Rhodium(II) catalyzed intramolecular insertion of carbenoids derived from 2-pyrrolyl and 3-indolyl α-diazo-β-ketoesters and α-diazoketones

Article abstract of DOI:10.1016/j.tet.2003.12.019

α-Diazo-β-ketoesters and α-diazoketones derived from 2-pyrrolylacetic, 2-pyrrolylpropionic, 3-indolylacetic and 3-indolylpropionic acids afforded carbenoid derived cyclization products on treatment with catalytic rhodium(II) acetate.

Full text of DOI:10.1016/j.tet.2003.12.019

Tetrahedron 60 (2004) 1505–1511
Rhodium(II) catalyzed intramolecular insertion of carbenoids
derived from 2-pyrrolyl and 3-indolyl a-diazo-b-ketoesters
and a-diazoketones
†
a
,
b
Erick Cuevas-Yan˜ez,a Joseph M. Muchowski and Raymundo Cruz-Almanza
,
*
a
´
´
´
Instituto de Quımica, UNAM. Circuito Exterior, Ciudad Universitaria, Coyoacan, 04510 Mexico, DF, Mexico
bDepartment of Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304-1320, USA
Received 24 July 2003; revised 8 December 2003; accepted 8 December 2003
Abstract—a-Diazo-b-ketoesters and a-diazoketones derived from 2-pyrrolylacetic, 2-pyrrolylpropionic, 3-indolylacetic and 3-indolyl-
propionic acids afforded carbenoid derived cyclization products on treatment with catalytic rhodium(II) acetate.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The a-diazo-b-ketoesters 6 and 7 were unaffected by
catalytic rhodium(II) acetate in dichloromethane, even at
reflux temperature. Conversion of these compounds into the
expected bicyclic ketones 8 and 9 did occur, however (ca.
50% yields), in 1,2-dichloroethane at reflux temperature (bp
72 8C in Mexico City). It is not clear what factors control the
rate of these reactions given that related b-ketoester
carbenoid insertions into aromatic CH bonds are reported
to require 1,2-dichloroethane at reflux temperature,9
whereas others take place at room temperature.10 It is
noteworthy that the cyclization of the carbenoids derived
from indoles 10 and 11 also require 1,2-dichloroethane at
reflux temperature (see below) (Scheme 1).
The first intramolecular carbenoid insertions at C-2 of
pyrroles were described by Muchowski, et al.1 and shortly
thereafter by Jefford and coworkers.2 The Jefford group
extensively studied the Rh(II) catalyzed process using
a-diazoketones as the carbenoid precursors, demonstrated
that it was high yielding process and utilized it to
synthesize several naturally occurring indolizine
derivatives.3
In connection with other projects, we some time ago
initiated studies on the insertion of a-keto carbenoids into
the C-3H of pyrroles, no examples of which were then
known, as well as into the C-2H of indoles. A recent
publication of Capretta and Salim,4 which describes
examples of both processes, causes us to disclose our
results in this area.
The indolyl a-diazo-b-ketoesters 10 and 11 were obtained
(ca. 50%) from the acid chlorides of indole-3-acetic and
indole-3-propionic acids (oxalyl chloride/265 8C) and ethyl
diazoacetate containing an equivalent of triethylamine using
a modification of a procedure described by Bestmann and
Kolm.11 Rhodium(II) catalyzed decomposition of the diazo
compounds 10 and 11 (ClCH2CH2Cl/reflux) generated the
anticipated tricyclic ketones 12 (55%) and 13 (52%) as the
major products in each case (Scheme 2).
The pyrrolyl a-diazo-b-ketoesters 6 and 7 were generated
(ca. 65%) by a diazo transfer reaction on the b-ketoesterers
4 and 5 with p-toluenesulfonylazide.5 These b-ketoesters
were obtained when the nitriles 26 and 3 were reacted with
excess ethyl bromoacetate and zinc.7 The pyrrolepropio-
nitrile 3 was obtained by catalytic hydrogenation of the
acrylonitrile 1, which in turn was prepared from 1-methyl-
pyrrole-2-aldehyde and triphenylphosphanylidene aceto-
nitrile.8
Additionally, some a-diazoketones derived from 2-pyrro-
lylacetic, 2-pyrrolylpropionic, 3-indolylacetic and
3-indolylpropionic acids were explored. The pyrrole-2-
alkanoic acids 17, 18 and 20 used in this study were
prepared by adaptations of literature methodology. Thus,
the pyrrole-2-acetic acids 17 and 18 were obtained by
alkaline hydrolysis12 of the nitriles 2 and 16, which in turn
were derived from the ammonium salts of the Mannich
bases 14 and 15 and sodium cyanide.6 Pyrrole-2-propionic
acid 20 was obtained by catalytic reduction and subsequent
hydrolysis of the acrylate derivative 19, which was prepared
Keywords: Rhodium carbenoids; a-diazo-b-ketoesters; a-diazoketones;
Insertion pyrrol,indol.
*
Corresponding author. Tel.: þ52-56-224408; fax: þ52-56-162217;
e-mail address: erick.cuevas@correo.unam.mx
Deceased on October, 2003.
†
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.019

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E. Cuevas-Yan˜ez et al. / Tetrahedron 60 (2004) 1505–1511
Scheme 1. Reagents and conditions: (a) Ph3PCHCN, toluene/CH2Cl2, reflux, 36 h; (b) H2, Pd/C, MeOH, RT, 6 h; (c) BrCH2CO2Et, Zn, THF, reflux, 8 h;
(d) TsN3, Et3N, CH2Cl2, RT, 12 h; (e) Rh2(OAc)4, ClCH2CH2Cl, reflux, 3 h.
Scheme 2. Reagents and conditions: (a) oxalyl chloride, DMAP, THF,
265 8C. 30 min; (b) ethyl diazoacetate, Et3N, 265 8C for 30 min and 12 h
at RT; (c) Rh2(OAc)4, ClCH2CH2Cl, reflux, 3 h.
from pyrrole-2-aldehyde and the mono ethyl ester of
malonic acid.13
The pyrrolyl diazoketones 21–23 were prepared (60–85%)
by addition of excess ethereal diazomethane at 0 8C to an
ethereal solution of the mixed ethyl carbonic–carboxylic
anhydrides generated in situ at 0 8C. Exposure of the diazo
compounds 21 and 22 to catalytic amounts of rhodium(II)
acetate in dichloromethane solution at room temperature
afforded the expected bicyclic ketones 26 and 27 respect-
85%) from the commercially available carboxylic acids in a
manner identical to that used for the synthesis of the
2-pyrrolyl analogs 21–23. Rhodium(II) catalyzed decompo-
sition of the diazo compound 24 (CH2Cl2/RT) and 25
(ClCH2CH2Cl/reflux) generated the anticipated tricyclic
ketones 30 (70%) and 31 (82%) as the major products in
each case.
ively, as the only isolable products in 55–60% yields.
However, the a-diazobutanone 23 gave a mixture of ketones
28 (30% yield) and 29 (15% yield) derived from
intramolecular insertion into the C-3H and N–H bonds of
the pyrrole ring. This product ratio was independent of both
the reaction temperature and the catalyst concentration. On
the other hand, Capretta and Salim4 report a 2.7:1 ratio of
N–H to C-3H insertion for both the a-diazopropanone 23
(n¼1) and the corresponding indole analog. Although the
formation of both 28 and 29 was expected, the preferential
formation of the CH insertion product 28, was not. We are
currently carrying out mechanistic studies on these
seemingly counterintuitive results.
In summary, this report shows that appropriately constituted
2-pyrrolyl and 3-indolyl-a-diazo-b-ketoesters and a-diazo
alkanones are efficiently converted into bicyclic and
tricyclic 5- and 6-membered ketones. These last results
display alternative synthesis methodologies to obtain
diverse pyrrolyl and indolyl diazo compounds, which
complement and extend the results of Capretta and
Salim.4 In addition, all the cyclic ketones described herein
The indolyl diazoketones 2414 and 25 were prepared (70–

E. Cuevas-Yan˜ez et al. / Tetrahedron 60 (2004) 1505–1511
1507
are useful points of departure enroute to certain natural
2.2. Preparation of pyrrolyl-b-ketoesters
products, and the cyclic b-ketoesters are particularly
interesting in this regard because of the facility which
further regiospecific chemical elaborations can be
effected.
Typical procedure. To a suspension of zinc dust (0.32 g,
5 mmol) in refluxing anhydrous THF (3 mL) under a
nitrogen atmosphere was added 4 drops of ethyl bromo-
acetate (0.055 mL, 0.08 g, 0.5 mmol). After the appearance
of the green color, the pyrrolyl nitrile (1 mmol) was added
in 1 portion, and ethyl bromoacetate (0.43 mL, 0.66 g,
4 mmol) was injected by syringe pump over 1 h and the
mixture was refluxed for additional 8 h. The dark solution
was cooled to 0 8C and it was treated with 10% aqueous HCl
(1 mL) for 30 min. The mixture was concentrated in vacuo,
diluted with CH2Cl2, washed with saturated aqueous
NaHCO3, dried over Na2SO4 and purified by column
chromatography (SiO2, hexane/AcOEt 8:2).
2. Experimental
2.1. General
The starting materials were purchased from Aldrich
Chemical Co. and were used without further purification.
The N-alkylated pyrroles were prepared according to the
literature.15 Solvents were distilled before use; ether and
tetrahydrofuran (THF) were dried over sodium using
benzophenone as indicator. Diazomethane was prepared
from N-methyl-N-nitroso-p-toluenesulfonamide (Diazaldw)
using a minimum amount of water and ethanol as cosolvent,
and dried over KOH pellets before use. Silica gel (230–400
mesh) and neutral alumina were purchased from Merck.
Silica plates of 0.20 mm thickness were used for thin layer
chromatography. Melting points were determined with a
Fisher–Johns melting point apparatus and they are uncor-
2.2.1. 4-(1-Methylpyrrol-2-yl)-3-oxo-butyric acid ethyl
ester (4). Colorless oil (63%). IR (CHCl3, cm21) 2985,
1
1732, 1316; H NMR (CDCl3, 200 MHz) d 1.26 (t, 3H),
2.61 (s, 2H), 3.44 (s, 3H), 3.79 (s, 2H), 4.18 (q, 2H), 6.02 (m,
1H), 6.08 (m, 1H), 6.60 (m, 1H); 13C NMR (CDCl3,
50 MHz) d 14.0, 40.5, 49.2, 59.0, 106.5, 107.1, 122.1, 131.2,
171.1, 194.8; MS [EIþ] m/z (RI%): 209 [M]þ (20), 94
[M2COCH2CO2Et]þ (100). HRMS (EIþ): for C11H15NO3
calcd 209.1052, found 209.1056.
1
rected. H and 13C NMR spectra were recorded using a
Varian Gemini 200, the chemical shifts (d) are given in ppm
relative to TMS as internal standard (0.00). For analytical
purposes the mass spectra were recorded on a JEOL JMS-
5X 10217 in the EI mode, 70 eV, 200 8C via direct inlet
probe. Only the molecular and parent ions (m/z) are
reported. IR spectra were recorded on a Nicolet Magna
55-X FT instrument.
2.2.2. 5-(1-Methylpyrrol-2-yl)-3-oxo-pentanoic acid
ethyl ester (5). Colorless oil (58%). IR (CHCl3, cm21
)
1
2940, 1728; H NMR (CDCl3, 200 MHz) d 1.27 (t, 3H),
2.85 (t, 2H), 3.19 (t, 2H), 3.42 (s, 2H), 3.56 (s, 3H), 4.21 (q,
2H), 5.93 (m, 1H), 6.06 (m, 1H), 6.52 (m, 1H); 13C NMR
(CDCl3, 50 MHz) d 14.2, 15.3, 33.8, 37.6, 49.4, 59.4, 106.2,
107.0, 121.9, 131.0, 171.0, 194.0; MS [EIþ] m/z (RI%): 223
[M]þ (5), 180 [M2C2H3O]þ (50), 94 [M2COCH2CO2Et]þ
(100). HRMS (EIþ): for C12H17NO3 calcd 223.1208, found
223.1210.
2.1.1. Preparation of 3-(1-methylpyrrol-2-yl)propio-
nitrile (3). A solution of triphenylphosphanylidene aceto-
nitrile8 (7.78 g, 25.8 mmol) in CH2Cl2 (20 mL) was added
to a solution of 1-methylpyrrole-2-aldehyde16 (0.76 g,
6.98 mmol) in toluene (50 mL). The resulting mixture was
refluxed under a nitrogen atmosphere for 36 h. The mixture
was cooled to room temperature and the solvent was
removed in vacuo. Purification by column chromatography
(SiO2, hexane/AcOEt 8:2) afforded the pyrrole acrylonitrile
1 (0.74 g, 80%) as a colorless oil. IR (CHCl3, cm21) 2949,
2.3. Preparation of pyrrolyl-a-diazo-b-ketoesters by
diazo transfer reaction
Typical procedure. An ice-cold solution of pyrrolyl-b-
ketoester (1 mmol) in CH2Cl2 (5 mL) was treated with
triethylamine (0.27 mL, 0.20 g, 2 mmol) and p-toluene-
sulfonyl azide (0.197 g, 1 mmol) and the mixture was
stirred under a nitrogen atmosphere at room temperature
overnight. The solvent was removed in vacuo, the solid
residue was triturated with ether (20 mL) and the
mixture including the insoluble residue was washed
successively with a 20% aqueous NaOH (3£20 mL). The
red ethereal phase was dried over Na2SO4, and the
solvent was removed in vacuo. The final product was
purified by column chromatography (SiO2, hexane/AcOEt
8:2).
1
2210, 1615; H NMR (CDCl3, 200 MHz) d 3.67 (s, 3H),
5.46 (d, 1H), 5.52 (d, 1H), 6.18 (m, 2H), 6.78 (t, 1H); 13C
NMR (CDCl3, 50 MHz) d 37.9, 101.6, 107.1, 108.0, 116.5,
117.4, 117.7, 131.3. MS [EIþ] m/z (RI%): 132 [M]þ (100),
131 [M2H]þ (40). HRMS (EIþ): for C8H8N2 calcd
132.0687, found 132.0690.
The pyrrole acrylonitrile 1 was dissolved in anhydrous
MeOH (50 mL) and hydrogenated (760 mm) over Pd/C
(0.08 g) for 6 h. The catalyst was removed by filtration and
the solvent was evaporated to give the crude pyrrole
propionitrile 3 (0.68 g, 90%) as a colorless oil which was
used without purification. IR (CHCl3, cm21) 2924, 2246,
2.3.1. 2-Diazo-4-(1-methylpyrrol-2-yl)-3-oxo-butyric
acid ethyl ester (6). Red oil (52%). IR (CHCl3, cm21
)
1
2987, 2139, 1725; H NMR (CDCl3, 200 MHz) d 1.26 (t,
3H), 2.42 (s, 2H), 3.64 (s, 3H), 4.24 (q, 2H), 5.79 (m, 1H),
5.98 (m, 1H), 6.62 (m, 1H); 13C NMR (CDCl3, 50 MHz) d
14.2, 40.5, 59.6, 72.0, 106.4, 107.0, 122.0, 131.1, 171.2,
205.0. MS [EIþ] m/z (RI%): 235 [M]þ (5), 94 [M2
COCH2CO2Et]þ (100). HRMS (EIþ): for C11H13N3O3
calcd 235.0957, found 235.0954.
1
1494; H NMR (CDCl3, 200 MHz) d 2.64 (t, 2H), 2.96 (t,
2H), 3.56 (s, 3H), 5.98m, 1H), 6.07 (m, 1H), 6.59 (t, 1H);
13C NMR (CDCl3, 50 MHz) d 21.6, 24.8, 37.6, 106.1, 108.0,
116.5, 117.7, 131.3. MS [EIþ] m/z (RI%): 134 [M]þ (50),
94 [M2CH2CN]þ (100). HRMS (FABþ): for C8H11N2
calcd 135.0922, found 135.0919.

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2.3.2. 2-Diazo-5-(1-methylpyrrol-2-yl)-3-oxo-pentanoic
acid ethyl ester (7). Red oil (65%). IR (CHCl3, cm21
NMR (CDCl3, 50 MHz) d 13.8, 30.9, 61.5, 71.0, 107.4,
111.2, 118.6, 119.7, 122.2, 123.3, 127.0, 136.0, 177.7,
213.6; MS [EIþ] m/z (RI%): 271 [M]þ (5), 243 [M2N2]þ
(5), 175 [M2COCN2CO]þ (65), 130 [M2COCN2CO2Et]þ
(100). HRMS (EIþ): for C14H13N3O3 calcd 271.0957, found
271.0963.
)
1
2939, 2138, 1715; H NMR (CDCl3, 200 MHz) d 1.25 (t,
3H), 2.85 (t, 2H), 2.92 (t, 2H), 3.61 (s, 3H), 4.20 (q, 2H),
5.82 (m, 1H), 6.00 (m, 1H), 6.51 (m, 1H); 13C NMR
(CDCl3, 50 MHz) d 14.3, 19.5, 33.7, 59.4, 71.1, 106.2,
107.0, 121.9, 131.0, 171.0, 204.0; MS [EIþ] m/z (RI%): 249
[M]þ (10), 94 [M2CH2COCH2CO2Et]þ (100). HRMS
(EIþ): for C12H15N3O3 calcd 249.1113, found 249.1119.
2.5.2. 2-Diazo-4-(indol-3-yl)-3-oxopentanoic acid ethyl
ester (11). Red oil (50%). IR (CHCl3, cm21) 3480, 2927,
1
2145, 1720, 1712; H NMR (CDCl3, 200 MHz) d 1.27 (t,
2.4. Cyclization of pyrrolyl-a-diazo-b-ketoesters
3H), 2.70 (t, 2H), 3.07 (t, 2H), 4.26 (q, 2H), 6.97–7.33 (m,
5H); 13C NMR (CDCl3, 50 MHz) d 13.9, 20.3, 34.5, 61.9,
71.0, 111.1, 114.1, 118.2, 118.7, 121.4, 121.6, 126.9, 136.0,
177.7, 213.6; MS [EIþ] m/z (RI%): 285 [M]þ (2), 284
[M2H]þ (5), 130 [M2CH2COCN2CO2Et]þ (100). HRMS
(EIþ): for C15H15N3O3 calcd 285.1113, found 285.1117.
Typical procedure. A solution of pyrrolyl-a-diazo-b-
ketoester (1 mmol) in dry 1,2-dichloroethane (10 mL) was
treated with Rh2(OAc)4 (2 mg) under a nitrogen atmosphere
and the resulting mixture was heated at reflux for 3 h. The
reaction mixture was cooled to room temperature and the
solvent was removed in vacuo. The final product was
purified by column chromatography (SiO2, hexane/AcOEt
8:2).
2.6. Cyclization of indolyl a-diazo-b-ketoesters
Typical procedure. A solution of indolyl diazo compound
(1 mmol) in dry 1,2-dichloroethane (10 mL) was treated
with Rh2(OAc)4 (2 mg) under a nitrogen atmosphere and the
resulting mixture was heated at reflux for 3 h. The reaction
mixture was cooled to room temperature and the solvent
was removed in vacuo. The final product was purified by
column chromatography (SiO2, hexane/AcOEt 8:2).
2.4.1. 1-Methyl-5-oxo-1,4,5,6-tetrahydrocyclopenta[b]-
pyrrole-4-carboxylic acid ethyl ester (8). Colorless oil
1
(54%). IR (CHCl3, cm21) 2986, 1731; H NMR (CDCl3,
200 MHz) d 1.29 (t, 3H), 3.40 (s, 2H), 3.63 (s, 3H), 4.12 (q,
2H), 4.16 (s, 1H) 5.92 (d, 1H), 6.70 (d, 1H); 13C NMR
(CDCl3, 50 MHz) d 14.1, 40.8, 40.9, 60.1, 60.6, 108.4,
119.0, 122.9, 133.3, 171.0, 215.0; MS [EIþ] m/z (RI%): 207
[M]þ (5), 134 [M2CO2Et]þ (40), 29 [CH2CH3]þ (100).
HRMS (EIþ): for C11H13NO3 calcd 207.0895, found
207.0897.
2.6.1. 2-Oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-3-
carboxylic acid ethyl ester (12). White solid (55%). Mp
145–147 8C (ether–hexane). IR (CHCl3, cm21) 3479,
1
2987, 1725, 1716; H NMR (CDCl3, 200 MHz) d 1.28 (t,
3H), 3.80 (s, 2H), 4.31 (q, 2H), 4.73 (s, 1H), 7.09–7.26 (m,
5H); 13C NMR (CDCl3, 50 MHz) d 13.8, 30.9, 61.5, 63.6,
107.4, 111.2, 118.6, 119.7, 122.2, 123.3, 127.0, 136.0,
177.7, 213.6; MS [EIþ] m/z (RI%): 243 [M]þ (2), 242
[M2H]þ (5), 130 [M2COCCO2Et]þ (100). HRMS (EIþ):
for C14H13NO3 calcd 243.0895, found 243.0896.
2.4.2. 1-Methyl-5-oxo-4,5,6,7-tetrahydroindole-4-car-
boxylic acid ethyl ester (9). Colorless oil (57%). IR
(CHCl3, cm21) 2929, 1726; 1H NMR (CDCl3, 200 MHz) d
1.25 (t, 3H), 2.85 (t, 2H), 2.92 (t, 2H), 3.61 (s, 3H), 4.11 (q,
2H), 4.16 (s, 1H) 6.05 (d, 1H), 6.55 (d, 1H); 13C NMR
(CDCl3, 50 MHz) d 14.1, 22.1, 38.2, 40.8, 60.1, 60.5, 108.3,
118.9, 122.8, 133.1, 171.0, 210.2; MS [EIþ] m/z (RI%): 221
[M]þ (10), 149 [M2C3H4O2]þ (65), 148 [M2CO2Et]þ
(100). HRMS (EIþ): for C12H15NO3 calcd 221.1052, found
221.1057.
2.6.2. 2-Oxo-2,3,4,9-tetrahydrocarbazole carboxylic acid
ethyl ester (13). White solid (52%). Mp 156 8C (ether–
1
hexane). IR (CHCl3, cm21) 3480, 2929, 1721, 1711; H
NMR (CDCl3, 200 MHz) d 1.27 (t, 3H), 2.75 (t, 2H), 3.10 (t,
2H), 4.22 (q, 2H), 4.67 (s, 1H), 6.99–7.35 (m, 5H); 13C
NMR (CDCl3, 50 MHz) d 14.0, 20.3, 34.5, 61.9, 68.0,
111.1, 114.5, 118.5, 119.3, 121.4, 122.0, 127.0, 136.2,
178.9, 213.0; MS [EIþ] m/z (RI%): 257 [M]þ (5), 130
[M2CH2COCCO2Et]þ (100). HRMS (EIþ): for
C15H15NO3 calcd 257.1052, found 257.1057.
2.5. Preparation of indolyl-a-diazo-b-ketoesters
Typical procedure. A dry ice-cold solution of the acid
(1 mmol) in freshly distilled THF (10 mL) was treated
successively with oxalyl chloride (0.087 mL, 0.127 g,
1 mmol) and 4-(dimethylamino)pyridine (0.012 g,
0.1 mmol), the mixture was stirred under a nitrogen
atmosphere for 30 min at 265 8C. The mixture was treated
with ethyl diazoacetate (0.105 mL, 0.114 g, 1 mmol) and
triethylamine (0.139 mL, 0.101 g, 1 mmol) at 265 8C. The
stirring was continuing for additional 2 h under nitrogen
atmosphere at 265 8C and the reaction was allowed to warm
to room temperature overnight. The solvent was removed in
vacuo and the product was purified by column chromato-
graphy (SiO2, hexane/AcOEt 8:2).
2.7. Preparation of dimethylaminomethylpyrroles
Typical procedure. A mixture of 37% aqueous formal-
dehyde (9 mL, 3.6 g, 0.12 mol) and dimethylamine hydro-
chloride (9.78 g, 0.12 mol) was added with stirring to the
pyrrole (0.10 mol) at a rate such that the reaction
temperature did not exceed 60 8C. The stirring was
continued a further 2 h. At the end of this time, 20%
NaOH (15 mL) and H2O (40 mL) were added and the
product was extracted with ether (3£20 mL). The organic
layers were combined, they were washed with saturated
NaCl solution (50 mL) and dried over Na2SO4. The solvent
was removed in vacuo, and the residue was purified by
distillation under a reduced pressure.
2.5.1. 2-Diazo-4-(indol-3-yl)-3-oxobutyric acid ethyl
ester (10). Red oil (50%). IR (CHCl3, cm21) 3479, 2987,
1
2154, 1725, 1716; H NMR (CDCl3, 200 MHz) d 1.28 (t,
3H), 3.80 (s, 2H), 4.31 (q, 2H), 7.09–7.26 (m, 5H); 13C

E. Cuevas-Yan˜ez et al. / Tetrahedron 60 (2004) 1505–1511
1509
2.7.1. 1-Methyl-2-(dimethylaminomethyl)pyrrole (14).
Colorless oil (71%). Bp 58 8C/5 mm. IR (film, cm21
122.6, 126.2, 126.2, 127.2, 127.3, 128.2, 128.3, 137.5,
179.1; MS [EIþ] m/z (RI%): 215 [M]þ (30), 170
[M2COOH]þ (20), 91 [PhCH2]þ (100). HRMS (EIþ): for
C13H13NO2 calcd 215.0946, found 215.0947.
)
3404, 2971, 2941, 2812; 1H NMR (CDCl3, 200 MHz) d 2.18
(s, 6H), 3.32 (s, 2H), 3.62 (s, 3H), 6.00 (m, 2H), 6.57 (m,
1H); 13C NMR (CDCl3, 50 MHz) d 37.7, 41.7, 41.7, 58.2,
108.6, 108.7, 121.1, 121.2; MS [EIþ] m/z (RI%): 138 [M]þ
(40), 94 [M2(CH3)2N]þ (100). HRMS (EIþ): for C8H14N2
calcd 138.1157, found 138.1159.
2.8.3. Preparation of 3-(pyrrol-2-yl)propionic acid (20).
Pyrrole-2-aldehyde (1 g, 10.3 mmol) was mixed with
hydrogen ethyl malonate (2.78 g, 21 mmol) in pyridine
(10 mL) and piperidine (0.5 mL) and the mixture was
warmed at 50 8C with stirring for 48 h and 80 8C for 24 h.
10% HCl (150 mL) was added, the product was extracted
with ether, the organic phase was washed with aqueous
Na2CO3 and dried over Na2SO4, and the solvent was
removed in vacuo. Purification by distillation under reduced
pressure afforded the 3-(pyrrol-2-yl)acrylic acid ethyl ester
2.7.2. 1-Benzyl-2-(dimethylaminomethyl)pyrrole (15).
Colorless oil (52%). Bp 110 8C/5 mm. IR (film, cm21
)
3400, 2970, 2938, 2824; 1H NMR (CDCl3, 200 MHz) d 2.15
(s, 6H), 3.30 (s, 2H), 3.59 (s, 3H), 5.09 (s, 2H), 6.13 (m, 2H),
6.67 (m, 1H). 13C NMR (CDCl3, 50 MHz) d 41.4, 41.4,
51.5, 58.0, 107.6, 109.8, 122.7, 126.3, 126.4, 127.2, 127.4,
128.4, 128.5, 137.5. MS [EIþ] m/z (RI%): 208 [M]þ (35),
164 [M2(CH3)2N]þ (25), 91 [PhCH2]þ (100). HRMS
(EIþ): for C14H18N2 calcd 214.1470, found 214.1475.
19 as colorless oil. Bp 120 8C/5 mm. IR (CHCl3, cm21
)
1
3463, 1695; H NMR (CDCl3, 200 MHz) d 1.21 (t, 3H),
4.20 (q, 2H), 5.94 (d, 3H), 5.99 (d, 1H), 6.18 (m, 1H), 6.28
(m, 1H), 6.91 (m, 1H); 13C NMR (CDCl3, 50 MHz) d 14.1,
22.6, 105.9, 107.9, 116.1, 123.4, 131.1, 142.8, 165.9; MS
[EIþ] m/z (RI%): 165 [M]þ (100). HRMS (EIþ): for
C9H11NO2 calcd 165.0790, found 165.0792. Compound 19
may be used without purification.
2.8. Preparation of pyrrole acetic acids
Typical procedure. Iodomethane (7.47 mL, 17.04 g,
0.12 mol) was added slowly to a stirred and cooled (0 8C)
solution of 2-(dimethylaminomethyl)pyrrole (0.1 mol) in
acetone (5 mL/g pyrrole) maintained in a nitrogen atmos-
phere, at a rate such that the reaction temperature did not
exceed 4 8C. When the addition was completed, the solution
was stirred at room temperature for 1 h, then the solvent was
removed and a solution of NaCN (14.7 g, 0.3 mol) in H2O
(150 mL) and EtOH (50 mL) was added and the resulting
solution was heated at reflux overnight. The reaction
mixture was cooled to room temperature, and the solvent
was removed in vacuo, then, H2O was added and the
product was extracted with ether. The extract was washed
with saturated NaCl solution and after drying the solvent
was removed in vacuo and the product was purified by
distillation under a reduced pressure (100 8C/5 mm). The
pyrroleacetonitriles (2 and 16) were mixed with a solution
of KOH (6 equiv.) H2O (1.5 mL/mmol pyrroleacetonitrile)
and EtOH (3.0 mL/mmol pyrroleacetonitrile) and the
mixture was heated at reflux overnight. The reaction
mixture was cooled to room temperature and the solvent
was removed in vacuo, then H2O was added and the
resulting solution was acidified with 10% HCl solution to
pH¼1. The product was extracted with ethyl acetate
(3£50 mL), the extract was washed and dried over
Na2SO4, the solvent was removed in vacuo and the product
was purified by crystallization.
The crude acrylic ester 19 was dissolved in anhydrous
MeOH (75 mL) and hydrogenated (760 mm) over 10% Pd/
C (0.1 g) for 6 h. The catalyst was removed by filtration and
the solvent was evaporated. Distillation of the product
afforded the ethyl propionic ester, as a colorless oil. Bp
100 8C/5 mm. IR (CHCl3, cm21) 3462, 1732; 1H NMR
(CDCl3, 200 MHz) d 1.25 (t, 3H), 2.74 (t, 2H), 3.09 (t, 2H),
4.13 (q, 2H), 6.08 (m, 1H), 6.13 (m, 1H), 6.81 (m, 1H); 13C
NMR (CDCl3, 50 MHz) d 14.1, 22.6, 41.0, 59.1, 105.9,
107.9, 116.1, 131.1, 171.5; MS [EIþ] m/z (RI%): 167 [M]þ
(10), 94 [M2CO2Et]þ (100). HRMS (EIþ): for C9H13NO2
calcd 167.0946, found 165.0745.
The ethyl propionic ester was added to a solution of K2CO3
(2 equiv.) in H2O (6 mL) and EtOH (24 mL) and the
mixture was heated at reflux overnight. The mixture was
cooled at room temperature, the solvent was removed and
H2O (50 mL) was added, the solution was acidified with
10% HCl solution to pH¼1, the product was extracted with
ethyl acetate, the organic phase was washed, dried and the
solvent was evaporated in vacuo. Crystallization afforded
the pyrrolepropionic acid 20 in 40% global yield. Mp
1
138 8C (ether). IR (CHCl3, cm21) 3479, 3060, 1712; H
NMR (CDCl3, 200 MHz) d 2.78 (t, 2H), 3.12 (t, 2H), 6.01
(m, 2H), 6.68 (m, 1H); 13C NMR (CDCl3, 50 MHz) d 22.5,
40.9, 105.9, 107.9, 116.1, 131.1, 176.3; MS [EIþ] m/z
(RI%): 139 [M]þ (50), 94 [M2COOH]þ (100). HRMS
(EIþ): for C7H9NO2 calcd 139.0633, found 139.0639.
2.8.1. 1-Methylpyrrol-2-yl acetic acid (17). White solid
(70%). Mp 135 8C (ether–hexane). IR (KBr, cm21) 3465,
1
3339, 1660, 1624; H NMR (CDCl3, 200 MHz) d 3.57 (s,
2H), 3.65 (s, 3H), 6.07 (m, 2H), 6.61 (m, 1H); 13C NMR
(CDCl3, 50 MHz) d 39.4, 41.8, 108.6, 108.7, 121.1, 121.2,
178.0. MS [EIþ] m/z (RI%): 139 [M]þ (50), 94
[M2COOH]þ (100). HRMS (FABþ): for C7H10NO2 calcd
140.0712, found 140.0719.
2.9. Preparation of pyrrolyldiazoketones
Typical procedure. An ice-cold solution of the acid
(1 mmol) in freshly distilled ether was treated successively
with ethyl chloroformate (0.10 mL, 0.11 g, 1.1 mmol) and
N-methylmorpholine (0.10 mL, 0.10 g, 1 mmol), the mix-
ture was stirred under nitrogen atmosphere for 15 min at
0 8C, then an ether solution of diazomethane (10 mmol)
from N-methyl-N-nitroso-4-toluenesulfonamide (3.06 g,
14.3 mmol) was added at 0 8C. A vigorous evolution of
2.8.2. 1-Benzylpyrrol-2-yl acetic acid (18). White solid
(40%). Mp 122 8C (ether–hexane). IR (film, cm21) 3201,
1
3032, 2929, 1645; H NMR (CDCl3, 200 MHz) d 3.52 (s,
2H), 5.09 (s, 2H), 6.14 (m, 2H), 6.67 (m, 1H), 7.00–7.31 (m,
5H); 13C NMR (CDCl3, 50 MHz) d 39.0, 50.9, 107.7, 109.8,

1510
E. Cuevas-Yan˜ez et al. / Tetrahedron 60 (2004) 1505–1511
nitrogen occurred, and the mixture was allowed to warm to
room temperature overnight. The solvent was removed in
vacuo and the product was purified by column chromato-
graphy (alumina activity III, hexane/AcOEt 95:5).
2.11. Reaction of 1-diazo-4-(2-pyrrolyl)-2-butanone (23)
with rhodium(II) acetate
The procedure was similar to that used in the cyclization of
pyrrolyldiazopropanones. Column chromatography (SiO2,
hexane/AcOEt 9:1) afforded the compounds 28 and 29.
2.9.1. 1-Diazo-3-(1-methylpyrrol-2-yl)propanone (21).
1
Orange oil (80%). IR (film, cm21) 2105, 1738, 1637; H
NMR (CDCl3, 200 MHz) d 3.53 (s, 3H), 3.59 (s, 2H), 5.13
(s, 1H), 6.02 (m 1H), 6.07 (t, 1H, J3–4¼3.5 Hz), 6.60 (m,
1H); 13C NMR (CDCl3, 50 MHz) d 39.4, 41.8, 52.4, 108.6,
108.7, 121.1, 121.2, 195.2; MS [EIþ] m/z (RI%): 163 [M]þ
(77), 135 ([M2N2]þ (10), 94 [M2COCHN2]þ
(100).HRMS (FABþ): for C8H10N3O calcd 164.0824,
found 164.0834.
2.11.1. 1,4,6,7-Tetrahydroindol-5-one (28). White solid
1
(30%). Mp 137 8C. IR (film, cm21) 3476, 2920, 1711; H
NMR (CDCl3, 200 MHz) d 2.68 (t, 2H), 2.97 (t, 2H), 3.40 (s,
2H), 5.98 (d, 1H, J4–5¼2.7 Hz), 6.68 (d, 1H,
J5–4¼2.76 Hz), 8.01 (s, 1H); 13C NMR (CDCl3, 50 MHz)
d 22.2, 38.3, 39.0, 107.4, 114.2, 117.7, 124.7, 210.7; MS
[EIþ] m/z (RI%): 135 [M]þ (100), 134 [M2H]þ
(10).HRMS (FABþ): for C8H10NO calcd 136.0762, found
136.0751.
2.9.2. 1-Diazo-3-(1-benzylpyrrol-2-yl)propanone (22).
Orange oil (63%). IR (CHCl3, cm21) 2104, 1745, 1638;
1H NMR (CDCl3, 200 MHz) d 3.49 (s, 2H), 5.02 (s, 2H),
5.06 (s, 1H), 6.09 (m, 1H), 6.15 (t, 1H, J3–4¼3.46 Hz), 6.71
(m, 1H)7.0–7.3 (m, 5H); 13C NMR (CDCl3, 50 MHz) d
39.0, 50.5, 53.9, 107.6, 109.8, 122.7, 126.3, 126.4, 127.2,
127.4, 128.4, 128.5, 137.5, 192.0; MS [EIþ] m/z (RI%): 239
[M]þ (15), 211 [M2N2]þ (10), 170 [M2COCHN2]þ (55),
91 [PhCH2]þ (100). HRMS (FABþ): for C14H14N3O calcd
240.1139, found 240.1137.
2.11.2. 7,8-Dihydroindolizin-6-one (29). Colorless oil
(15%). IR (film, cm21) 2958, 1724; 1H NMR (CDCl3,
200 MHz) d 2.70 (t, 2H), 3.06 (t, 2H), 4.52 (s, 2H), 5.98 (dd,
1H), 6.17 (d, 1H), 6.58 (d, 1H); 13C NMR (CDCl3, 50 MHz)
d 20.8, 38.1, 54.8, 104.7, 108.9, 118.8, 128.0, 205.9; MS
[EIþ] m/z (RI%): 135 [M]þ (40), 134 [M2H]þ (75), 80
[M2CH2COCH]þ (100).HRMS (FABþ): for C8H10N3O
calcd 136.0762, found 136.0774.
2.9.3. 1-Diazo-4-(pyrrol-2-yl)-butan-2-one (23). Orange
1
2.12. Preparation of indolyl diazoalkanones 24 and 25
oil (70%). IR (CHCl3, cm21) 3478, 2976, 2109, 1730; H
NMR (CDCl3, 200 MHz) d 2.73 (t, 2H), 2.95 (t, 2H), 6.10
(m, 2H), 6.66 (m, 1H); 13C NMR (CDCl3, 50 MHz) d
22.5, 40.9, 55.1, 105.9, 107.9, 116.1, 131.1, 195.5; MS
[EIþ] m/z (RI%): 163 [M]þ (10), 94 [M2COCHN2]þ
(100).HRMS (FABþ): for C8H10N3O calcd 164.0824, found
164.0833.
The procedure was similar to that used in the preparation of
pyrrolyldiazoketones.
2.12.1. 1-Diazo-3-(indol-3-yl)propanone (24). Orange oil
(84%). IR (CHCl3, cm21) 3477, 2108, 1735, 1633; 1H NMR
(CDCl3, 200 MHz) d 3.77 (s, 2H), 5.17 (s, 1H), 7.1–7.3 (m,
5H); 13C NMR (CDCl3, 50 MHz) d 37.9, 54.3, 108.5, 111.3,
118.8, 119.9, 122.4, 123.4, 127.2, 136.2, 194.2; MS [EIþ]
m/z (RI%): 199 [M]þ (10), 171 [M2N2]þ (11), 130
[M2COCHN2]þ (100). HRMS (EIþ): for C11H9N3O
calcd 199.0746, found 199.0743.
2.10. Cyclization of pyrrolyldiazopropanones
Typical procedure. A solution of the diazopropanone
(1 mmol) in dry CH2Cl2 (5 mL) was stirred with
Rh2(OAc)4 (2 mg) under a nitrogen atmosphere at room
temperature. After 2 h, the mixture was evaporated in vacuo
and purified by column chromatography (SiO2, hexane/
AcOEt 8:2).
2.12.2. 1-Diazo-4-(indol-3-yl)butan-2-one (25). Orange oil
(87%). IR (CHCl3, cm21) 3481, 2110, 1732; 1H NMR
(CDCl3, 200 MHz) d 2.72 (t, 2H), 3.11 (t, 2H), 5.15 (s, 1H),
6.99–7.45 (m, 5H), 7.61 (s, 1H); 13C NMR (CDCl3,
50 MHz) d 20.6, 41.1, 54.6, 111.2, 114.3, 118.6, 119.4,
121.6, 121.6, 127.2, 136.4, 195.0; MS [EIþ] m/z (RI%): 213
[M]þ (10), 185 [M2N2]þ (15), 130 [M2CH2COCHN2]þ
(100). HRMS (EIþ): for C12H11N3O calcd 213.0902, found
213.0907.
2.10.1. 1-Methyl-4,6-dihydrocyclopenta[b]pyrrol-5-one
(26). Colorless oil (60%). IR (film, cm21) 2925, 2854,
1
1738; H NMR (CDCl3, 200 MHz) d 3.56 (s, 2H), 3.58 (s,
3H), 3.69 (s, 2H), 6.04 (d, 1H, J4–5¼2.7 Hz), 6.56 (d, 1H,
J5–4¼2.76 Hz); 13C NMR (CDCl3, 50 MHz) d 37.9, 40.8,
40.9, 108.6, 119.3, 122.9, 131.2, 215.2; MS [EIþ] m/z
(RI%): 135 [M]þ (40), 134 [M2H]þ (100). HRMS (EIþ):
for C8H9NO calcd 135.0684, found 135.0686.
2.12.3. Cyclization of 1-diazo-3-(indol-3-yl)propanone
(24) with rhodium(II) acetate. The procedure was similar
to that used in the cyclization of pyrrolyldiazopropanones.
Purification by column chromatography (SiO2, hexane/
AcOEt 8:2) afforded 3,4-dihydrocyclopenta[b]indol-2-one
2.10.2. 1-Benzyl-4,6-dihydrocyclopenta[b]pyrrol-5-one
(27). Colorless oil (55%). IR (CHCl3, cm21) 2956, 2927,
1
1724; H NMR (CDCl3, 200 MHz) d 3.50 (s, 2H), 4.56
30 as white solid (70%). Mp 145 8C. IR (CHCl3, cm21
)
1
(s, 2H), 5.01 (s, 2H), 6.10 (d, 1H, J4–5¼2.74 Hz), 6.65
(d, 1H, J5–4¼2.72 Hz), 7.0–7.3 (m, 5H); 13C NMR
(CDCl3, 50 MHz) d 32.5, 40.7, 52.2, 109.5, 119.5, 122.8,
126.4, 127.1, 127.8, 128.6, 128.8, 131.0, 137.3, 215.4;
MS [EIþ] m/z (RI%): 211 [M]þ (5), 210 [M2H]þ (100).
HRMS (EIþ): for C14H13NO calcd 211.0997, found
211.0999.
3477, 2916, 1753; H NMR (CDCl3, 200 MHz) d 3.49 (s,
2H), 3.78 (s, 2H), 7.1–7.3 (m, 5H); 13C NMR (CDCl3,
50 MHz) d 39.2, 39.3, 111.1, 111.6, 118.8, 120.2, 121.9,
136.0, 136.0, 138.8, 214.2; MS [EIþ] m/z (RI%): 171 [M]þ
(20), 143 [M2CO]þ (30), 130 [M2CHCO]þ (100).).
HRMS (EIþ): for C11H9NO calcd 171.0684, found
171.0697.

E. Cuevas-Yan˜ez et al. / Tetrahedron 60 (2004) 1505–1511
1511
3. (a) Jefford, C. W.; Kubota, T.; Zaslona, A. Helv. Chim. Acta
1986, 69, 2048. (b) Jefford, C. W.; Tang, Q.; Zaslona, A. Helv.
Chim. Acta 1989, 72, 1749. (c) Jefford, C. W.; Tang, Q.;
Zaslona, A. J. Am. Chem. Soc. 1991, 113, 3513. (d) Jefford,
C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 3119.
4. Capretta, A.; Salim, M. Tetrahedron 2000, 56, 8063.
5. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern catalytic
methods for organic synthesis with diazo compounds: from
cyclopropanes to ylides; Wiley: New York, 1998; p 10.
6. (a) Herz, W.; Rogers;, J. J. Am. Chem. Soc. 1951, 73, 4921.
(b) Herz, W.; Ditter, K.; Cristol, S. J. J. Am. Chem. Soc. 1947,
69, 1698.
2.12.4. Cyclization of indolyl diazoketone 25. A solution
of indolyl diazoketone 25 (1 mmol) in dry 1,2-dichloro-
ethane (10 mL) was treated with Rh2(OAc)4 (2 mg) under a
nitrogen atmosphere and the resulting mixture was heated at
reflux for 3 h. The reaction mixture was cooled to room
temperature and the solvent was removed in vacuo.
Purification by column chromatography (SiO2, hexane/
AcOEt 8:2) afforded 1,3,4,9-tetrahydrocarbazol-2-one 31 as
a white solid (82%). Mp 150 8C. IR (CHCl3, cm21) 3481,
1
2957, 1732; H NMR (CDCl3, 200 MHz) d 2.74 (t, 2H),
3.12 (t, 2H), 3.68 (s, 2H), 7.0–7.3 (m, 5H); 13C NMR
(CDCl3, 50 MHz) d 20.6, 29.7, 34.7, 111.1, 114.9, 118.6,
119.2, 121.3, 122.0, 130.8, 136.2, 218.0; MS [EIþ] m/z
(RI%): 185 [M]þ (5), 130 [M2CHCH2CO]þ (100). HRMS
(EIþ): for C12H11NO calcd 185.0841, found 185.0845.
7. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
8. Tamiaki, H.; Kouraba, M. Tetrahedron 1997, 53, 10677.
9. Hashimoto, S.; Watanabe, N.; Ikegami, S. J. Chem. Soc.
Chem. Commun. 1992, 1508.
10. Zaragoza, F. Tetrahedron 1995, 51, 8829.
Acknowledgements
11. Bestmann, H. J.; Kolm, H. Chem. Ber. 1963, 96, 1948.
12. Carpio, H.; Cho, D.; Gallegra, P.; Halpern, O.; Koehler, R.;
Maddox, M. L.; Muchowski, J. M.; Prince, A.; Tegg, D.;
Thurber, T. C.; Van Horn, A. R.; Wren, D. Can. J. Chem.
1982, 60, 2295.
Financial support from CONACyT (No. 37312-E) is
gratefully acknowledged. The authors would like to thank
R. Patin˜o, M. Adaya, A. Pen˜a, E. Huerta, N. Zavala, C.
´ ´
Marquez, J. Perez and L. Velasco for the technical support.
13. (a) Bates;, H. A.; Rapoport, H. J. Am. Chem. Soc. 1979, 101,
1259. (b) Volz, H.; Draese, R. Tetrahedron Lett. 1970, 11,
4917.
14. Franceschetti, L.; Garzon-Aburbeh, A.; Mahmoud, M. R.;
Natalini, B.; Pellicciari, R. Tetrahedron Lett. 1993, 34, 3185.
15. Heany, H.; Ley, S. J. Chem. Soc., Perkin Trans. 1 1973, 499.
16. 1-Methylpyrrole-2-aldehyde was prepared using the procedure
described by Muchowski, J. M.; Solas, D. R. J. Org. Chem.
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References and notes
1. (a) Galeazzi, E.; Guzman, A.; Pin˜edo, A.; Saldan˜a, A.; Torre,
D.; Muchowski, J. M. Can. J. Chem. 1983, 61, 454. (b) Mu¨ller,
P.; Polleux, P. Helv. Chim. Acta 1998, 81, 317.
2. Jefford, C. W.; Johncock, W. Helv. Chim. Acta 1983, 66, 2666.