Pd(II)-catalyzed intramolecular aminopalladation/direct C-H arylation under aerobic conditions: Synthesis of pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1016/j.tet.2013.01.003

Heating a DMA/pivalic acid (v/v=4/1) solution of diversely substituted 6-(phenylamino)hex-2-ynoates in the presence of a catalytic amount of Pd(OAc)₂ under oxygen atmosphere afforded pyrrolo[1,2-a]indoles in moderate to good yields. A domino sequence involving intramolecular aminopalladation followed by C-H activation and reductive elimination was proposed to account for the observed bis-cyclization.

Full text of DOI:10.1016/j.tet.2013.01.003

Tetrahedron 69 (2013) 4415e4420
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-catalyzed intramolecular aminopalladation/direct CeH
arylation under aerobic conditions: synthesis of pyrrolo[1,2-a]indoles
,
,
a,b,
Tiffany Piou a b, Luc Neuville b , Jieping Zhu
*
*
a
ꢀ ꢀ
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Laboratoire International Associe, CNRS, 91198 Gif-sur-Yvette Cedex, France
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Heating a DMA/pivalic acid (v/v¼4/1) solution of diversely substituted 6-(phenylamino)hex-2-ynoates in
the presence of a catalytic amount of Pd(OAc)2 under oxygen atmosphere afforded pyrrolo[1,2-a]indoles
in moderate to good yields. A domino sequence involving intramolecular aminopalladation followed by
CeH activation and reductive elimination was proposed to account for the observed bis-cyclization.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 27 November 2012
Received in revised form 21 December 2012
Accepted 2 January 2013
Available online 9 January 2013
Keywords:
Palladium catalysis
Domino reaction
CeH activation
Indole
Aminopalladation
1. Introduction
Pyrrolo[1,2-a]indole is an important structural motif found in
many bioactive natural products and pharmaceuticals (Fig. 1).1
Therefore, development of new synthetic methodologies allowing
a rapid construction of this skeleton is highly desirable. Most of the
existing methods required the pre-construction of functionalized
indoles or pyrrolidines,2,3 which were in turn prepared by multi-
step processes.4 Based on the Larock’s indole synthesis,5 Lu and
co-workers at Boehringer-Ingelheim pharmaceuticals developed
recently a one-step synthesis of polycyclic indoles by way of
a
Pd(0)-catalyzed intramolecular cyclization of 2-haloanilides
bearing a properly tethered alkynyl function (Eq. 1, Scheme 1).6
While the reaction is applicable to a wide range of substrates, it
relied on the use of ortho-halogenated anilides as starting mate-
rials. In connection with our ongoing projects dealing with the
development of palladium-catalyzed domino processes7 involving
CeH functionalization8 as a key step,9 we became interested in
the development of a Pd(II)-catalyzed cyclization of 1 for the syn-
thesis of pyrrolo[1,2-a]indoles 2 (Eq. 2, Scheme 1). If realized,
this reaction would be more atom-economic and sustainable rela-
tive to Boehringer-Ingelheim Pharmaceuticals’ protocol. Recent
elegant work from Glorius10 on the Pd(II)-catalyzed oxidative cy-
clization of N-aryl enaminones to indoles11 and from Jiao12 on the
Fig. 1. Representative compounds containing pyrrolo[1,2-a]indole cores.
Pd(II)-catalyzed one pot synthesis of indoles from simple aniline
and an activated alkyne provided hints to our reaction design.13
Although aminometallation/CeC bond formation via CeH func-
tionalization has been widely exploited in rhodium catalysis,14 we
noted that examples involving Pd(II)-catalyzed aminopalladation/
CeH functionalization under oxidative conditions are scarce.15,16
* Corresponding authors. E-mail addresses: luc.neuville@icsn.cnrs-gif.fr (L. Neuville),
jieping.zhu@epfl.ch (J. Zhu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.003

4416
T. Piou et al. / Tetrahedron 69 (2013) 4415e4420
Table 2
Scope of the reactiona
Entry
1
Substrate 1
Product 2
Yieldb (%)
2b, R¼OMe, 41
2c, R¼CO2Et, 63
2d, R¼CN, 46
2e, R¼Me, 51
2f, R¼Cl, 46
2
2g, R¼6-Me and 2g0,
R¼4-Me, 83 (1.2/1)
Scheme 1. Palladium-catalyzed synthesis of pyrrolo[1,2-a]indoles.
3
4
2h, 18
2. Results and discussions
We began our studies using the easily accessible ethyl 6-(phe-
nylamino)hex-2-ynoate 1a17 as a model substrate for the survey of
reaction conditions. As shown in Table 1, the double cyclization of
1a proceeded in the presence of palladium acetate (0.1 equiv),
pivalic acid18 (1.0 equiv) under oxygen atmosphere19 in DMA at
120 ꢀC to afford the desired ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]
indole-9-carboxylate (2a) in 34% yield (entry 1, Table 1). When the
reaction was performed in a mixture of DMA/PivOH (v/v¼4/1), we
were pleased to isolate the expected pyrrolo[1,2-a]indole 2a in 63%
yield. Using palladium dichloride as catalyst instead of palladium
acetate under the otherwise identical conditions led to complete
degradation of the starting material (entry 10). Compound 2a was
isolated in lower yield when the reaction was performed in pure
pivalic acid (entry 3) and other solvent mixtures (entries 4 and 5).
Addition of a co-oxidant in the reaction in combination with mo-
lecular oxygen is detrimental to the reaction efficiency (entries
7e9). It should be mentioned that air was also a competent ter-
minal oxidant to afford the desired product 2a (entry 6).
2i, 72
5
6
2j/2j0, 72 (3.2/1)
2k, R1¼R2¼R3¼H, 70
2l, R1¼R3¼H,
R2¼CO2Et, 69
2m, R1¼R3¼Me,
R2¼H, 77
Table 1
Pd-catalyzed bis-cyclization of ethyl 6-(phenylamino)hex-2-ynoate, survey of re-
action conditions
7
2n, R¼CO2Me, 51
2o, R¼CO2iPr, 47
2p, R¼Ph, trace
a
Reactions were carried out under oxygen atmosphere using 1a (1.0 equiv),
Pd(OAc)2 (0.1 equiv), and DMA/PivOH (v/v¼4/1) at 120 ꢀC, 4e8 h.
Entry
Co-oxidantb
Solvent
DMAc
DMA/PivOH (4/1)
PivOH
Xylene/PivOH (4/1)
DMSO/PivOH (4/1)
DMA/PivOH (4/1)
DMA/PivOH (4/1)
DMA/PivOH (4/1)
DMA/PivOH (4/1)
DMA/PivOH (4/1)
Yielda (%)
b
Isolated yield.
1
2
3
4
5
6
7
8
d
34
63
57
50
10
52
35
18
34
n. d.
d
d
groups at para-position of aniline were tolerated furnishing the
corresponding tricyclic indoles (2bef) (entry 1, Table 2). When
N-meta-tolyl-anilide was employed, a mixture of two separable
regioisomers 2g and 2g0 (1.2/1 ratio) was isolated in 83% overall
yield in favor of the 6-substituted pyrrolo[1,2-a]indole 2g (entry 2).
However, the presence of a substituent ortho to anilide reduced
dramatically the yield of the domino process (entry 3). Ethyl 6-
((3,5-dimethylphenyl)amino)hex-2-ynoate 1i underwent double
cyclizations to produce the indole derivative 2i in good yield (entry
4). Substrates containing gem-dimethyl group on the side chain
reacted smoothly to provide the corresponding pyrrolo[1,2-a]in-
d
d
dd
BQ
Cu(OAc)2
PhI(OAc)2
d
9
10e
a
Isolated yield.
Co-oxidant (2.0 equiv).
PivOH (1.0 equiv).
Under air atmosphere instead of O2.
PdCl2 (0.1 equiv).
b
c
d
e
doles in good yields (entry 6). Cyclization of the b-naphthylaniline
With the optimum conditions [Pd(OAc)2 (0.1 equiv), O2
derivative 1j furnished two separable regioisomers 2j and 2j0 in 72%
overall yield in favor of the 1,2-fused indole 2j (ratio 3.2:1, entry 5).
The presence of an electron-withdrawing group at the terminal
position of alkyne is mandatory as the N-(5-phenylpent-4-yn-1-yl)
(1.0 atm), DMA/PivOH¼4/1, c 0.2 M at 120 ꢀC] in hand, the scope of
the domino process was next examined. The results are summa-
rized in Table 2. Substrates with electron-withdrawing or -donating

T. Piou et al. / Tetrahedron 69 (2013) 4415e4420
4417
aniline (1p) failed to produce the expected pyrrolo[1,2-a]indole 2p
(entry 7).
Treatment of 1a in the presence of a stoichiometric amount of
palladium acetate under an argon atmosphere afforded cyclization
product 2a in a similar yield (Scheme 3). This result is consistent
with the Pd(II)/Pd(0) catalytic cycle. Mechanistically, either an
intramolecular aza-Michael addition (voie a, Scheme 2) or an
intramolecular aminopalladation (voie b, Scheme 2) could
initiate the present domino process. To probe the reaction mech-
anism, (E)-ethyl-2-(1-phenylpyrrolidin-2-ylidene)acetate (3a) was
synthesized.20 Submitting 3a to our standard conditions afforded
2a in only 7% yield together with pyrrole (5, 8%)21 and recovered
starting material (Scheme 4). The result of this control experiment
indicated that the voie a might not be the main pathway re-
sponsible for the conversion of 1a to 2a. It is interesting to note that
Glorius has observed that N-methyl N-phenyl enaminone 6 failed to
undergo the intramolecular dehydrogenative coupling to form in-
dole under the conditions that were effective for the cyclization of
secondary enaminone 7.10b The deviation from the co-planarity
between nitrogen atom and the double bond in tertiary enami-
Scheme 4. Control experiment: attempted cyclization of enaminone 3a under opti-
mized conditions.
3. Conclusion
In summary, we disclosed a palladium-catalyzed one-step syn-
nones 3a and 6 could reduce the nucleophilicity of its b-carbon,
thesis of pyrrolo[1,2-a]indoles (2) from diversely substituted ethyl
impeding therefore the formation of the vinyl palladium in-
termediate of type B, hence the failure of the cyclization.
6-(phenylamino)hex-2-ynoates.
A domino sequence involving
intramolecular aminopalladation followed by direct CeH arylation
was proposed to account for the bis-cyclization process.
4. Experimental part
4.1. General information
€
Melting points (mp) were recorded using Buchi B-540 melting
point apparatus and are uncorrected. Infrared spectra were recor-
ded on a Perkin Elmer Spectrum BX FT-IR spectrometer. Proton
NMR (1H) spectra were recorded at 500 MHz on a Bruker AC-500
spectrometer or at 300 MHz on a Bruker AC-300 spectrometer.
Carbon NMR (13C) spectra were similarly recorded at 125 or
75 MHz. Proton NMR (1H NMR) and carbon NMR (13C NMR)
chemical shifts (d) are reported in parts per million (ppm) relative
to residual proton signals in CDCl3
(d
¼7.26, 77.23). Coupling con-
stants (J) are reported in Hertz (Hz) and refer to apparent multi-
plicities. The following abbreviations are used for the multiplicities:
s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sex: sextet,
sept: septet, m: multiplet. Mass spectra were obtained either from
an AEI MS-50 (EI) or an AEI MS-9 using positive or negative electron
spray (ESþ or ESꢁ) for the high resolution mass spectra (HRMS).
Flash chromatography was performed using SDS silicagel 60
Scheme 2. Proposed mechanism for the domino process.
(35e70 mm). Thin layer chromatography (TLC) was carried out on
5ꢂ20 cm plates with a layer thickness of 0.25 mm (SDS Silicagel 60
F254). Visualization was achieved under a UVP mineralight UVGL-
58 lamp. All reagents were obtained from commercial suppliers
unless otherwise stated. When necessary, organic solvents were
routinely dried and/or distilled prior to use and stored over mo-
lecular sieves under argon. Procedures for the synthesis of sub-
strates 1aep and 3a are detailed in the Supplementary data.
Scheme 3. Reaction of 1a in the presence of a stoichiometric amount of palladium
acetate under argon atmosphere.
4.2. General procedure for the pyrrolo[1,2-a]indoles
On the basis of these preliminary results, we assumed that voie
b (Scheme 2) would be operative to account for the formation of
pyrrolo[1,2-a]indoles (2) from linear precursors 1. Coordination of
Pd(II) to the substrate 1 followed by syn-aminopalladation of alkyne
via intermediate A would afford the vinyl-Pd(II) complex B.22 Acti-
vation of the neighboring aromatic CeH bond would lead to the
formation of a six-membered palladacycle C, which upon reductive
elimination would provide the pyrrolo[1,2-a]indole 2 and Pd(0).
Oxidation of Pd(0) to Pd(II) by O2 completed then the catalytic cycle.
formations
To a solution of 1 (1.0 equiv) in a mixture of DMA/PivOH (v/v¼4/
1, c 0.16 M) was added Pd(OAc)2 (0.1 equiv). The reaction mixture
was stirred under oxygen atmosphere at 120 ꢀC until the complete
disappearance of the starting material (monitored by TLC, usually
4 h). The solution was then cooled to rt, diluted with ethyl acetate,
and washed with water, saturated aqueous NaHCO3, successfully.
The organic phase was dried over Na2SO4 and filtered. The filtrate

4418
T. Piou et al. / Tetrahedron 69 (2013) 4415e4420
was concentrated under vacuum. The residue was purified by flash
1299, 1190, 1138, 1089, 762, 735. 1H NMR (300 MHz, CDCl3)
d 7.52 (s,
column chromatography on silica gel.
1H), 7.30e7.23 (m, 1H), 7.16 (d, J¼7.6 Hz, 1H), 4.50 (q, J¼7.2 Hz, 2H),
4.28 (t, J¼7.0 Hz, 2H), 3.48 (t, J¼7.0 Hz, 2H), 3.04 (s, 3H), 2.80 (quint,
J¼7.0 Hz, 2H), 1.57 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)
4.3. Characterization data
d
165.4, 153.3, 133.6, 132.6, 129.5,124.1,122.1, 107.7,100.8, 59.6, 44.9,
4.3.1. Ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate
27.6, 26.4, 22.9, 14.8. HRMS m/z (ESþ) calcd for C15H18NO2:
(2a). Yield¼63%. Orange solid. Mp 87e89 ꢀC. 1H NMR (300 MHz,
244.1338, found 244.1341.
CDCl3)
d
7.95 (dd, J¼2.1, 6.0 Hz, 1H), 7.09e7.00 8 (m, 3H), 4.20 (q,
J¼7.0 Hz, 2H), 3.90 (t, J¼7.2 Hz, 2H), 2.46 (quint, J¼7.0 Hz, 2H), 1.26
(t, J¼7.0 Hz, 3H). 1H NMR spectroscopic data is identical to those
reported in the literature.3h
4.3.8. Ethyl 8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
xylate (2g0). Yield¼38%. Orange solid. Mp 98e100 ꢀC. Rf (toluene/
EtOAc 9:1) 0.56. IR (neat, cmꢁ1
) n 2978, 1679, 1542, 1427, 1372, 1209,
1128, 1106, 1038, 811, 781, 744. 1H NMR (500 MHz, CDCl3)
d 7.97 (dd,
4.3.2. Ethyl 7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
J¼0.9, 7.78 Hz, 1H), 7.05 (m, 2H), 4.35 (q, J¼7.1 Hz, 2H), 4.06 (t,
xylate (2b). Yield¼41%. Orange solid. Mp 114e116 ꢀC. Rf (heptane/
J¼7.0 Hz, 2H), 3.26 (t, J¼7.0 Hz, 2H), 2.63 (quint, J¼7.0 Hz, 2H), 2.47
EtOAc 9:1) 0.53. IR (neat, cmꢁ1
)
n
2900, 1673, 1606, 1578, 1479, 1377,
(s, 3H), 1.41 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 165.8,
1301,1229,1132,1041, 805, 796, 713.1H NMR (300 MHz, CDCl3)
d
7.64
152.5, 133.2, 131.7, 128.9, 123.3, 121.3, 110.1, 99.4, 59.4, 44.5, 26.8,
26.3, 21.8, 14.9. HRMS m/z (ESþ) calcd for C15H17NO2Na: 266.1157,
found 266.1161.
(d, J¼2.4 Hz, 1H), 7.12 (d, J¼8.6 Hz, 1H), 6.83 (dd, J¼2.4, 8.6 Hz, 1H),
4.35 (q, J¼7.2 Hz, 2H), 4.07 (t, J¼7.0 Hz, 2H), 3.89 (s, 3H), 3.27 (t,
J¼7.0 Hz, 2H), 2.63 (quint, J¼7.0 Hz, 2H), 1.41 (t, J¼7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3)
d
165.8, 155.9, 153.1, 132.1, 128.0, 111.7, 110.7,
4.3.9. Ethyl 5-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
103.7, 99.3, 59.4, 56.0, 44.9, 26.8, 26.6,14.9. HRMS m/z (ESþ) calcd for
xylate (2h). Yield¼18%. Orange solid. Mp 117e118 ꢀC. Rf (toluene/
C15H18NO3: 260.1287, found 260.1300.
EtOAc 8:2) 0.55. IR (neat, cmꢁ1
) n 2996, 1668, 1618, 1551, 1469, 1383,
1231, 1161, 1047, 838, 742. 1H NMR (500 MHz, CDCl3)
d 7.98 (d,
4.3.3. Diethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-7,9-dicarboxylate
J¼8.1 Hz, 1H), 7.11 (t, J¼8.1 Hz, 1H), 6.94 (d, J¼8.1 Hz, 1H), 4.42 (t,
J¼7.2 Hz, 2H), 4.37 (q, J¼7.0 Hz, 2H), 3.26 (t, J¼7.2 Hz, 2H), 2.66 (s,
3H), 2.63 (quint, J¼7.2 Hz, 2H), 1.43 (t, J¼7.0 Hz, 3H). 13C NMR
(2c). Yield¼63%. Yellow solid. Mp 130e131 ꢀC. Rf (toluene/EtOAc
9:1) 0.41. IR (neat, cmꢁ1
) n 2980, 1706, 1685, 1424, 1269, 1198, 1109,
1024, 923, 835, 767, 677. 1H NMR (300 MHz, CDCl3)
d
8.81 (d,
(75 MHz, CDCl3) d 165.8, 153.3, 132.5, 131.4, 123.6, 121.9, 120.9, 119.4,
J¼1.2 Hz, 1H), 7.90 (dd, J¼1.2, 8.3 Hz, 1H), 7.20 (d, J¼8.3 Hz, 1H),
4.43-4.33 (m, 4H), 4.09 (t, J¼7.2 Hz, 2H), 4.27 (t, J¼7.2 Hz, 2H), 2.65
(quint, J¼7.2 Hz, 2H), 1.42 (t, J¼7.1 Hz, 3H), 1.41 (t, J¼7.1 Hz, 3H). 13C
99.5, 59.4, 47.8, 27.0, 25.8, 18.1, 14.9. HRMS m/z (ESþ) calcd for
C15H18NO2: 244.1338, found 244.1339.
NMR (75 MHz, CDCl3)
d
ppm 167.8, 165.2, 154.3, 135.2, 130.6, 124.1,
4.3.10. Ethyl 6,8-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-car-
124.0, 123.5, 109.6, 100.7, 60.8, 59.7, 44.7, 26.8, 26.3, 14.8, 14.6.
HRMS m/z (ESþ) calcd for C17H19NO4Na: 324.1212, found 324.1227.
boxylate (2i). Yield¼72%. Yellow solid. Mp 155e158 ꢀC. Rf (toluene/
EtOAc 9:1) 0.67. IR (neat, cmꢁ1
) n 2978, 1681, 1525, 1420, 1370, 1202,
1176, 1093, 1034, 841, 783, 748. 1H NMR (500 MHz, CDCl3)
d 6.83 (d,
4.3.4. Ethyl 7-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxy-
J¼2.2 Hz, 2H), 4.31 (q, J¼7.1 Hz, 2H), 4.00 (t, J¼7.0 Hz, 2H), 3.24 (t,
late (2d). Yield¼46%. Orange solid. Mp 190e193 ꢀC. Rf (toluene/
J¼7.0 Hz, 2H), 2.83 (s, 3H), 2.56 (quint, J¼7.0 Hz, 2H), 2.42 (s, 3H),1.38
EtOAc 8:2) 0.30. IR (neat, cmꢁ1
)
n
2986, 2215, 1675, 1614, 1421, 1224,
(t, J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 165.4, 152.8, 133.9, 132.1,
1156, 1111, 888, 832, 783, 744. 1H NMR (300 MHz, CDCl3)
d
8.40 (d,
131.8, 127.2, 125.7, 107.7, 100.4, 59.4, 44.6, 27.5, 26.2, 22.7, 21.5, 14.8.
J¼1.5 Hz, 1H), 7.40 (dd, J¼1.5, 8.4 Hz, 1H), 7.26 (d, J¼8.4 Hz, 1H), 4.38
(q, J¼7.4 Hz, 2H), 4.15 (t, J¼7.4 Hz, 2H), 3.31 (t, J¼7.2 Hz, 2H), 2.71
(quint, J¼7.2 Hz, 2H), 1.43 (t, J¼7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3)
HRMS m/z (ESþ) calcd for C16H19NO2Na: 280.1313, found 280.1319.
4.3.11. Ethyl 9,10-dihydro-8H-benzo[e]pyrrolo[1,2-a]indole-11-carbo-
d
164.7, 155.0,134.3, 130.7, 126.8, 125.0, 120.7, 110.8,104.7, 100.5, 60.0,
xylate (2j). Yield¼54%. Orange solid. Mp 169e172 ꢀC. Rf (toluene/
44.9, 26.8, 26.2, 14.8. HRMS m/z (ESþ) calcd for C15H14N2O2Na:
EtOAc 9:1) 0.65. IR (neat, cmꢁ1
) n 2987, 1706,1682, 1453, 1379, 1264,
277.0953, found 277.0951.
1139, 1027, 800, 768, 685. 1H NMR (300 MHz, CDCl3)
d 9.80 (d,
J¼8.7 Hz, 1H), 7.89 (d, J¼7.9 Hz, 1H), 7.62e7.56 (m, 2H), 7.45 (t,
J¼7.9 Hz, 1H), 7.27 (d, J¼7.9 Hz, 1H), 4.38 (q, J¼7.2 Hz, 2H), 4.03 (t,
J¼7.1 Hz, 2H), 3.18 (t, J¼7.1 Hz, 2H), 2.48 (quint, J¼7.1 Hz, 2H),1.43 (t,
4.3.5. Ethyl 7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
xylate (2e). Yield¼51%. Orange solid. Mp 77e78 ꢀC. 1H NMR
(300 MHz, CDCl3)
d
7.91 (d, J¼1.4 Hz, 1H), 7.12 (d, J¼8.0 Hz, 1H), 7.01
J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 165.8, 151.4, 130.6, 129.8,
(dd, J¼1.4, 8.0 Hz, 1H), 4.36 (q, J¼7.2 Hz, 2H), 4.06 (t, J¼7.0 Hz, 2H),
3.26 (t, J¼7.0 Hz, 2H), 2.62 (quint, J¼7.0 Hz, 2H), 2.48 (s, 3H), 1.41 (t,
J¼7.2 Hz, 3H). 1H NMR spectroscopic data is identical to those re-
ported in the literature.3b
129.1, 128.5, 127.2, 125.7, 125.2, 123.9, 123.8, 111.2, 102.5, 59.7, 45.0,
28.0, 26.0, 14.8. HRMS m/z (ESþ) calcd for C18H17NO2Na: 302.1157,
found 302.1167.
4.3.12. Ethyl 2,3-dihydro-1H-benzo[f]pyrrolo[1,2-a]indole-11-carbo-
4.3.6. Ethyl 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
xylate (2j0). Yield¼18%. Red solid. Mp 160e164 ꢀC. Rf (heptane/
xylate (2f). Yield¼46%. Orange solid. Mp 141e142 ꢀC. Rf (toluene/
EtOAc 9:1) 0.51. IR (neat, cmꢁ1 1H NMR (500 MHz, CDCl3)
) n d 8.59
EtOAc 9:1) 0.65. IR (neat, cmꢁ1
)
n
2978,1682,1544,1448,1425,1376,
(s, 1H), 8.02e7.99 (m, 1H), 7.91e7.88 (m, 1H), 7.64 (s, 1H), 7.40e7.37
(m, 2H), 4.42 (q, J¼7.2 Hz, 2H), 4.19 (t, J¼6.9 Hz, 2H), 3.38 (t,
J¼6.9 Hz, 2H), 2.72 (quint, J¼6.9 Hz, 2H), 1.46 (t, J¼7.2 Hz, 3H). 13C
1317, 1202, 1103, 1037, 886, 778. 1H NMR (300 MHz, CDCl3)
d 8.07
(m, 1H), 7.13 (m, 2H), 4.36 (q, J¼7.0 Hz, 2H), 4.09 (t, J¼7.4 Hz, 2H),
3.28 (t, J¼7.4 Hz, 2H), 2.66 (quint, J¼7.4 Hz, 2H), 1.41 (t, J¼7.0 Hz,
NMR (75 MHz, CDCl3) d 157.9, 133.7, 132.0, 130.1, 129.9, 128.8, 127.5,
3H). 13C NMR (75 MHz, CDCl3)
d
165.3, 154.1, 132.1, 131.3, 127.7,
124.3,123.5,119.4,105.7, 59.6, 44.7, 29.9, 26.8,15.0. HRMS m/z (ESþ)
122.2, 121.3, 110.9, 99.5, 59.7, 44.9, 26.8, 26.4, 14.9. HRMS m/z (ESþ)
calcd for C18H17NO2Na: 302.1157, found 302.1167.
calcd for C14H14NO2NaCl: 286.0611, found 286.0617.
4.3.13. Ethyl 2,2-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
4.3.7. Ethyl 6-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carbo-
carboxylate (2k). Yield¼70%. White solid. Mp 83e84 ꢀC. Rf (tolu-
xylate (2g). Yield¼45%. Orange solid. Mp 94e97 ꢀC. Rf (toluene/
ene/EtOAc 9:1) 0.58. IR (neat, cmꢁ1
) n 2954, 1674, 1543, 1431, 1208,
EtOAc 9:1) 0.77. IR (neat, cmꢁ1
)
n
2924, 1684, 1528, 1443, 1421, 1342,
1102, 1042, 1012, 922, 784, 747, 736. 1H NMR (500 MHz, CDCl3)

T. Piou et al. / Tetrahedron 69 (2013) 4415e4420
4419
d
8.13 (d, J¼7.6 Hz, 1H), 7.27e7.19 (m, 3H), 4.38 (q, J¼7.1 Hz, 2H),
References and notes
3.85 (s, 2H), 3.12 (s, 2H), 1.43 (t, J¼7.1 Hz, 3H), 1.34 (s, 6H). 13C NMR
1. (a) Orlemans, E. O. M.; Verboom, W.; Scheltinga, M. W.; Reinhoudt, D. N.;
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(75 MHz, CDCl3) d 165.8, 152.3, 133.2, 130.6, 121.9, 109.9, 100.2, 59.5,
57.8, 43.7, 41.7, 28.2, 14.9. HRMS m/z (ESþ) calcd for C16H19NO2Na:
€ €
280.1313, found 280.1321.
Thorson, J. S.; Shen, B. Chem. Rev. 2005, 105, 739e758; (c) Vepsalainen, J. J.;
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dole-7,9-dicarboxylate (2l). Yield¼69%. Yellow solid. Mp 100e102 ꢀC.
Rf (toluene/EtOAc 9:1) 0.80. IR (neat, cmꢁ1
) n 2960, 1698, 1536, 1415,
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1339, 1168, 1086, 1038, 820, 782. 1H NMR (500 MHz, CDCl3)
d 6.84 (s,
2H), 4.32 (q, J¼7.0 Hz, 2H), 3.78 (s, 2H), 3.09 (s, 2H), 2.84 (s, 3H), 2.43
(s, 3H), 1.39 (t, J¼7.0 Hz, 3H), 1.32 (s, 6H). 13C NMR (75 MHz, CDCl3)
d
165.4, 152.0, 134.2, 132.1, 131.8, 126.7, 125.6, 107.6, 101.1, 59.5, 57.8,
42.9, 42.9, 28.2, 22.7, 21.5,14.8. HRMS m/z (ESþ) calcd for C18H24NO2:
286.1807, found 286.1795.
4.3.15. Ethyl 2,2,6,8-tetramethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-
9-carboxylate (2m). Yield¼77%. Yellow solid. Mp 100e102 ꢀC. Rf
(toluene/EtOAc 9:1) 0.80. IR (neat, cmꢁ1
) n 2960, 1698, 1536, 1415,
1339, 1168, 1086, 1038, 820, 782. 1H NMR (500 MHz, CDCl3)
d 6.84 (s,
2H), 4.32 (q, J¼7.0 Hz, 2H), 3.78 (s, 2H), 3.09 (s, 2H), 2.84 (s, 3H), 2.43
(s, 3H), 1.39 (t, J¼7.0 Hz, 3H), 1.32 (s, 6H). 13C NMR (75 MHz, CDCl3)
d
165.4, 152.0, 134.2, 132.1, 131.8, 126.7, 125.6, 107.6, 101.1, 59.5, 57.8,
42.9, 42.9, 28.2, 22.7, 21.5,14.8. HRMS m/z (ESþ) calcd for C18H24NO2:
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286.1807, found 286.1795.
4.3.16. Methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate
(2n). Yield¼51%. White solid. Mp 75e78 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
8.12e8.09 (m, 1H), 7.26e7.19 (m, 3H), 4.07 (t, J¼7.2 Hz,
2H), 3.90 (s, 3H), 3.27 (t, J¼7.2 Hz, 2H), 2.63 (quint, J¼7.2 Hz, 2H). 1H
NMR spectroscopic data is identical to those reported in the
literature.3h
4.3.17. Isopropyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate
(2o). Yield¼47%. Orange solid. Mp 94e96 ꢀC. Rf (toluene/EtOAc
9:1) 0.62. IR (neat, cmꢁ1
) n 2978, 1678, 1543, 1425, 1382, 1300, 1203,
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d
8.03 (dd, J¼1.9,
~
ꢀ
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8.3 Hz, 1H), 7.12e7.04 (m, 3H), 5.13 (sept, J¼6.2 Hz, 1H), 3.94
(t, J¼7.1 Hz, 2H), 3.14 (t, J¼7.1 Hz, 2H), 2.50 (quint, J¼7.1 Hz, 2H),
1.25 (d, J¼6.2 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d 165.3,
152.9, 132.9, 131.1, 121.8, 121.7, 121.6, 110.0, 99.9, 66.6, 44.6, 26.8,
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266.1150.
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1460, 1368, 1324, 1324, 1257, 1178, 1141, 1031, 768, 697, 676. 1H NMR
(500 MHz, CDCl3)
d
7.44 (t, J¼7.0 Hz, 2H), 7.37 (t, J¼7.0 Hz, 1H), 7.32
(d, J¼7.0 Hz, 2H), 6.80 (m, 1H), 6.26 (t, J¼2.7 Hz, 1H), 6.24 (m, 1H),
4.06 (q, J¼7.4 Hz, 2H), 3.59 (s, 2H), 1.17 (t, J¼7.4 Hz, 3H). 13C NMR
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Acknowledgements
Financial support from EPFL (Switzerland), Swiss National Sci-
ence Foundation (SNF), Swiss National Centres of Competence in
Research (NCCR) and ICSN, CNRS (France) are gratefully acknowl-
edged. T.P. thanks ICSN and EPFL for a doctoral fellowship.
Supplementary data
€
€
10. (a) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int.
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.01.003.
€
€
Ed. 2008, 47, 7230e7233; (b) Neumann, J. J.; Souvik, R.; Droge, T.; Wurtz, S.;
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T. Piou et al. / Tetrahedron 69 (2013) 4415e4420
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