Reactions of substituted 2,3-dihydro-1H-indol-3-ones and pyrrolo[2,3-b]pyridin-3-ones with Wittig and Horner-Emmons reagents: Synthesis of 7-azatryptamine

Article abstract of DOI:10.1016/S0040-4020(01)00047-3

The reactivity of indolinone 1 towards Wittig and Horner-Emmons reactions was reported; the influence of the nature of substituent on the nitrogen atom was examined. 7-Azaindolinone 2 reacted with diethyl cyanomethanephosphonate for giving the corresponding (7-azaindol-3-yl)acetonitrile or more unexpectedly, a C-2 alkylated product; this behavior has been extended to another nucleophilic reagent. Finally the synthesis of 7-azatryptamine was reported.

Full text of DOI:10.1016/S0040-4020(01)00047-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1995±2002
Reactions of substituted 2,3-dihydro-1H-indol-3-ones and
pyrrolo[2,3-b]pyridin-3-ones with Wittig and Horner±Emmons
reagents: synthesis of 7-azatryptamine
p
Â
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Jean-Yves Merour, Philippe Gadonneix, Beatrice Malapel-Andrieu and Eric Desarbre
   Â
Institut de Chimie Organique et Analytique associe au CNRS, BP 6759, Universite d'Orleans, 45067 Orleans Cedex 2, France
Received 29 September 2000; revised 15 December 2000; accepted 12 January 2001
AbstractÐThe reactivity of indolinone 1 towards Wittig and Horner±Emmons reactions was reported; the in¯uence of the nature of
substituent on the nitrogen atom was examined. 7-Azaindolinone 2 reacted with diethyl cyanomethanephosphonate for giving the corre-
sponding (7-azaindol-3-yl)acetonitrile or more unexpectedly, a C-2 alkylated product; this behavior has been extended to another nucleo-
philic reagent. Finally the synthesis of 7-azatryptamine was reported. q 2001 Elsevier Science Ltd. All rights reserved.
For many years now, our interest of the behavior of the 2,3-
dihydro-1H-indol-3-one 11 (Fig. 1) is driven by different
aspects of the molecule. This framework is not only found
in different natural products like Austamide2 or Brevi-
anamide,3 but 1 has also been used as synthon for the
preparation of biological compounds4 such as trypta-
mine,5±7 d-carboline8 and cryptoline.9 In framework 1, the
carbonyl in 3-position possesses different properties
depending on the nature of substituents in 1, 2 and 5-posi-
tion. This paper summarizes the new results we have
recently obtained on 7-azaindolinone 210±13 (pyrrolo[2,3-b]-
pyridin-3-one), after we have tried to complete the tre-
mendous work already described by Sakamoto and his
coworkers on the behavior of 1 in Wittig reaction,14±16
Claisen rearrangement,17,18or Michael addition.19
To start with, we have considered the nature of the sub-
stituent on the nitrogen atom in 1-position and the substi-
tution in 2-position of indolinone 1 in the Wittig reactions
with stabilized ylide, ethoxycarbonylmethylenetriphenyl-
phosphorane (Chart 1).
Table 1, where we gather Sakamoto14,15 and own results
highlights, once again gives the great importance of the
substituents in 1- and 2-position.
Upon reaction with ethoxycarbonylmethylenetriphenyl-
phosphorane (2 equiv.) in re¯uxing toluene, indolinone 1
afforded either the a,b-ethylenic ester 3 or the ethyl indole-
acetate 4. If the nitrogen atom of 1 is protected with an
acetyl group (1a±f) we generated compounds 3b±d, with
the exception for the 2-unsubstituted indolinone 1a and the
2-benzylsubstituted indolinone 1e which gave respectively,
Figure 1.
Chart 1.
Keywords: 2,3-dihydro-1H-indol-3-one; pyrrolo[2,3-b]pyridin-3-one; Horner±Emmons reactions; 7-azatryptamine.
Corresponding author. Tel.: 133-2-3849-4592; fax: 133-2-3841-7281; e-mail: jean-yves.merour@univ-orleans.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00047-3

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J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
1996
Table 1.
Compound
R1
R2
R5
Compound
Yield (%)
Compound
Yield (%)
86
1a
1b
1c
1d
1e
1f
Ac
Ac
Ac
Ac
Ac
Ac
H
CH3
C6H5
4-CH3Bn
Bn
OCH3
H
4-CH3Bn
H
H
H
4aa
3b
3c
3d
72
75
72
OCH3
H
4e15
86b
H
H
H
3f14
3h
99b
0
1g
1h
SO2C6H5
SO2C6H5
4g
4h
32
0
BnˆBenzyl
a
Methyl ester of 4a was also described by Sakamoto.15
4e in re¯uxing toluene and 3f were obtained by Sakamoto14 as methyl ester, in re¯uxing benzene.
b
the ethyl indoleacetates 4a or 4e.15 Formation of 4e was
The relative inertness of 1-acetyl-2-methoxy-2-benzyl-1H-
indol-3-one 1f towards Wittig reagents has already been
reported;14 nevertheless, spiroindolinones 6 and 7 (single
diastereomers), obtained from the oxidation of pyrano-
[2,3-b]indole,12 cleanly reacted with the ethoxycarbonyl-
methylenephosphorane to give the ethylenic esters 8 and
9, respectively, in 60 and 94% yield, as a E/Z mixture
(ratio 4:7 for 8, 7:3 for 9) (Chart 2).
explained by isomerization of 3e to the more stable structure
4e. Compounds 3 were obtained as Z isomers predominantly
due to the steric demand of the transition states to form the
oxaphosphetane.14
Using the allyl substituted ylide, ([(C6H5)3]PvC-
(CH2CHvCH2)COOC2H5), with the more reactive indoli-
none 1a afforded only decomposition of the mixture, after
extending heating in toluene; no Cope rearrangement was
observed.
Figure 2.
The reactivity of the carbonyl group of indolinone 1 is
obviously dependant on the substituent of the nitrogen
atom; the phenylsulfonyl group decreased the reactivity of
indolinone 1 towards Wittig reagent. The electron with-
drawing effect of this substituent might stabilize the enol
form of 1 compared to the acetyl group.
The protection of the nitrogen atom with a sulfonyl group
dramatically modi®es the reactivity; so compound 1g
afforded only in 32% yield the indolic compound 4g; the
2-substituted indolinone 1h, obtained by catalytic hydroge-
nation of 2-[(1-(4-methylphenyl)methylidene]-1-phenyl-
sulfonyl-1H-indol-3-one, did not give condensation
product but rather, the formation of the desulfonylated
a,b-ethylenic ketone 520 in 64% yield (Fig. 2).
These studies should be compared with our previous works
to synthetize tryptamine derivatives.5±7 If diethyl cyano-
methanephosphonate was used to perform Horner±Emmons
Chart 2.
Figure 3.

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J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
1997
Chart 3.
Table 2.
Compound
R1
R2
R5
Compound
Yield (%)
Compound
Yield (%)
2a
2b
2c
2d
2e
Ac
H
H
H
H
H
H
Br
14a
14b
14c
14d
14e
0
0
0
69
55
15a
15b
15c
15d
15e
25
60
0
0
0
SO2C6H5
SO2C6H5
COt-Bu
COt-Bu
4-CH3OBn
OCH3
OCH3
reaction in the presence of indolinone 1a, a mixture of a,b-
ethylenic nitriles 10, 11 and indolacetonitrile 12a has been
isolated. The a,b-ethylenic nitriles 10 and 11 were always
the minor isomers and could be quickly isomerized in basic
medium into compound 12a (Fig. 3). Indolinone 1c gave
exclusively the indolic structures 12c and 13c in a ratio
62:38 (Among all the indolinones 1 used, only 1c gave
the acetylated indolic product 13c).
2c did not afforded neither 14c nor 15c, but rather the unex-
pected compound 17 (Chart 4).
The catalytic hydrogenation conditions over palladium,
usually used in the indolinone series, for preparing the
2-benzylindolinones 1d and e from the corresponding a,b-
ethylenic ketone6,7 were unfruitful in the 7-azaindolinone
series. Therefore, 2c was prepared in 72% yield by ionic
reduction (triethylsilane/tri¯uoroacetic acid) of the double
bond of compound 1610,11 (Chart 4).
In order to prepare more tryptamine derivatives, 7-azaindo-
linone 2 has been considered to be an excellent synthon; we
started this program few years ago considering the rather
poor investigation21±25 done on this moiety, despite the
biological potential of 7-azaindoles: NADH models,26
mimics of adenosine base27 and dopaminergic ligands.28
The diethyl cyanomethanephosphonate anion did not react
with the keto group in 3-position of the 7-azaindolinone 2c
as indicated supra but afforded unexpectedly, the 7-aza-
indolinone 17 (76% yield) substituted in 2-position, as a
result of the alkylation of the methylene group of the diethyl
cyanomethanephosphonate. Compound 17 was obtained as
a mixture of diastereomers in the ratio 47:53.
We discovered that the 7-azaindolinones 2a±e behaved
differently in the presence of phosphonate derivatives
compared to the indole counterparts (Chart 3); the unsub-
stituted azaindolinones in 2-position, 2a and b, afforded the
7-azaindoleacetonitriles 15a and b in 25 and 60% yield,
respectively; but if a pivaloyl group is used as a protecting
group on the nitrogen atom, the ketones 2d and e afforded
the ethylenic nitriles 14d and e in 69 and 55% yield (Table
2).
The formation of 17 can be explained as shown in Chart 5;
®rst a desulfonylation reaction in basic medium which
generates an imine intermediate (A), then followed by an
addition of the nucleophilic phosphonate on the C-2 carbon
atom. The spectroscopic data of 17 were compatible with
1
the presence of a carbonyl and a cyano group; in the H
NMR spectrum, a coupling constant of 22.8 Hz (JP±CH) indi-
cates a connection P±CH±CN. The molecular peak in mass
spectra is observed at 429.
Compounds 14d and e were obtained as a mixture of E/Z
isomers in ratio 50:50 and 42:58, respectively. Compound
14d heated in toluene in the presence of a catalytic amount
of sodium hydroxide gave the isomeric compound 15d; but
puri®cation of 15d on a silica gel column gave back 14d, so
compound 15d was only obtained as trace amount. The
1-sulfonyl-2-[(4-methoxyphenyl)methyl]-7-azaindolinone
In order to check this hypothesis of a nucleophilic attack on
the C-2 carbon atom of 2c, we reacted the dimethyl
malonate anion with 2c; the substituted malonate 18 was
obtained (Fig. 4) in 94% yield, as the result of a nucleophilic
Chart 4.

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J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
1998
Chart 5.
attack on the C-2 carbon atom. The structure of 18 is in
agreement inter alia with its 13C NMR spectrum: a quater-
nary carbon atom C2 at 68.4 ppm, a CH at 57.1 ppm, two
CO at 166.2 and 168.2 ppm and ®nally a CO at 199.3 ppm;
the molecular mass is equal to 384.
In this paper, we have shown the importance of the nature of
substituents on the nitrogen and carbon C-2 atoms in indo-
linones 1 and 2 towards the reactivity with Wittig and
Horner±Emmons reagents. A different behavior was
observed between indolinone 1 and 7-azaindolinone 2,
notably in the susceptibility of nucleophilic attack on the
C-2 carbon atom.
The formation of an imine intermediate with indolic struc-
ture, postulated in Chart 5 is frequently observed.14b For
instance, we have recently described nucleophilic alkylation
in 2-position of 3-indolic tri¯ate via an iminium inter-
mediate.29,30
1. Experimental
1.1. General
We have precedently5,7 shown that the mixture of indolic
nitriles 10, 11 and 12 upon hydrogenation with Raney nickel
gave a sole tryptamine 19 (Fig. 4). The reduction of the
nitrile function of the 7-azaderivative 15b was not so easy
as for the corresponding indolic nitrile 12a. Hydrogenation
over Raney nickel afforded the desulfonylated nitrile
compound 2031 in 60% yield; the use of lithium aluminium
hydride gave a mixture of the tryptamine 21 (30%) and
starting material 15b (35%). Using Adams' catalyst (PtO2)
in hydrogenation, at atmospheric pressure, in ethanol/THF
afforded the desired 7-azatryptamine 2132 in 51% yield
(Chart 6).
1H and 13C NMR spectra were obtained with a BruÈker
instrument Avance DPX250 (250 MHz); for samples in
CDCl3 solution with TMS as internal standard, chemical
shifts (d values) were reported in ppm and coupling
constants (J values) in Hz. IR were recorded as a thin ®lm
on NaCl plates for the oils and in KBr pellet for the solids on
a Perkin Elmer spectrometer FT Paragon 1000PC. Mass
spectra were recorded on a Perkin Elmer mass spectrometer
SCIEX API 300 (ion spray). Mps were measured using a
Ko¯er hot stage apparatus and are uncorrected. Flash
chromatography was performed on silica gel Merck 60,
Figure 4.
Chart 6.

Â
J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
1999
230±400 mesh). Compounds 2a,10 2b,12 2d,11 2e11 and 1610
have been previously described.
(C), 165.8 (CO), 168.8 (CO). Anal. calcd for C20H19NO3: C,
74.75; H, 5.96; N, 4.36. Found: C, 75.07; H, 6.12; N, 4.20.
1.1.1. 2-(4-Methoxyphenyl)methyl-1-phenylsulfonyl-1,2-
dihydropyrrolo[2,3-b]pyridin-3-one (2c). Under nitrogen
atmosphere, tri¯uoroacetic acid is added dropwise
(0.423 ml, 5.50 mmol) to a solution of 16 (276 mg,
0.55 mmol), triethylsilane (0.01 ml, 0.61 mmol) in
dichloroethane (10 ml) at rt. The mixture was re¯uxed for
7 h. After cooling, water (15 ml) was added and after
neutralisation, the mixture was twice extracted with
CH2Cl2 (2£10 ml); drying over MgSO4, evaporation under
vacuum and puri®cation on a silica gel column (elution
CH2Cl2) afforded 2c; m 156 mg; yield 72%. Mp 171±
1.2.3. Ethyl 2-[1-acetyl-2-(4-methylbenzyl)-5-methoxy-
2,3-dihydro-1H-3-indolyliden]acetate (3d). Yield 72%.
Oil. IR (®lm): 1705, 1670 cm21 1H NMR (CDCl3) d:
.
1.20 (3H, t, Jˆ7.2 Hz, CH3), 1.69 (3H, s, CH3), 2.23 (3H,
s, COCH3), 2.81 (1H, dd, Jˆ7.5, 13.5 Hz, CH2), 3.20 (1H,
dd, Jˆ3.5, 13.5 Hz, CH2), 3.75 (3H, s, OCH3), 4.26 (2H, q,
Jˆ7.2 Hz, OCH2), 5.75 (1H, brd, Jˆ4.1 Hz, CH), 6.16 (1H,
d, Jˆ1.7 Hz, CHˆ), 6.80±7.05 (6H, m, Harom), 8.12 (1H, d,
Jˆ8.9 Hz, Harom). 13C NMR (CDCl3) d: 14.2 (CH3), 21.0
(CH3), 22.8 (CH3), 41.3 (CH2), 55.6 (OCH3), 60.3 (OCH2),
66.2 (CH), 104.7 (CH), 106.3 (CH), 119.5 (CH), 119.8
(CH), 127.6 (C), 129.0 (2£CH), 129.8 (2£CH), 133.3(C),
136.5 (C), 139.8 (C), 156.4 (C), 157.9 (C), 166.2 (CO),
168.3 (CO). Anal. calcd for C23H25NO4: C, 72.80; H,
6.64; N, 3.69. Found: C, 72.59; H, 6.47; N, 3.83.
1
1738C (Ethanol). IR (®lm): 1710 cm21. H NMR (CDCl3)
d: 3.45 (1H, dd, Jˆ3.0, 14.0 Hz, CH2), 3.60 (1H, dd, Jˆ5.9,
14.0 Hz, CH2), 3.65 (3H, s, OCH3), 4.62 (1H, dd, Jˆ3.0,
5.9 Hz, H2), 6.61 (2H, d, Jˆ8.8 Hz, Harom), 6.93 (1H, dd,
Jˆ5.2, 7.4 Hz, H5), 7.05 (2H, d, Jˆ8.8 Hz, Harom), 7.46±
7.52 (2H, m, Harom), 7.56±7.62 (1H, m, Harom), 7.71 (1H, dd,
Jˆ2.2, 7.4 Hz, H4), 8.09 (2H, d, Jˆ7.4 Hz, Harom), 8.48 (1H,
dd, Jˆ2.2, 5.2 Hz, H6). MS (NH3) m/z: 395 (MH1). Anal.
calcd for C21H18N2O4S: C, 63.95; H, 4.60; N, 7.10. Found:
C, 64.31; H, 4.43; N, 7.27.
1.2.4. Ethyl 2-(1-phenylsulfonyl-2,3-dihydro-1H-indol-3-
yl)acetate (4g). Yield 32%. Oil. H NMR (CDCl3) d: 1.23
1
(3H, t, Jˆ7.5 Hz, CH3), 3.67 (2H, s, CH2), 4.13 (2H, q,
Jˆ7.5 Hz, OCH2), 7.20±7.51 (6H, m, Harom), 7.57 (1H, s,
CHv), 7.86±7.89 (2H, m, Harom), 7.98 (1H, d, Jˆ7.9 Hz,
Harom). 13C NMR (CDCl3) d: 14.1 (CH3), 31.0 (CH2), 61.0
(OCH2), 113.6 (CH), 115.3 (C), 119.5 (CH), 123.3 (CH),
124.6 (CH), 124.9 (CH), 126.7 (2£CH), 129.2 (2£CH),
130.4 (C), 133.7 (CH), 135.0 (C), 138.2 (C), 170.4 (CO).
Anal. calcd for C18H17NO4S: C, 62.96; H, 4.99; N, 4.08.
Found: C, 62.64; H, 4.77; N, 3.95.
1.2. Reaction of indolinones 1 with ethoxycarbonyl-
methylenetriphenylphosphorane: general procedure
A solution of indolinone 1 (2 mmol), ethoxycarbonylmethyl-
enetriphenylphosphorane (4.5 mmol) in toluene (20 ml) was
re¯uxed for 24 h. Water (20 ml) was added, the toluene
layer was decanted and the aqueous layer was twice
extracted with CH2Cl2 (2£15 ml); after drying over
MgSO4 and evaporation, the residue was chromatographed
on a silica gel column using ethyl acetate: petroleum ether
1:9 (v/v) as eluent.
1.2.5. Spiro[(3-{4-methylphenyl}-tetrahydro-5-furanone)-
2,20(ethyl{10-acetyl-20,30-dihydro-1H-30-indolyliden}acetate)]
(8). Compound 612 (65 mg. 0.194 mmol) was dissolved in
toluene (2 ml), and carbethoxymethylene triphenylphos-
phorane (236 mg, 0.679 mmol) was added; the mixture
was re¯uxed for 24 h. After evaporation, the residue was
puri®ed by silica gel column chromatography using CH2Cl2/
petroleum ether 1:1 (v/v) as eluent; two isomers E and Z
were obtained (ratio 36:64); mˆ40 mg. Yield 60%. Mp 60±
628C (mixture of isomers E and Z). IR (KBr): 1800, 1715,
1.2.1. Ethyl 2-(1-acetyl-2-methyl-2,3-dihydro-1H-3-indo-
lyliden)acetate (3b). Yield 72%. Mp 97±998C (ethanol). IR
1
(KBr): 1694, 1680 cm21. H NMR (CDCl3) d: 1.33 (3H, t,
1
Jˆ7.2 Hz, CH3), 1.52 (3H, d, Jˆ6.2 Hz, CH3), 2.35 (3H, s,
COCH3), 4.20 (2H, q, Jˆ7.2 Hz, OCH2), 5.62±5.64 (1H, m,
CH), 6.16 (1H, brs, CHv), 7.11 (1H, t, Jˆ7.8 Hz, Harom),
7.42 (1H, t, Jˆ7.8 Hz, Harom), 7.53 (1H, d, Jˆ7.8 Hz, Harom),
8.32 (d, 1H, Jˆ7.8 Hz, Harom). 13C NMR (CDCl3) d: 14.7
(CH3), 21.3 (CH3), 23.8 (CH3), 60.7 (CH2), 61.1 (CH), 106.3
(CH), 118.9 (CH), 122.0 (CH), 124.6 (CH), 126.3 (C), 133.4
(CH), 144.5 (C), 157.2 (C), 165.5 (CO), 167.4 (CO). Anal.
calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.18; H, 6.40; N, 5.59.
1670 cm21. E isomer: H NMR (CDCl3) d: 1.21 (3H, t,
Jˆ7.0 Hz, CH3), 2.15 (3H, s, CH3), 2.48 (3H, s, COCH3),
3.12 (1H, dd, Jˆ8.7, 18.2 Hz, CH2), 3.28 (1H, dd, Jˆ10.3,
18.2 Hz, CH2,), 4.09 (2H, q, Jˆ7.0 Hz, OCH2), 4.48 (1H,
dd, Jˆ8.7, 10.3 Hz, CH), 5.57 (1H, s, CHv), 6.70 (2H, d,
Jˆ8.1 Hz, Harom), 6.85 (2H, d, Jˆ8.1 Hz, Harom), 6.94 (1H, t,
Jˆ7.7 Hz, Harom), 7.28±7.37 (2H, m, Harom), 8.29 (1H, d,
Jˆ7.7 Hz, Harom). Z isomer: 1H NMR (CDCl3) d: 1.19 (3H,
t, Jˆ7.1 Hz, CH3), 2.15 (3H, s, CH3), 2.49 (3H, s, COCH3),
3.16 (1H, dd, Jˆ11.1, 17.4 Hz, CH2), 3.57 (1H, dd, Jˆ7.9,
17.4 Hz, CH2), 4.08 (2H, q, Jˆ7.1 Hz, OCH2), 4.60 (1H, dd,
Jˆ7.9, 11.1 Hz, CH), 5.96 (1H, s, CHv), 6.75 (2H, d,
Jˆ7.9 Hz, Harom), 6.79 (2H, d, Jˆ7.9 Hz, Harom), 6.98 (1H,
t, Jˆ7.7 Hz, Harom), 7.25 (1H, d, Jˆ7.7 Hz, Harom), 7.28±
7.37 (2H, m, Harom). MS (NH3) m/z: 406 (MH1).
1.2.2. Ethyl 2-(1-acetyl-2-phenyl-2,3-dihydro-1H-3-indo-
lyliden)acetate (3c). Yield 75%. Mp 111±1138C (ethanol).
IR (®lm): 1704, 1673 cm21. 1H NMR (CDCl3) d: 1.25 (3H,
t, Jˆ7.2 Hz, CH3), 2.12 (3H, s, COCH3), 4.16 (2H, m,
OCH2), 6.16 (1H, d, Jˆ1.9 Hz, CHv); 6.61 (1H, d, Jˆ
1.9 Hz, CH), 7.15±7.32 (6H, m, Harom), 7.47 (1H, t, Jˆ
7.8 Hz, Harom), 7.56 (1H, d, Jˆ7.8 Hz, Harom), 8.44 (1H, d,
Jˆ7.8 Hz, Harom). 13C NMR (CDCl3) d: 14.2 (CH3), 24.4
(COCH3), 60.2 (CH2), 66.9 (CH), 107.4 (CH), 117.8 (CH),
121.6 (CH), 124.3 (CH), 124.3 (C), 127.4 (2£CH), 128.2
(CH), 128.4 (2 CH), 133.1 (CH), 138.9 (C), 146.6 (C), 155.7
1.2.6. Spiro[(3-{4-methylphenyl}-5-ethoxytetrahydro-
furane)-2,20(ethyl{10-acetyl-20,30-dihydro-1H-30-indolyl-
iden}acetate)] (9). Similarly obtained as for 8 starting from
compound 7. Two isomers E and Z were obtained (ratio
7:3). Yield 94%. Mp 126±1288C (mixture of isomers E
1
and Z). IR (KBr): 1710, 1670 cm21. E isomer: H RMN

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J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
2000
(CDCl3) d: 1.16±1.32 (6H, m, COOCH2CH3 and
OCH2CH3), 2.04 (3H, s, CH3), 2.18 (1H, dd, Jˆ7.0,
13.8 Hz, CH2), 2.63 (3H, s, COCH3), 2.91 (1H, ddd, Jˆ
6.3, 13.5, 13.8 Hz, CH2), 3.52±4.25 (4H, m, COOCH2 and
OCH2), 4.04 (1H, dd, Jˆ7.0, 13.5 Hz, CH), 5.65 (1H, d,
Jˆ6.3 Hz, HCO), 5.69 (1H, s, CHv), 6.60±6.85 (5H, m,
Harom), 7.10±7.19 (1H, m, Harom), 7.95 (1H, d, Jˆ7.9 Hz,
(14e). Elution CH2Cl2. Yield 55%. Mixture E/Z 42:58. Mp
214±2168C. IR (®lm): 2200, 1660 cm21. E isomer: 1H NMR
(CDCl3) d: 1.44 (9H, s, 3£CH3), 3.34 (3H, s, OCH3), 5.73
(1H, d, Jˆ1.5 Hz, CH), 6.33 (1H, d, Jˆ1.5 Hz, CHv), 8.43
(1H, d, Jˆ2.2 Hz, H6), 8.52 (1H, d, Jˆ2.2 Hz, H4). Z
isomer: 1.44 (9H, s, 3£CH3), 3.69 (3H, s, OCH3), 5.85
(1H, d, Jˆ2.2 Hz, CH,), 6.46 (1H, d, Jˆ2.2 Hz, CHv),
7.82 (1H, d, Jˆ2.2 Hz, H4), 8.41 (1H, d, Jˆ2.2 Hz, H6,).
Anal. calcd for C15H16BrN3O2: C, 51.44; H, 4.60; N, 12.00.
Found: C, 51.81; H, 4.40; N, 12.16.
1
Harom), 8.15 (1H, d, Jˆ7.9 Hz, Harom). Z isomer: H RMN
(CDCl3) d: 1.16±1.32 (6H, m, COOCH2CH3 and
OCH2CH3), 2.06 (3H, s, CH3), 2.18 (1H, dd, Jˆ7.0,
13.8 Hz, CH2), 2.64 (3H, s, COCH3), 3.31 (1H, ddd, Jˆ
6.3, 13.5, 13.8 Hz, CH2), 3.52±4.25 (4H, m, COOCH2 and
OCH2), 4.09 (1H, dd, Jˆ7.0, 13.5 Hz, CH), 5.55 (1H, d,
Jˆ6.3 Hz, HCO), 6.04 (1H, s, CHv), 6.60±6.85 (6H, m,
Harom), 7.10±7.19 (1H, m, Harom), 8.07 (1H, d, Jˆ7.9 Hz,
Harom). Anal. calcd for C26H29NO5: C, 71.70; H, 6.71; N,
3.22. Found: C, 72.03; H, 6.55; N, 3.37.
1.3.4. 2-(1-Acetyl-1H-pyrrolo[2,3-b]pyridin-3-yl)aceto-
nitrile (15a). Mp 127±1298C (ethanol/petroleum ether).
1
Yield 25%. IR (KBr): 2240, 1670 cm21. H NMR (CDCl3)
d: 3.06 (3H, s, CH3), 3.78 (2H, s, CH2), 7.28 (1H, dd, Jˆ5.2,
8.1 Hz, H5), 7.94 (1H, dd, Jˆ1.5, 8.1 Hz, H4), 8.09 (1H, s,
H2), 8.45 (1H, dd, Jˆ1.5, 5.2 Hz, H6). MS (NH3) m/z: 200
(MH1). Anal. calcd for C11H9N3O: C, 66.32; H, 4.55; N,
21.09. Found: C, 66.11; H, 4.35; N, 20.94.
1.3. General procedure for Horner±Emmons reactions
with indolinones 1 or 7-azaindolinones 2
1.3.5. 2-(1-Phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)
acetonitrile (15b). Mp 187±1898C (ethanol). IR (KBr):
To a suspension of sodium hydride (0.46 mmol) in THF
(2 ml) at 08C, the diethyl cyanomethane phosphonate
(0.46 mmol) was added dropwise; after disappearance of
the sodium hydride, the 7-azaindolinone (0.23 mmol) in
THF (2 ml) was added dropwise to the solution; the mixture
was stirred for 2 h at 08C then for 1 h at rt. Water (4 ml) and
CH2Cl2 (4 ml) were added; the aqueous layer was made
neutral with addition of diluted HCl and twice extracted
with CH2Cl2 (2£5 ml). After drying of the organic layers
over MgSO4 and evaporation, the residue was puri®ed by
column chromatography on a silica gel column using
CH2Cl2 as eluent.
1
2250 cm21. H NMR (CDCl3) d: 3.77 (2H, s, CH2), 7.25
(1H, dd, Jˆ5.2, 8.1 Hz, H5), 7.48±7.52 (2H, m, Harom),
7.58±7.62 (1H, m, Harom), 7.78 (1H, s, H2), 7.89 (1H, dd,
Jˆ1.5, 8.1 Hz, H4), 8.19±8.23 (2H, m, Harom), 8.50 (1H, dd,
Jˆ1.5, 5.2 Hz, H6). MS (NH3) m/z: 298 (MH1). Anal. calcd
for C15H11N3O2S: C, 60.59; H, 3.73; N, 14.13. Found: C,
60.41; H, 3.88; N, 14.30.
1.3.6.
2-[1-(2,2-Dimethylpropanoyl)-2-methoxy-1H-
pyrrolo[2,3-b]pyridin-3-yl]acetonitrile (15d). Obtained
as trace compound after puri®cation on a silica gel column
chromatography (CH2Cl2) of the products resulting of the
isomerization of 14d (heating in toluene at re¯ux for 24 h in
1.3.1. (2-Phenyl-1H-3-indolyl)acetonitrile (12c) and (1-
acetyl-2-phenyl-1H-3-indolyl)acetonitrile (13c). Obtained
as a mixture: 62:38. Yield 48%. Oil. IR (®lm): 3250, 2250,
1
presence of a catalytic amount of sodium hydroxide). H
NMR (CDCl3) d: 1.45 (9H, s, CH3), 3.72 (2H, s, CH2),
4.04 (3H, s, OCH3), 7.13 (1H, dd, Jˆ5.2, 7.9 Hz, H5),
7.81 (1H, d, Jˆ7.9 Hz, H4), 8.29 (1H, d, Jˆ5.2 Hz, H6).
1
1710 cm21. 12c: H NMR (CDCl3) d: 3.88 (2H, s, CH2),
7.25±7.75 (9H, m, Harom), 8.37 (1H, brs, NH). Characteristic
signals for 13C NMR (CDCl3) d: 13.9 (CH2), CH and C
signals for the mixture of 12c and 13c can be attributed to
1.3.7. Diethyl cyano-[2-(4-methoxybenzyl-3-oxo-2,3-di-
hydro-1H-2-pyrrolo[2,3-b]pyridin-2-yl]methylphospho-
nate (17). Mixture of diasteromers A and B, 47:53. Yield
76%. Oil. IR (®lm): 3240±3140 (NH), 2200 (CN), 1705
1
12c and/or 13c. MS (NH3) m/z: 233 (MH1). 13c: H NMR
(CDCl3) d: 1.98 (3H, s, COCH3), 3.56 (2H, s, CH2), 7.25±
7.75 (8H, m, Harom), 8.45 (1H, dd, Jˆ1.3, 7.5 Hz, H7arom).
Characteristic signals for 13C NMR (CDCl3) d: 13.8 (CH2),
29.4 (CH3), 171.1 (CO). MS (NH3) m/z: 275 (MH1).
1
(CO) cm21. H NMR (CDCl31D2O) d: 1.15±1.45 (6H, m,
CH3A1B), 3.06 (1H, d, Jˆ14.0 Hz, CH2A), 3.19 (1H, d, Jˆ
14.0 Hz, CH2B), 3.30 (1H, d, Jˆ14.0 Hz, CH2B), 3.42 (1H,
d, Jˆ14.0 Hz, CH2A), 3.61 (3H, s, OCH3B), 3.63 (3H, s,
OCH3A), 3.67 (1H, d, Jˆ22.8 Hz, P±CHA), 3.70 (1H, d,
Jˆ22.8 Hz, P±CHB), 4.00±4.45 (4H, m, OCH2A1B), 6.55±
6.62 (3H, m, 2HaromA1B1H5A1B), 6.95±7.05 (2H, m,
HaromA1B), 7.63 (1H, dd, Jˆ1.5, 7.4 Hz, H4A1B), 8.21 (1H,
dd, Jˆ1.4, 5.2 Hz, H6B), 8.27 (dd, Jˆ1.4, 5.2 Hz, 1H, H6A).
MS (NH3) m/z: 430 (MH1). Anal. calcd for C21H24N3O5P:
C, 58.74; H, 5.63; N, 9.79. Found: C, 58.37; H, 5.46; N,
9.93.
1.3.2. 2-[1-(2,2-Dimethylpropanoyl)-2-methoxy-2,3-di-
hydro-1H-pyrrolo[2,3-b]pyridin-3-yliden]acetonitrile
(14d). Elution CH2Cl2. Yield 69%. Mixture E/Z 50:50. Oil.
IR (®lm): 2200, 1660 cm21. E isomer 1H NMR (CDCl3) d:
1.48 (9H, s, 3£CH3), 3.32 (3H, s, OCH3), 5.67 (1H, d, Jˆ
1.5 Hz, CH), 6.33 (1H, d, Jˆ1.5 Hz, CHv), 7.06 (1H, dd,
Jˆ5.2, 8.1 Hz, H5), 8.35±8.38 (1H, m, H6), 8.45 (1H, dd,
Jˆ1.5, 8.1 Hz, H4). Z isomer:1.49 (9H, s, 3£CH3), 3.62 (3H,
s, OCH3), 5.84 (1H, d, Jˆ2.2 Hz, CH), 6.47 (1H, d, Jˆ
2.2 Hz, CHv), 6.99 (1H, dd, Jˆ5.2, 8.1 Hz, H5), 7.72
(1H, dd, Jˆ1.5, 8.1 Hz, H4), 8.35±8.38 (1H, m, H6). Anal.
calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found:
C, 66.02; H, 6.44; N, 15.37.
1.3.8. Dimethyl 2-[(4-methoxybenzyl)-3-oxo-2,3-dihydro-
1H-pyrrolo-[2,3-b]pyridin-2-yl)]malonate (18). Dimethyl
malonate (50 mg, 0.38 mmol) were added to a cooled (08C)
suspension of NaH (9 mg, 0.38 mmol) in THF (5 ml); after
disappearance of NaH, compound 2c (100 mg, 0.25 mmol)
in THF (5 ml) was added dropwise; the mixture was stirred
1.3.3. 2-[5-Bromo-1-(2,2-dimethylpropanoyl)-2-methoxy-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yliden]acetonitrile

Â
J.-Y. Merour et al. / Tetrahedron 57 (2001) 1995±2002
2001
Â
7. Buzas, A.; Merour, J. Y. Synthesis 1989, 458±461.
for 1 h at 08C then for 3 h at rt. Water (10 ml) was added and
the solution was made neutral; extraction with CH2Cl2
(3£15 ml), drying over MgSO4 and evaporation in vacuo
leave a yellow solid which was puri®ed by column chroma-
tography using CH2Cl2 as eluent; mˆ90 mg. Yield 94%. Mp
215±2178C (ethanol/petroleum ether). IR (KBr): 3180
Â
8. Merour, J. Y.; Merour, A. Synthesis 1994, 767±769.
Â
9. Bierer, D. E.; Dubenko, L. G.; Zhang, P.; Lu, Q.; Imbach,
P. A.; Garofalo, A. W.; Phuang, P.-W.; Fort, D. M.; Litvak,
J.; Gerber, R. E.; Sloan, B.; Luo, J.; Cooper, R.; Reaven, G. M.
J. Med. Chem. 1998, 41, 2754±2764.
Â
10. Desarbre, E.; Merour, J. Y. Tetrahedron Lett. 1994, 35, 1995±
1998.
1
(NH), 1730, 1700 (CO) cm21. H NMR (CDCl3) d: 2.97
(1H, d, Jˆ14 Hz, CH2), 3.05 (1H, d, Jˆ14 Hz, CH2), 3.53
(3H, s, OCH3), 3.65 (3H, s, OCH3), 3.83 (3H, s, OCH3), 4.13
(1H, s, CH), 6.40 (1H, brs, NH), 6.56 (1H, dd, Jˆ5.2,
8.1 Hz, H5), 6.61 (2H, d, Jˆ8.8 Hz, Harom), 7.00 (2H, d,
Jˆ8.8 Hz, Harom), 7.62 (1H, d, Jˆ8.1 Hz, H4), 8.18 (1H, d,
Jˆ5.2 Hz, H6). 13C NMR (CDCl3) d: 40.8 (CH2), 52.9
(2£COOCH3), 55.1 (OCH3), 57.1 (CH), 68.4 (C2), 113.3
(2£CH), 114.4 (CH), 114.6 (C), 124.9 (C), 131.4 (2£CH),
132.3 (C), 132.7 (CH), 156.5 (CH), 158.6 (C), 166.2 (CO),
168.2 (CO), 199.3 (CO). MS (NH3) m/z: 385 (MH1). Anal.
calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C,
62.35; H, 5.36; N, 7.38.
Â
11. Desarbre, E.; Merour, J. Y. Tetrahedron Lett. 1996, 37, 43±
46.
Â
12. Merour, J. Y.; Mamai, A.; Malapel, B.; Gadonneix, P.
Tetrahedron 1997, 53, 987±1002.
Â
13. Desarbre, E.; Merour, J. Y. Synthesis 1997, 73±78.
14. (a) Kawasaki, T.; Nonaka, Y.; Ohtsuka, H.; Sato, H.;
Sakamoto, M. J. Chem. Soc., Perkin Trans. 1 1990, 1101±
1106.
(b) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.;
Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027±3029.
(c) Nonaka, Y.; Kawasaki, T.; Sakamoto, M. Heterocycles
2000, 53, 1681±1684.
1.3.9. 2-(1-Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-
yl)ethylamine (21). Compound 15b (0.060 g, 0.2 mmol)
was dissolved in a mixture of THF/ethanol (4 ml/4 ml)
and PtO2 (0.025 g) was added. The suspension was stirred
under 1 atm. of hydrogen for 24 h at rt. After ®ltration and
evaporation of the solvent, the residue was treated with
ethanol containing a few drops of concentrated HCl;
evaporation of the alcoholic solution left a residue which
was treated with water, neutralized and extracted with
CH2Cl2 (2£5 ml); drying over MgSO4 and evaporation
afforded 21. Yield 51%. Mp 167±1698C (ethanol). IR
15. Kawasaki, T.; Nonaka, Y.; Uemura, M.; Sakamoto, M.
Synthesis 1991, 701±702.
16. Kawasaki, T.; Watanabe, K.; Masuda, K.; Sakamoto, M.
J. Chem. Soc., Chem. Commun. 1995, 381±382.
17. (a) Kawasaki, T.; Masuda, K.; Baba, Y.; Terashima, R.;
Takada, K.; Sakamoto, M. J. Chem. Soc., Perkin Trans. 1
1996, 729±733. (b) Kawasaki, T.; Masuda, K.; Baba, Y.;
Takada, K.; Sakamoto, M. Chem. Pharm. Bull. 1994, 42,
1974±1976.
18. Kawasaki, T.; Terashima, R.; Sakaguchi, K.; Sekiguchi, H.;
Sakamoto, M. Tetrahedron Lett. 1996, 37, 7525±7528.
19. Kawasaki, T.; Tang, C.-Y.; Nakanishi, H.; Hirai, S.; Ohshita,
T.; Tanizawa, M.; Himori, M.; Satoh, H.; Sakamoto, M.;
Miura, K.; Nakano, F. J. Chem. Soc., Perkin Trans. 1 1999,
327±333.
1
(KBr): 3450±3250 (NH2) cm21. H NMR (CDCl3) d: 1.60
(2H, brs, NH2), 3.15 (2H, t, Jˆ7.4 Hz, CH2), 3.37 (2H, t,
Jˆ7.4 Hz, NCH2), 7.42 (1H, dd, Jˆ5.2, 8.1 Hz, H5), 7.56±
7.60 (2H, m, Harom), 7.68±7.74 (1H, m, Harom), 7.83 (1H, s,
H2), 8.01±8.05 (2H, m, Harom), 8.11 (1H, d, Jˆ8.1 Hz, H4),
8.36 (1H, d, Jˆ5.2 Hz, H6). MS (NH3) m/z: 302 (MH1).
Anal. calcd for C15H15N3O2S: C, 59.78; H, 5.02; N, 13.94.
Found: C, 60.02; H, 5.17; N, 14.11.
20. Katritzky, A. R.; Li, Q.-L.; Fan, W.-Q. J. Heterocycl. Chem.
1998, 25, 1287±1292.
Â
21. (a) Desarbre, E.; Coudret, S.; Meheust, C.; Merour, J. Y.
Tetrahedron 1997, 53, 3637±3648. (b) Alvarez, M.; Fernandez,
D.; Joule, J. Synthesis 1999, 615±620.
22. Curtis, N. L.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.;
Emns, F.; Freedman, S. B.; Patel, S. Bioorg. Med. Chem. Lett.
1999, 9, 585±588.
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Â
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È
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Â
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