane–
ethyl acetate 7:3). IR (KBr): ν (cm–1): 2925 (C-H), 1682
(C=O). 1H NMR (CDCl3, 200 MHz): δ (ppm): 3.01 [s, 6 H,
N(CH3)2], 4.00 (s, 3 H, NCH3), 5.19 (d, J = 8.4, 1 H, H-1),
6.13 (dd, J = 15.7, J′ = 8.2, 1 H, CHCHAr), 6.79 (d,
C1′), 141.9 (C, C4a), 162.5 (C, C=O). MS: m/z = 332 [M+ +
1]. Anal. Calcd for C21H21N3O: C, 76.1; H, 6.4; N, 12.7.
Found: C, 76.2; H, 6.7; N, 12.5. 1-Methyl-3-(4-
methoxyphenylcarbonyl)indole-2-yl-carboxylic acid
(26): Mp: 124–126 ºC (hexane–ethyl acetate, 7:3). IR (KBr):
ν (cm–1): 2959 (O-H), 1715 (C=O). 1H NMR (CDCl3, 200
MHz): δ (ppm) = 3.93 (s, 3 H, NCH3), 4.25 (s, 3 H, OCH3),
6.98 (d, J = 8.8, 2 H, C3′H, and C5′H), 7.03–7.45 (m, 4 H,
H-4, H-5, H-6, CO2H), 7.54 (d, J = 8.4, 1 H, H-7), 7.84 (d,
J = 8.8, 2 H, H-2′ and H-6′). 13C NMR (CDCl3, 50.3 MHz):
δ (ppm) = 33.0 (CH3, NCH3), 55.6 (CH3, OCH3), 111.0 (CH,
C7H), 113.7 (CH, C3′H and C5′H), 116.8 (C, C2), 122.6,
122.8 and 125.6 (CH, C4H, C5H and C6H), 125.8 (C, C3),
131.0 (C, C1′), 132.7 (CH, C2′H and C6′H), 133.2 (C, C3a),
137.5 (C, C7a), 161.4 (C, C4′), 164.1 (C, CO2H), 194.6 (C,
C=O). MS: m/z = 310 [M+ + 1]. Anal. Calcd for C18H15NO4:
C, 69.9; H, 4.9; N, 4.5. Found: C, 69.7; H, 5.2; N, 4.2.
J = 15.6, 1 H, CHCHAr), 7.10–7.45 (m, 8 H, H-2′, H-3′, H-
4′, H-5′, H-6′, H-6, H-7, H-8), 7.56 (d, J = 8, 1 H, H-5). 13
NMR (CDCl3, 50.3 MHz): δ (ppm) = 30.2 (CH3, NCH3),
45.0 [CH3, N(CH3)2], 60.6 (CH, C1H), 110.1 (CH, C8H),
C
120.0 (CH, C5H), 120.5 (CH, C6H), 121.7 (C, C8b), 124.2
(CH, C7H), 124.6 (C, C8a), 126.3 (CH, CHCHAr), 126.6
(CH, C3′H and C5′H), 128.0 (CH, C4′H), 128.6 (CH, C2′H
and C6′H), 132.5 (C, C3a), 133.9 (CH, CHCHAr), 136.3 (C,
Synlett 2003, No. 2, 173–178 ISSN 0936-5214 © Thieme Stuttgart · New York