Improved preparation of alkyl 2-(3-indolyl)-3-nitroalkanoates under fully heterogeneous conditions: stereoselective synthesis of alkyl (E)-2-(3-indolyl)-2-alkenoates

Article abstract of DOI:10.1016/j.tet.2008.04.014

Ethyl 3-nitro-2-alkenoates can be generated starting from nitroalkanes and ethyl 2-oxoacetate under heterogeneous conditions that minimize work-up procedures, avoid any purification step and direct manipulation of the nitroalkene system. Reaction of ethyl 3-nitro-2-alkenoates, formed in situ from their acetoxy precursors, with indoles in the presence of basic alumina affords ethyl 2-(3-indolyl)-3-nitroalkanoates that are central intermediates for the preparation of tryptamines and carboline alkaloids. A base promoted elimination of nitrous acid from these nitroindolyl derivatives readily produces ethyl 2-(3-indolyl)-2-alkenoates with high E stereoselectivity. The latter compounds can be used as Michael acceptors in intra- and intermolecular reactions with nucleophilic reagents.

Full text of DOI:10.1016/j.tet.2008.04.014

Tetrahedron 64 (2008) 5435–5441
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved preparation of alkyl 2-(3-indolyl)-3-nitroalkanoates under
fully heterogeneous conditions: stereoselective synthesis of alkyl
(E)-2-(3-indolyl)-2-alkenoates
*
*
Roberto Ballini, Serena Gabrielli, Alessandro Palmieri , Marino Petrini
`
Dipartimento di Scienze Chimiche, Universita di Camerino, via S. Agostino, 1. I-62032 Camerino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethyl 3-nitro-2-alkenoates can be generated starting from nitroalkanes and ethyl 2-oxoacetate under
heterogeneous conditions that minimize work-up procedures, avoid any purification step and direct
manipulation of the nitroalkene system. Reaction of ethyl 3-nitro-2-alkenoates, formed in situ from their
acetoxy precursors, with indoles in the presence of basic alumina affords ethyl 2-(3-indolyl)-3-nitro-
alkanoates that are central intermediates for the preparation of tryptamines and carboline alkaloids. A
base promoted elimination of nitrous acid from these nitroindolyl derivatives readily produces ethyl
2-(3-indolyl)-2-alkenoates with high E stereoselectivity. The latter compounds can be used as Michael
acceptors in intra- and intermolecular reactions with nucleophilic reagents.
Received 29 January 2008
Received in revised form 19 March 2008
Accepted 3 April 2008
Available online 8 April 2008
Keywords:
Conjugate addition
Heterogeneous catalysis
Indoles
Ó 2008 Elsevier Ltd. All rights reserved.
Nitroaldol reaction
Nitroalkenes
1. Introduction
involving a base promoted elimination of nitrous acid leading to
a,
b
-unsaturated esters 4 (Scheme 1).6
The addition reaction of indole derivatives to electron-poor
olefins represents a useful procedure to introduce functionalized
substituents at the 3-position of this heterocyclic ring. Activation of
the alkene moiety toward this addition can be realized using
Brønsted or Lewis acid catalysts, in a process that can be regarded
as a Friedel–Crafts reaction.1 Conversely, deprotonation of the ni-
trogen atom in indoles by basic reagents, affords the corresponding
anion that is nucleophilic enough to undergo a conjugate addition
to Michael acceptors.2 The latter option is particularly effective
when strong electrophilic olefins such as nitroalkenes are used in
the conjugate addition.3 The interest in such adducts is widely
justified by their role as central intermediates for the synthesis of
many pharmacologically active compounds.4 Among different
nitroalkenes, 3-nitro-2-alkenoates 1 occupy an intriguing position
since the nitro and the carboxylic groups activate both termini of
the carbon–carbon double bond. The superior electron-withdraw-
ing aptitude exerted by the nitro group usually leads to an anti-
Michael addition of nucleophiles to these derivatives (resulting in
3).5 The obtained products, besides the usual transformations of the
nitro and ester groups, may enjoy an additional synthetic option
O2N
CO2R
2
Michael addition
Nu
R
Nu
O2N
CO2R
Nu
Nu
R
B
-HNO2
O2N
1
CO2R
CO2R
R
R
3
4
anti-Michael addition
Scheme 1.
Recently, we have devised a new procedure for the conjugate
addition of indoles 5 to nitroalkenes 6 in the presence of basic
alumina under solventless conditions (Scheme 2).7 Basic alumina is
also able to promote the nitroaldol condensation8 between
a nitroalkane 8 and an aldehyde 9 leading to the corresponding
nitro alcohol 10, which upon heating under the same conditions
dehydrates to the parent nitroalkene 6.9
Therefore, using basic alumina as the single promoter, it is
possible to avoid direct manipulation of nitroalkenes 6 that often
are toxic and lachrymatory compounds, generating them directly in
the reaction vessel from their remote precursors.10 This appealing
procedure is not applicable to 3-nitro-2-alkenoates 1 since their
nitro alcohol precursors are not efficiently dehydrated under the
* Corresponding authors. Tel.: þ39 0737 402253; fax: þ39 0737 402297.
E-mail addresses: alessandro.palmieri@unicam.it (A. Palmieri), marino.petrini@
unicam.it (M. Petrini).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.014

5436
R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
NO2
MeO
NO2
R1
O
NO2
Al2O3
EtO2C
R
Ph
+
R1
basic, r.t.
R
H
N
H
CO2Et
Ph
MeO
5c
OH
O2N
8
9
10
OAc
basic Al2O3, 2 h, 60 °C
90%
N
[-H2O]
H
60 °C
7k
11k
NO2
R
NO2
R1
Scheme 3.
R3
R1
R2
R3
R
6
R2
N
basic Al2O3, 60 °C
N
H
H
Further studies aimed at optimization of the overall procedure
gave the results displayed in Table 2. The nitroaldol condensation of
nitroalkanes 8 with ethyl 2-oxoacetate 9a is carried out under
heterogeneous conditions using Amberlyst A21 as basic promo-
ter.12c,16 After the appropriate time (see Table 2), the solution
containing the nitro alcohol 10 is filtered and to this solution are
added acetic anhydride and Amberlyst 15, a macroreticular resin
endowed with acid character which is able to promote the acety-
lation process.
Once the esterification is complete, the solvent and excess of
acetic anhydride are removed at reduced pressure and compound
11 thus obtained can be used for the next step that simply involves
addition of indole 5 and basic alumina and heating the solid mix-
ture at 60 ꢀC. Reaction on solid support avoids any work-up pro-
cedure at the end of the process since direct application of the
mixture to the head of a chromatographic column and elution with
an appropriate solvent system affords pure 3-substituted indoles 7.
The whole procedure is thus effected using a limited amount of
ethyl acetate,17 and executing a single purification step as regards
the final product. The yields of the obtained 3-substituted indoles 7
are particularly good given that they refer to four synthetic oper-
ations. The diastereomeric ratio for compounds 7 is generally rather
modest in most of the prepared products. Ethyl 2-(3-indolyl)-3-
nitroalkanoates 7 obtained by this procedure find several applica-
tions as pivotal intermediates for the synthesis of tryptamine
derivatives 12 easily obtainable by simple reduction of the nitro
group (Scheme 4). Tryptamines are, in turn, starting materials for
7
5
Scheme 2.
usual reaction conditions. Keeping in mind that organic reactions
on solid supports represent a crucial feature for the development of
environmentally friendly chemical processes,11 a study has been
undertaken with the aim to realize an efficient conjugate addition
of indole derivatives to 3-nitro-2-alkenoates produced in situ from
their forerunners. In this paper, we present the results of our syn-
thetic efforts and, in addition, we demonstrate that a base-induced
elimination of nitrous acid from 2-(3-indolyl)-3-nitroalkanoates
provides a rapid entry into the corresponding
esters.
a,b-unsaturated
2. Results and discussion
Direct utilization of 3-nitro-2-alkenoates in the reaction with
indoles in the presence of basic alumina has been previously tested
only for a single example,7 and therefore we decided to verify its
applicability for a selected combination of substrates. As shown in
Table 1, conjugate addition of indoles 5 to 3-nitro-2-alkenoates 112
occurs with a satisfactory degree of efficiency to give excellent
yields of the obtained adducts 7.
The observed failure in direct dehydration of nitro alcohols 10
often stems from a retro aldol reaction that shifts the equilibrium
toward the starting materials.13 Acylation of the hydroxy group in
compound 10 would represent a doubly favorable issue since it
avoids the retro aldol process and makes the ester a better leaving
group for the elimination reaction.14 As a possible acyl moiety for
this process, we preferred the acetyl group since it is easily in-
troduced using acetic anhydride under heterogeneous conditions
and upon elimination produces non-toxic acetic acid salts.15 This
solution proved to be successful since acetylated nitro alcohol 11k
undergoes addition to indole 5c via the corresponding nitroalkene
leading to 3-substituted indole 7k (Scheme 3).
the preparation of tetrahydro
b-carbolines 13 exploiting a Pictet–
Spengler reaction with carbonyl derivatives.18 Compounds 13 can
be easily conveted into
aromatization.7b
b-carboline alkaloids 14 by a final oxidative
However, we were attracted by the possibility, offered by the
presence of the nitro group at the -position, of introducing a fur-
ther unsaturation in the alkyl framework thus generating an a,b-
b
unsaturated ester. Elimination of nitrous acid from 3-nitro esters is
a common practice in many synthetic processes and can be easily
carried out under basic conditions.19 As testified by the high yields
obtained in the conjugate additions of indoles 5 to ethyl 3-nitro-2-
alkenoates 1, basic alumina is practically unable to provide this
elimination (Table 1). The basic character of alumina can be en-
hanced upon addition of KF but this operation provides only
a modest result in the elimination of nitrous acid from indole 7h
(Table 3, entry 1).20
A survey of other base/solvent combinations running under
homogeneous conditions, allowed us to identify tetramethylgua-
nidine (TMG) as the best promoter for elimination of nitrous acid
from 3-substituted indoles 7h (Table 3, entry 3). This base gives
satisfactory results with most of the nitro esters 7 leading to the
Table 1
Basic alumina promoted conjugate addition of indoles 5 to ethyl 3-nitro-2-alke-
noates 1
NO2
EtO2C
CO2Et
R3
R1
R2
R3
basic Al2O3
2 h, 60°C
NO2
R2
+
N
H
R1
N
H
1
5
7
corresponding a,b-unsaturated esters 15 in good yields (Table 4).
The only disappointing result is obtained using ethyl 2-(3-indolyl)-
3-nitropropanoate 7g. Since it is unsubstituted at the 3-position it
probably gives a rather unstable alkenoate 15g that is difficult to
recover in pure form. A considerable level of diastereoselectivity is
also observed in compound 15 with the E stereoisomer largely
prevalent. The E stereochemistry of the double bond has been
assigned by evaluating the NOE effect by irradiation of the methyl
Entry
R1
R2
R3
Product 7
Yielda (%)
1
2
3
4
5
Me
n-Pr
CH3(CH2)3
CH3(CH2)3
AcO(CH2)3
H
H
H
Me
H
H
OMe
H
H
OMe
7a
7b
7c
7d
7e
90
88
94
92
91
a
Yield of pure isolated product.

R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
5437
Table 2
Synthesis of ethyl 2-(3-indolyl)-3-nitroalkanoates 7 by conjugate addition of indoles 5 to ethyl 3-nitro-2-alkenoates obtained from their remote precursors under hetero-
geneous conditions
R3
NO2
R2
EtO2C
OH
CO2Et
NO2
OAc
CO2Et
O
N
H
R1
R2
Amberlyst A21
AcOEt, r.t.
5
R1
R3
Amberlyst 15
Ac2O, AcOEt, r.t.
R1
+
R1
H
CO2Et
basic Al2O3, 60°C
NO2
NO2
N
H
8
9a
10
11
7
Entry
R1
R2
R3
H
OMe
H
Reaction time (h)
Yielda (%)
Diastereomeric ratioc
10
11
7
1
2
3
4
5
6
7
8
Me
n-Pr
CH3(CH2)3
CH3(CH2)3
AcO(CH2)3
Me
H
H
H
Me
H
H
H
Me
H
Me
H
17
16
16
16
16
18
d
18
17
17
17
1
1
5.5
6.5
5
2
3
7a
7b
7c
7d
7e
7f
7g
7h
7i
56
57
55
56
55
55
80b
53
51
55
56
1:1
3:2
3:1
3:1
1:1
3:1
d
1.5
1.5
1
1
d
H
OMe
OMe
H
H
H
6
H
Et
1.5
1.5
8
2.5
5
1
1.5
1
4:1
3:1
3:2
3:2
9
10
11
CH3(CH2)4
Ph(CH2)2
Ph(CH2)2
H
OMe
7j
7k
1
a
Yield of pure isolated product after three steps.
b
c
Yield of pure isolated product 7g (methyl ester) starting from compound 11g (methyl ester) and indole.
Diastereomeric ratio was evaluated by 1H NMR spectroscopy.
Table 4
NO2
R2
NH2
R2
R1O2C
R1O2C
Synthesis of ethyl 2-(3-indolyl)-2-alkenoates 15 by TMG promoted elimination of
nitrous acid from ethyl 2-(3-indolyl)-3-nitroalkanoates 7
R
R
R3CHO
R
[H]
NO2
EtO2C
EtO2C
Lewis acid
N
or H+
N
R1
R2
R1
R2
H
R3
H
R3
2 eq. TMG
MeCN, r.t.
7
12 tryptamines
N
N
R2
H
H
R1O2C
R2
R1O2C
7
15
[O]
R
N
NH
R3
Entry
Nitro ester 7
Product 15
Reaction time (h)
Yielda (%)
E:Zc
R3
N
H
N
H
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
15a
15b
15c
15d
15e
15f
15g
15h
15i
4
4.5
6
14
2
2
2
17
12
7
85
93
97
80
91
95
20b
84
76
90
96
94:6
94:6
92:8
95:5
95:5
96:4
d
13 tetrahydro β-carbolines
14 β-carbolines
Scheme 4.
signal in compound 15a. The enhancement of the peak intensity of
protons at C-2 and C-4 of the indole ring reveals a proximity effect
with the methyl group that is compatible with the E stereochem-
istry. The chemical shift of the vinyl protons for the E stereoisomer
is always downfield relative to those of the Z in compounds 15 and
this correlates with the values reported for a similar derivative
bearing a phenyl group instead of the indole ring.21 Finally, these
96:4
93:7
93:7
95:5
9
10
11
7j
7k
15j
15k
2
a
Yield of pure isolated product.
Extensive product decomposition is observed soon after isolation.
Diastereomeric ratio was evaluated by 1H NMR spectroscopy.
b
c
Table 3
results are consistent with those obtained in a related process
involving a tandem conjugate addition of nitroalkanes to dialkyl
2-butenedioates followed by elimination of nitrous acid.19 Un-
saturated esters of type 15 are rather uncommon, but according to
their structural features these derivatives are possible candidates
for conjugate additions with external nucleophiles or involved in
intramolecular processes.
As a matter of fact, ethanolysis of the acetoxy group in
compound 15e is followed by a ring closure leading to the forma-
tion of a tetrahydrofuran derivative 16 by an oxy-Michael process
(Scheme 5).
Alternatively, chemoselective hydrolysis of the acetoxy group in
compound 15e leads to ester 17 in which the free hydroxy group is
amenable to further synthetic transformations. A further synthetic
option concerning compounds 15 could involve their utilization as
dienes in Diels–Alder reactions. Indeed, the modest aromaticity
Screening of different base/solvent combinations for elimination of nitrous acid
from ethyl 2-(3-indolyl)-3-nitroalkanoates 7
NO2
EtO2C
EtO2C
base
N
N
H
H
7h
15h
Entry
Reaction conditions
Reaction time (h)
Yielda (%)
1
2
3
4
KF/basic Al2O3, THF, refluxb
2 equiv DBU, MeCN, rt
2 equiv TMG, MeCN, rt
2 equiv Bu3P, MeCN, rt
2.5
1.5
44
52
84
17
No reaction
a
Yield of pure isolated product.
1.2 g of solid base/mmol of substrate was employed.
b

5438
R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
AcO
EtOAc (3ꢁ4 mL). The combined organic solutions were treated with
EtO2C
Ac2O (5 mmol, 0.51 g, 0.47 mL) and Amberlyst 15 (1.5 g). The
resulting mixture was stirred at room temperature for the appro-
priate time (see Table 2) and the resin was filtered off and washed
with EtOAc (3ꢁ6 mL). The crude product 11 obtained after removal
of the solvent and excess of Ac2O was mixed with indole 5
(2.5 mmol) and activated basic alumina (3 g) and then vigorously
stirred at 60 ꢀC. After the reaction was complete (see Table 2), the
solid mixture upon cooling was directly charged on a chromatog-
raphy column and eluted (hexanes/ethyl acetate 9:1) to afford pure
product 7.
MeO
N
H
15e
EtONa
EtOH, r.t., 3 h
0.25 N NaOH
THF-H2O, r.t., 7 h
EtO2C
O
HO
EtO2C
MeO
MeO
4.2.1. Ethyl 2-(1H-3-indolyl)-3-nitrobutanoate, 7a
N
H
Yield: 56% (diastereomeric ratio 1:1). Viscous red oil. IR (cmꢂ1
,
N
neat): 1360, 1557, 1732, 3410. 1H NMR (CDCl3, 400 MHz)
d: 1.17 (t,
H
(84%)
(55%)
16
17
1.5H, J¼7.3 Hz), 1.21 (t, 1.5H, J¼7.3 Hz), 1.40 (d, 1.5H, J¼6.8 Hz), 1.73
(d, 1.5H, J¼6.4 Hz), 4.01–4.27 (m, 2H), 4.45–4.53 (m, 1H), 5.29–5.40
(m, 1H), 7.09–7.27 (m, 3H), 7.28–7.32 (m, 0.5H), 7.34–7.38 (m, 0.5H),
7.66–7.74 (m, 1H), 8.68 (br s, 0.5H), 8.82 (br s, 0.5H). 13C NMR
Scheme 5.
level of the pyrrole nucleus in the indole system usually makes 3-
vinylindole derivatives suitable substrates in the inter- or intra-
molecular reaction with reactive dienophiles.22
(CDCl3, 100 MHz) d: 14.2, 14.3, 18.4, 18.6, 47.4, 48.0, 61.9, 62.0, 83.7,
85.0, 107.8, 108.2, 111.8, 112.0, 119.0, 119.1, 120.3, 120.5, 122.7, 122.9,
124.0, 124.1, 126.1, 126.2, 136.3, 136.6, 170.7, 171.8. GC–MS (70 eV):
m/z: 276 (Mþ), 229, 202, 174, 157 (100), 130. Anal. Calcd for
3. Conclusions
C14H16N2O4 (276.29): C, 60.86; H, 5.84; N, 10.14. Found: C, 61.04; H,
5.89; N, 10.12.
Organic reactions working under heterogeneous conditions are
usually featured by reduced solvent consumption, simplified work-
up procedures, and waste minimization. Application of these
principles to the preparation of ethyl 2-(3-indolyl)-3-nitro-
alkanoates involves a three-step procedure in which two macro-
reticular resins and a solid base are employed to produce four
synthetic transformations. The same solvent is used for the first
two synthetic operations, while the third one is carried out under
solventless conditions. Filtrations and solvent evaporation are the
only work-up procedures required until column chromatography
leading to pure ethyl 2-(3-indolyl)-3-nitroalkanoates that are im-
portant intermediates for the synthesis of tryptamines and carbo-
line alkaloids. A stereoselective base promoted elimination of
nitrous acid from these nitro esters allows a direct access to ethyl
(E)-2-(3-indolyl)-2-alkenoates that are amenable to further syn-
thetic transformations.
4.2.2. Ethyl 2-(5-methoxy-1H-3-indolyl)-3-nitrohexanoate, 7b
Yield: 57% (diastereomeric ratio 3:2). Yellow solid; mp 87–
91 ꢀC. IR (cmꢂ1, Nujol): 1377, 1556, 1728, 3402. 1H NMR (CDCl3,
400 MHz)
d
: 0.77 (t, 1.8H, J¼7.3 Hz), 0.98 (t, 1.2H, J¼7.3 Hz), 1.12–
1.51 (m, 5H), 1.58–1.78 (m, 1H), 1.83–1.94 (m, 0.4H), 2.03–2.19 (m,
0.6H), 3.86 (s, 1.8H), 3.87 (s, 1.2H), 4.00–4.26 (m, 2H), 4.39 (d, 0.4H,
J¼10.7 Hz), 4.47 (d, 0.6H, J¼11.5 Hz), 5.21–5.32 (m, 1H), 6.84 (dd,
0.4H, J¼2.2, 8.6 Hz), 6.89 (dd, 0.6H, J¼2.2, 8.6 Hz), 7.10–7.17 (m,
2H), 7.19 (d, 0.4H, J¼9.0 Hz), 7.27 (d, 0.6H, J¼8.6 Hz), 8.32 (br s,
0.4H), 8.46 (br s, 0.6H). 13C NMR (CDCl3, 100 MHz)
d: 13.4, 13.5,
14.1, 14.2, 18.6, 19.5, 33.8, 34.9, 46.4, 47.4, 56.0, 56.1, 61.8, 88.0, 89.9,
100.6, 100.8, 107.9, 108.1, 112.3, 112.6, 113.0, 113.3, 124.3, 126.6,
126.7, 131.3, 131.5, 154.6, 154.7, 170.7, 171.5. GC–MS (70 eV): m/z:
334 (Mþ), 287, 232 (100), 214, 186, 160, 115, 29. Anal. Calcd for
C17H22N2O5 (334.37): C, 61.07; H, 6.63; N, 8.38. Found: C, 60.93; H,
6.80; N, 8.16.
4. Experimental
4.1. General
4.2.3. Ethyl 2-(1H-3-indolyl)-3-nitroheptanoate, 7c
Yield: 55% (diastereomeric ratio 3:1). Yellow solid; mp 70–
75 ꢀC. IR (cmꢂ1, Nujol): 1365, 1552, 1733, 3405. 1H NMR (CDCl3,
1H NMR spectra were recorded at 400 MHz on a Varian Mercury
Plus 400 in CDCl3 as solvent. 13C NMR spectra were recorded at
75 MHz in CDCl3 as solvent. Microanalyses were performed with
a CHNS-O analyzer Model EA 1108 from Fisons Instruments. IR
spectra were recorded with a Perkin–Elmer Paragon 500 FT-IR. All
400 MHz)
d
: 0.74 (t, 2.4H, J¼7.3 Hz), 0.92 (t, 0.6H, J¼7.3 Hz), 1.00–
1.49 (m, 7H), 1.61–1.78 (m, 1.8H), 1.89–2.01 (m, 0.1H), 2.06–2.21
(m, 0.1H), 3.99–4.27 (m, 2H), 4.44 (d, 0.2H, J¼10.7 Hz), 4.53 (d,
0.8H, J¼11.1 Hz), 5.24–5.34 (m, 1H), 7.10–7.28 (m, 3H), 7.33 (d,
0.2H, J¼8.1 Hz), 7.40 (d, 0.8H, J¼8.1 Hz), 7.68–7.76 (m, 1H), 8.26
chemicals used are commercial. b
-Nitroacrylates 112 and 4-nitro-
(br s, 0.2H), 8.36 (br s, 0.8H). 13C NMR (CDCl3, 100 MHz)
d: 13.8,
butyl acetate 8j23 were prepared as previously reported. Commer-
cial basic alumina (Fluka) was activated by heating at 150 ꢀC/
1 mmHg for 5 h before utilization. Potassium fluoride on basic
alumina was prepared using commercial basic alumina (Baker)
following the Bergbreiter’s procedure.24
13.9, 14.1, 14.2, 22.0, 22.1, 27.2, 28.2, 31.6, 32.6, 46.4, 47.5, 61.8,
88.2, 90.2, 108.3, 108.6, 111.6, 111.8, 119.1, 119.2, 120.4, 120.6, 122.8,
123.0, 123.7, 123.8, 126.1, 136.2, 136.4, 170.7, 171.5. GC–MS (70 eV):
m/z: 318 (Mþ), 271, 242, 225, 202 (100), 156, 130. Anal. Calcd for
C17H22N2O4 (318.37): C, 64.14; H, 6.96; N, 8.80. Found: C, 64.20;
H, 7.02; N, 8.74.
4.2. General procedure for the preparation of ethyl
2-(3-indolyl)-3-nitroalkanoates 7
4.2.4. Ethyl 2-(2-methyl-1H-3-indolyl)-3-nitroheptanoate, 7d
Yield: 56% (diastereomeric ratio 3:1). Yellow oil. IR (cmꢂ1, neat):
To a stirred solution of ethyl oxoacetate 9a (50% in toluene,
3 mmol, 0.6 mL) and nitroalkane 8 (3.3 mmol) in EtOAc (1 mL),
Amberlyst A21 (0.825 g) was added at room temperature. The
heterogeneous solution was stirred for the appropriate time (see
Table 2) and the catalyst was then filtered off and washed with
1369, 1554, 1730, 3399. 1H NMR (CDCl3, 400 MHz)
d: 0.77 (t, 2.25H,
J¼6.8 Hz), 0.93 (t, 0.75H, J¼6.8 Hz), 1.00–1.51 (m, 7H), 1.56–1.68 (m,
1.75H), 1.97–2.16 (m, 0.25H), 2.36 (s, 0.75H), 2.48 (s, 2.25H), 3.97–
4.25 (m, 2H), 4.31 (d, 0.25H, J¼11.1 Hz), 4.49 (d, 0.75H, J¼11.1 Hz),
5.42–5.53 (m,1H), 7.05–7.32 (m, 3H), 7.61 (d, 0.75H, J¼7.7 Hz), 7.70–

R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
5439
7.74 (m, 0.25H), 7.94 (br s, 0.25H), 8.07 (br s, 0.75H). 13C NMR
(CDCl3, 100 MHz) : 11.9, 12.3, 13.8, 14.0, 14.2, 14.3, 22.1, 22.2, 27.3,
28.3, 31.6, 33.1, 46.1, 47.4, 61.7, 87.0, 88.9, 103.9, 104.0, 110.7, 110.9,
118.8,119.0,120.2,120.4,121.7,122.0,126.7, 134.1,134.4,135.3,135.5,
170.5, 171.2. GC–MS (70 eV): m/z: 332 (Mþ), 286, 216 (100), 170, 146.
Anal. Calcd for C18H24N2O4 (332.39): C, 65.04; H, 7.28; N, 8.43.
Found: C, 65.00; H, 7.25; N, 8.47.
4.2.9. Ethyl 2-(1H-3-indolyl)-3-nitrooctanoate, 7i
d
Yield: 51% (diastereomeric ratio 3:1). White solid; mp 98–
104 ꢀC. IR (cmꢂ1, Nujol): 1362, 1557, 1729, 3417. 1H NMR (CDCl3,
400 MHz)
d
: 0.77 (t, 2.1H, J¼6.8 Hz), 0.90 (t, 0.9H, J¼6.8 Hz), 0.98–
1.50 (m, 9H), 1.60–1.78 (m, 1.7H), 1.89–2.01 (m, 0.15H), 2.07–2.22
(m, 0.15H), 4.00–4.26 (m, 2H), 4.44 (d, 0.3H, J¼10.7 Hz), 4.54 (d,
0.7H, J¼11.1 Hz), 5.25–5.35 (m, 1H), 7.11–7.29 (m, 3H), 7.32 (d, 0.3H,
J¼8.1 Hz), 7.39 (d, 0.7H, J¼8.1 Hz), 7.68–7.77 (m, 1H), 8.30 (br s,
4.2.5. Ethyl 6-(acetyloxy)-2-(5-methoxy-1H-3-indolyl)-3-
nitrohexanoate, 7e
0.3H), 8.40 (br s, 0.7H). 13C NMR (CDCl3, 100 MHz)
d: 14.0, 14.1, 14.2,
14.3, 22.4, 22.5, 24.9, 25.8, 31.0, 31.2, 31.9, 33.0, 46.5, 47.6, 61.9, 88.3,
90.3, 108.3, 108.5, 111.7, 111.9, 119.2, 120.4, 120.6, 122.8, 123.0, 123.8,
123.9, 126.2, 136.2, 136.5, 170.8, 171.6. GC–MS (70 eV): m/z: 332
(Mþ), 285, 239, 212, 202 (100), 156, 130, 29. Anal. Calcd for
Yield: 55% (diastereomeric ratio 1:1). Yellow viscous oil. IR
(cmꢂ1, neat): 1370, 1551, 1727, 3416. 1H NMR (CDCl3, 400 MHz)
d:
1.17 (t, 1.65H, J¼7.3 Hz), 1.22 (t, 1.35H, J¼7.3 Hz), 1.48–1.61 (m,
0.55H), 1.63–1.86 (m, 2.45H), 1.83 (s, 1.65H), 1.97–2.10 (m, 0.45H),
2.06 (s, 1.35H), 2.13–2.26 (m, 0.55H), 3.86 (s, 1.65H), 3.87 (s, 1.35H),
3.91 (t, 1.10H, J¼6.4 Hz), 4.00–4.26 (m, 2.90H), 4.40 (d, 0.45H,
J¼10.7 Hz), 4.47 (d, 0.55H, J¼11.1 Hz), 5.21–5.32 (m, 1H), 6.85 (dd,
0.45H, J¼2.6, 9.0 Hz), 6.89 (dd, 0.55H, J¼2.4, 8.8 Hz), 7.09 (d, 0.55H,
J¼2.2 Hz), 7.12–7.17 (m, 1.45H), 7.21 (d, 0.45H, J¼8.5 Hz), 7.27 (d,
0.55H, J¼9.0 Hz), 8.22 (br s, 0.45H), 8.32 (br s, 0.55H). 13C NMR
C18H24N2O4 (332.39): C, 65.04; H, 7.28; N, 8.43. Found: C, 64.88; H,
7.21; N, 8.32.
4.2.10. Ethyl 2-(2-methyl-1H-3-indolyl)-3-nitro-5-
phenylpentanoate, 7j
Yield: 55% (diastereomeric ratio 3:2). Viscous yellow oil. IR
(cmꢂ1, neat): 1372, 1552, 1727, 3402. 1H NMR (CDCl3, 400 MHz)
d:
(CDCl3, 100 MHz)
d: 14.1, 14.2, 20.8, 21.1, 24.5, 25.4, 28.3, 29.5, 46.2,
1.11–1.17 (m, 3H), 1.88–2.03 (m, 1H), 2.29–2.83 (m, 3H), 2.36 (s,
1.8H), 2.37 (s, 1.2H), 3.97–4.08 (m, 1H), 4.10–4.21 (m, 1H), 4.34 (d,
0.4H, J¼11.1 Hz), 4.55 (d, 0.6H, J¼11.1 Hz), 5.44–5.58 (m, 1H), 6.89–
6.94 (m, 1H), 7.03–7.38 (m, 7H), 7.52 (d, 0.6H, J¼7.7 Hz), 7.62–7.67
(m, 0.4H), 7.96 (br s, 0.4H), 8.06 (br s, 0.6H). 13C NMR (CDCl3,
47.3, 56.0, 61.9, 62.9, 63.2, 87.4, 89.6, 100.5, 100.7, 107.6, 107.9, 112.3,
112.6, 113.1, 113.5, 124.3, 124.4, 126.5, 131.3, 131.5, 154.6, 154.8, 170.5,
171.1,171.2. GC–MS (70 eV): m/z: 392 (Mþ), 345, 273, 232 (100), 212,
186, 160, 43. Anal. Calcd for C19H24N2O7 (392.40): C, 58.16; H, 6.16;
N, 7.14. Found: C, 58.34; H, 6.20; N, 7.12.
100 MHz) d: 11.8, 12.2, 14.1, 14.2, 31.4, 32.4, 33.4, 35.0, 45.9, 47.3,
61.7, 86.2, 88.3, 103.6, 103.7, 110.7, 110.8, 118.6, 118.9, 120.2, 120.4,
121.7, 122.0, 126.5, 126.6, 126.7, 128.5, 128.6, 128.8, 134.0, 134.4,
135.3, 135.4, 139.6, 139.9, 170.3, 171.1. GC–MS (70 eV): m/z: 380
(Mþ), 260, 216, 170 (100), 146, 129, 91. Anal. Calcd for C22H24N2O4
(380.44): C, 69.46; H, 6.36; N, 7.36. Found: C, 69.79; H, 6.46; N, 7.38.
4.2.6. Ethyl 2-(5-methoxy-1H-3-indolyl)-3-nitrobutanoate, 7f
Yield: 55% (diastereomeric ratio 3:1). Viscous yellow oil. IR
(cmꢂ1, neat): 1372, 1550, 1733, 3409. 1H NMR (CDCl3, 400 MHz)
d:
1.18 (t, 1.05H, J¼7.3 Hz), 1.23 (t, 1.95H, J¼7.3 Hz), 1.42 (d, 1.05H,
J¼6.8 Hz), 1.73 (d, 1.95H, J¼6.8 Hz), 3.86 (s, 1.05H), 3.87 (s, 1.95H),
4.02–4.27 (m, 2H), 4.41–4.46 (m, 1H), 5.25–5.35 (m, 1H), 6.82–6.93
4.2.11. Ethyl 2-(5-methoxy-1H-3-indolyl)-3-nitro-5-
phenylpentanoate, 7k
(m, 1H), 7.09–7.28 (m, 3H), 8.29 (br s, 0.65H), 8.39 (br s, 0.35H). 13
C
NMR (CDCl3, 100 MHz)
d
: 14.1, 14.2, 18.3, 18.5, 47.3, 47.9, 56.0, 56.1,
Yield: 56% (diastereomeric ratio 3:2). Yellow waxy solid. IR
61.8, 61.9, 83.5, 84.9, 100.6, 107.7, 108.2, 112.4, 112.6, 113.1, 113.3,
124.3, 124.4, 126.6, 131.3, 131.5, 154.6, 154.7, 170.6, 171.5. GC–MS
(70 eV): m/z: 306 (Mþ), 259, 232, 204, 187 (100), 172, 160, 144, 115,
29. Anal. Calcd for C15H18N2O5 (306.31): C, 58.82; H, 5.92; N, 9.15.
Found: C, 58.63; H, 5.86; N, 9.07.
(cmꢂ1, Nujol): 1372, 1548, 1731, 3414. 1H NMR (CDCl3, 400 MHz)
d:
1.14–1.21 (m, 3H), 1.96–2.11 (m, 1H), 2.20–2.31 (m, 0.6H), 2.38–2.57
(m, 1H), 2.62–2.78 (m, 1.4H), 3.83 (s, 1.8H), 3.85 (s, 1.2H), 3.99–4.23
(m, 2H), 4.42 (d, 0.4H, J¼10.7 Hz), 4.51 (d, 0.6H, J¼11.1 Hz), 5.23–
5.31 (m, 1H), 6.82–7.35 (m, 9H), 8.17 (br s, 0.4H), 8.22 (br s, 0.6H).
13C NMR (CDCl3, 100 MHz)
d: 14.2, 14.3, 31.5, 32.3, 33.5, 34.5, 46.4,
4.2.7. Methyl 2-(1H-3-indolyl)-3-nitropropanoate, 7g
47.5, 56.0, 56.1, 61.9, 87.1, 89.4, 100.6, 100.7, 107.7, 108.1, 112.4, 112.6,
113.3, 113.6, 124.2, 124.3, 126.6, 126.7, 128.6, 128.7, 128.8, 128.9,
131.3, 131.5, 139.6, 139.7, 154.7, 154.8, 170.5, 171.3. GC–MS (70 eV):
m/z: 396 (Mþ), 349, 276, 258, 232 (100), 186, 154, 117, 91. Anal. Calcd
for C22H24N2O5 (396.44): C, 66.65; H, 6.10; N, 7.07. Found: C, 66.91;
H, 6.19; N, 7.01.
Yield: 80%. Yellow oil. IR (cmꢂ1, neat): 1368, 1554, 1733, 3401. 1H
NMR (CDCl3, 400 MHz)
d
: 3.74 (s, 3H), 4.65 (dd, 1H, J¼5.1, 14.5 Hz),
4.74–4.80 (m, 1H), 5.21 (dd, 1H, J¼9.8, 14.5 Hz), 7.13 (d, 1H, J¼3.0
Hz), 7.16–7.21 (m, 1H), 7.23–7.28 (m, 1H), 7.36–7.40 (m, 1H), 7.65
(dd, 1H, J¼0.9, 7.7 Hz), 8.32 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d:
40.8, 53.0, 75.4, 108.0, 111.8, 118.7, 120.7, 123.1, 123.2, 125.8, 136.4,
171.9. GC–MS (70 eV): m/z: 248 (Mþ), 201, 160, 143 (100), 115. Anal.
Calcd for C12H12N2O4 (248.23): C, 58.06; H, 4.87; N, 11.29. Found: C,
58.21; H, 4.95; N, 11.24.
4.3. Ethyl 2-(acetyloxy)-3-nitro-5-phenylpentanoate, 11k
To a stirred solution of nitro alcohol 10k12c (1 mmol, 0.25 g) in
ethyl acetate (4 mL), Ac2O (1.5 mmol, 0.15 g, 0.14 mL) and Amber-
lyst 15 (0.45 g) were successively added at room temperature. The
resulting mixture was stirred at the same temperature for 1 h and
then the resin was filtered off and washed with EtOAc (3ꢁ3 mL).
The crude product obtained after removal of the solvent and excess
of Ac2O was purified by column chromatography (hexanes/ethyl
acetate 8:2) leading to 0.3 g of acetoxy derivative 11k as a yellow oil
(yield 97%). IR (cmꢂ1, neat): 1369, 1553, 1621, 1726. 1H NMR (CDCl3,
4.2.8. Ethyl 2-(2-methyl-1H-3-indolyl)-3-nitropentanoate, 7h
Yield: 53% (diastereomeric ratio 4:1). Yellow oil. IR (cmꢂ1
,
neat): 1375, 1340, 1551, 1731, 3400. 1H NMR (CDCl3, 400 MHz)
d:
0.87 (t, 2.4H, J¼7.3 Hz), 1.04–1.24 (m, 3.6H), 1.56–1.89 (m, 1H),
2.02–2.26 (m, 1H), 2.32 (s, 0.6H), 2.45 (s, 2.4H), 3.93–4.30 (m, 2H),
4.36 (d, 0.2H, J¼11.7 Hz), 4.55 (d, 0.8H, J¼10.6 Hz), 5.39–5.56 (m,
1H), 7.05–7.34 (m, 3H), 7.57–7.69 (m, 0.8H), 7.72–7.82 (m, 0.2H),
8.18 (br s, 0.2H), 8.38 (br s, 0.8H). 13C NMR (CDCl3, 100 MHz)
d: 9.7,
10.6, 11.5, 11.9, 14.0, 14.1, 25.2, 26.7, 45.6, 47.1, 61.6, 88.2, 90.4, 103.5,
103.6, 110.8, 110.9, 118.5, 118.8, 119.9, 120.2, 121.4, 121.8, 126.5,
126.6, 134.3, 134.5, 135.3, 135.4, 170.4, 171.3. GC–MS (70 eV): m/z:
304 (Mþ), 216, 185, 170, 146 (100), 128, 115. Anal. Calcd for
400 MHz)
d
: 1.96 (t, 1.5H, J¼7.3 Hz), 1.96 (t, 1.5H, J¼7.3 Hz), 2.00–
2.15 (m, 1H), 2.12 (s, 1.5H), 2.13 (s, 1.5H), 2.40–2.52 (m, 0.5H), 2.54–
2.87 (m, 2.5H), 4.10–4.29 (m, 2H), 4.75–4.82 (m, 0.5H), 4.83–4.90
(m, 0.5H), 5.37 (d, 0.5H, J¼6.0 Hz), 5.59 (d, 0.5H, J¼3.4 Hz), 7.11–7.18
C
16H20N2O4 (304.34): C, 63.14; H, 6.62; N, 9.20. Found: C, 63.41; H,
(m, 2H), 7.19–7.33 (m, 3H). 13C NMR (CDCl3, 100 MHz)
d: 14.0, 14.1,
6.72; N, 9.16.
20.4, 20.5, 30.3, 31.0, 31.8, 32.0, 62.6, 62.7, 71.6, 71.7, 85.3, 85.5,

5440
R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
126.8, 126.9, 128.5, 128.6, 128.9, 129.0, 139.1, 139.3, 166.0, 166.4,
169.5, 169.7.
J¼8.6 Hz), 8.37 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 14.6, 21.0,
26.8, 28.1, 56.0, 61.2, 64.0, 101.5, 110.0, 112.2, 112.6, 125.2, 127.7,
127.8, 131.0, 144.0, 154.4, 168.1, 171.4. GC–MS (70 eV): m/z: 345
(Mþ), 299, 272, 257, 228, 212 (100), 198, 184, 154, 128, 43. Anal.
Calcd for C19H23NO5 (345.39): C, 66.07; H, 6.71; N, 4.06. Found: C,
66.27; H, 6.69; N, 4.10.
4.4. General procedure for the preparation of ethyl 2-(3-
indolyl)-2-alkenoates 15
To a stirred solution of product 7 (2 mmol) in acetonitrile
(10 mL), TMG (4 mmol) was added and the solution was stirred at
room temperature for the appropriate time (see Table 4). After
removal of the solvent at reduced pressure, the crude product was
purified by flash chromatography (hexanes/ethyl acetate 95:5)
affording the pure product 15.
4.4.6. Ethyl (E)-2-(5-methoxy-1H-3-indolyl)-2-butenoate, 15f
Yield: 95%. Yellow oil. IR (cmꢂ1, neat): 1624, 1697, 3400. 1H NMR
(CDCl3, 400 MHz)
d
: 1.13 (t, 3H, J¼7.3 Hz),1.68 (d, 3H, J¼7.3 Hz), 3.66
(s, 3H), 4.08 (q, 2H, J¼7.3 Hz), 6.61 (d, 1H, J¼2.6 Hz), 6.67 (dd, 1H,
J¼2.6, 8.6 Hz), 6.97 (d, 1H, J¼2.6 Hz), 7.06 (q, 1H, J¼7.3 Hz), 7.14 (d,
1H, J¼8.9 Hz), 9.68 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 14.2,
4.4.1. Ethyl (E)-2-(1H-3-indolyl)-2-butenoate, 15a
16.0, 55.5, 60.4, 101.3, 108.8, 111.6, 112.1, 125.5, 127.2, 127.7, 130.9,
139.4, 153.6, 167.8. GC–MS (70 eV): m/z: 259 (Mþ), 185, 170, 154,
142, 128, 115, 29. Anal. Calcd for C15H17NO3 (259.30): C, 69.48; H,
6.61; N, 5.40. Found: C, 69.33; H, 6.53; N, 5.36.
Yield: 85%. Yellow oil. IR (cmꢂ1, neat): 1628, 1695, 3401. 1H NMR
(CDCl3, 400 MHz)
d
: 1.28 (t, 3H, J¼7.3 Hz), 1.81 (d, 3H, J¼6.9 Hz),
4.25 (q, 2H, J¼7.3 Hz), 7.03 (d, 1H, J¼2.6 Hz), 7.09–7.22 (m, 2H), 7.26
(q, 1H, J¼7.3 Hz), 7.32 (d, 1H, J¼7.7 Hz), 7.40 (d, 1H, J¼7.7 Hz), 8.38
(br s, 1H). 13C NMR (CDCl3, 100 MHz)
d
: 14.5, 16.3, 61.0, 110.0, 111.5,
4.4.7. Ethyl 2-(1H-3-indolyl)acrylate, 15g
119.8, 120.2, 122.0, 124.7, 127.2, 127.7, 135.9, 140.5, 168.2. GC–MS
(70 eV): m/z: 229 (Mþ), 200, 183, 155 (100), 154, 129, 77. Anal. Calcd
for C14H15NO2 (229.27): C, 73.34; H, 6.59; N, 6.11. Found: C, 73.56; H,
6.51; N, 6.16.
Yield: 20%. GC–MS (70 eV): m/z: 201 (Mþ), 142 (100), 115, 88, 70.
4.4.8. Ethyl (E)-2-(2-methyl-1H-3-indolyl)-2-pentenoate, 15h
Yield: 84%. Red waxy solid. IR (cmꢂ1, Nujol): 1622,1686, 3340. 1H
NMR (CDCl3, 400 MHz)
d
: 0.99 (t, 3H, J¼7.7 Hz), 1.25 (t, 3H,
4.4.2. Ethyl (E)-2-(5-methoxy-1H-3-indolyl)-2-hexenoate, 15b
J¼7.3 Hz), 1.98–2.12 (m, 2H), 2.18 (s, 3H), 4.22 (q, 2H, J¼7.3 Hz),
Yield: 93%. Yellow oil. IR (cmꢂ1, neat): 1626, 1700, 3402. 1H NMR
7.03–7.14 (m, 2H), 7.16–7.31 (m, 3H), 8.14 (br s, 1H). 13C NMR (CDCl3,
(CDCl3, 400 MHz)
d
: 0.87 (t, 3H, J¼7.7 Hz), 1.23 (t, 3H, J¼7.3 Hz),
100 MHz) d: 12.5, 13.3, 14.4, 23.5, 60.8, 107.5, 110.5, 118.9, 119.5,
1.39–1.52 (m, 2H), 2.15 (q, 2H, J¼7.3 Hz), 3.81 (s, 3H), 4.23 (q, 2H,
J¼7.3 Hz), 6.79–6.87 (m, 2H), 7.03 (d, 1H, J¼2.6 Hz), 7.14 (t, 1H,
J¼7.7 Hz), 7.21 (d, 1H, J¼8.5 Hz), 8.40 (br s, 1H). 13C NMR (CDCl3,
121.1, 125.9, 128.7, 133.4, 135.4, 148.8, 168.2. GC–MS (70 eV): m/z:
257 (Mþ), 182, 168 (100), 154. Anal. Calcd for C16H19NO2 (257.33): C,
74.68; H, 7.44; N, 5.44. Found: C, 74.64; H, 7.46; N, 5.46.
100 MHz) d: 14.1, 14.6, 22.5, 32.3, 56.0, 61.0, 101.7, 110.3, 112.2, 112.5,
125.3, 126.8, 127.9, 131.1, 145.9, 154.4, 168.4. GC–MS (70 eV): m/z:
287 (Mþ), 258, 212 (100), 198, 184, 172, 154, 142, 128, 115, 29. Anal.
Calcd for C17H21NO3 (287.35): C, 71.06; H, 7.37; N, 4.87. Found: C,
71.15; H, 7.41; N, 4.90.
4.4.9. Ethyl (E)-2-(1H-3-indolyl)-2-octenoate, 15i
Yield: 76%. Yellow oil. IR (cmꢂ1, neat): 1628, 1700, 3410. 1H NMR
(CDCl3, 400 MHz)
d
: 0.84 (t, 3H, J¼7.3 Hz), 1.16–1.30 (m, 4H), 1.27 (t,
3H, J¼7.3 Hz), 1.37–1.49 (m, 2H), 2.17 (q, 2H, J¼7.3 Hz), 4.24 (q, 2H,
J¼7.3 Hz), 7.03 (d, 1H, J¼2.6 Hz), 7.09–7.22 (m, 3H), 7.33 (d, 1H,
J¼8.1 Hz), 7.40 (d, 1H, J¼7.7 Hz), 8.31 (br s, 1H). 13C NMR (CDCl3,
4.4.3. Ethyl (E)-2-(1H-3-indolyl)-2-heptenoate, 15c
Yield: 97%. Yellow oil. IR (cmꢂ1, neat): 1633, 1694, 3404. 1H NMR
100 MHz) d: 14.2, 14.5, 22.7, 29.0, 30.3, 31.7, 61.0, 110.6, 111.5, 119.9,
(CDCl3, 400 MHz)
d
: 0.82 (t, 3H, J¼7.3 Hz), 1.21–1.48 (m, 4H), 1.27 (t,
120.2, 122.1, 124.5, 126.5, 127.5, 135.9, 146.3, 168.4. GC–MS (70 eV):
m/z: 285 (Mþ, 100), 256, 239, 228, 212, 196, 182, 168, 154, 142, 130,
115, 41, 29. Anal. Calcd for C18H23NO2 (285.38): C, 75.76; H, 8.12; N,
4.91. Found: C, 75.77; H, 8.20; N, 4.96.
3H, J¼7.3 Hz), 2.18 (q, 2H, J¼7.3 Hz), 4.24 (q, 2H, J¼7.3 Hz), 7.04 (d,
1H, J¼2.6 Hz), 7.09–7.23 (m, 3H), 7.33 (d, 1H, J¼8.1 Hz), 7.40 (d, 1H,
J¼8.1 Hz), 8.30 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 14.1, 14.5,
22.6, 30.0, 31.4, 61.0, 110.6, 111.4, 119.9, 120.2, 122.1, 124.4, 126.5,
127.5, 135.9, 146.1, 168.3. GC–MS (70 eV): m/z: 271 (Mþ, 100),
242, 225, 196, 182, 168, 154, 142, 127, 115, 29. Anal. Calcd for
4.4.10. Ethyl (E)-2-(2-methyl-1H-3-indolyl)-5-phenyl-2-
pentenoate, 15j
C
17H21NO2 (271.35): C, 75.25; H, 7.80; N, 5.16. Found: C, 75.54; H,
Yield: 90%. Yellow foam. IR (cmꢂ1, neat): 1620, 1683, 3345. 1H
7.89; N, 5.11.
NMR (CDCl3, 400 MHz)
2.48 (m, 2H), 2.73 (t, 2H, J¼7.7 Hz), 4.20 (q, 2H, J¼7.3 Hz), 7.00–7.33
(m, 10H), 7.99 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
: 12.6, 14.5,
31.8, 35.0, 60.9, 107.6, 110.5, 119.1, 119.7, 121.2, 126.1, 127.0, 128.4,
128.5, 128.6, 133.3, 135.3, 141.3, 146.1, 167.9. GC–MS (70 eV): m/z:
333 (Mþ), 242 (100), 214, 168, 154, 91. Anal. Calcd for C22H23NO2
(333.42): C, 79.25; H, 6.95; N, 4.20. Found: C, 79.47; H, 6.99; N, 4.23.
d
: 1.23 (t, 3H, J¼7.7 Hz), 2.16 (s, 3H), 2.28–
4.4.4. Ethyl (E)-2-(2-methyl-1H-3-indolyl)-2-heptenoate, 15d
d
Yield: 80%. Yellow solid; mp 55–57 ꢀC. IR (cmꢂ1, Nujol): 1624,
1688, 3347. 1H NMR (CDCl3, 400 MHz)
d
: 0.80 (t, 3H, J¼7.3 Hz), 1.17–
1.30 (m, 2H), 1.24 (t, 3H, J¼7.3 Hz), 1.33–1.46 (m, 2H), 1.97–2.11 (m,
2H), 2.21 (s, 3H), 4.20 (q, 2H, J¼7.3 Hz), 7.03–7.14 (m, 2H), 7.19–7.30
(m, 3H), 8.04 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 12.6, 14.0, 14.5,
22.5, 29.8, 30.9, 60.8, 107.7, 110.5, 119.1, 119.6, 121.1, 126.3, 128.8,
133.3, 135.4, 147.7, 168.1. GC–MS (70 eV): m/z: 285 (Mþ), 212, 196
(100), 168, 154, 29. Anal. Calcd for C18H23NO2 (285.38): C, 75.76; H,
8.12; N, 4.91. Found: C, 75.61; H, 8.41; N, 4.91.
4.4.11. Ethyl (E)-2-(5-methoxy-1H-3-indolyl)-5-phenyl-2-
pentenoate, 15k
Yield: 96%. Viscous yellow oil. IR (cmꢂ1, neat): 1619, 1702, 3410.
1H NMR (CDCl3, 400 MHz)
d
: 1.23 (t, 3H, J¼7.3 Hz), 2.47 (q, 2H,
J¼7.3 Hz), 2.72 (t, 2H, J¼7.3 Hz), 3.77 (s, 3H), 4.19 (q, 2H, J¼7.3 Hz),
6.73–6.83 (m, 2H), 6.89 (s, 1H), 7.06 (d, 2H, J¼7.3 Hz), 7.13 (t, 2H,
J¼7.3 Hz), 7.17–7.24 (m, 3H), 8.88 (br s, 1H). 13C NMR (CDCl3,
4.4.5. Ethyl (E)-6-(acetyloxy)-2-(5-methoxy-1H-3-indolyl)-2-
hexenoate, 15e
Yield: 91%. Yellow oil. IR (cmꢂ1, neat): 1622, 1701, 1730, 3422. 1H
100 MHz) d: 14.5, 31.9, 35.3, 55.9, 60.9, 101.5, 109.8, 112.2, 112.3,
NMR (CDCl3, 400 MHz)
d
: 1.27 (t, 3H, J¼7.3 Hz), 1.72–1.81 (m, 2H),
125.2, 126.1, 127.4, 127.7, 128.4, 128.5, 131.1, 141.2, 144.1, 154.2, 168.1.
1.91 (s, 3H), 2.26 (q, 2H, J¼7.3 Hz), 3.81 (s, 3H), 3.99 (t, 2H, J¼6.4 Hz),
4.23 (q, 2H, J¼7.3 Hz), 6.77 (d, 1H, J¼2.6 Hz), 6.84 (dd, 1H, J¼2.6,
9.0 Hz), 7.03 (d, 1H, J¼2.6 Hz), 7.11 (t, 1H, J¼7.7 Hz), 7.22 (d, 1H,
GC–MS (70 eV): m/z: 349 (Mþ), 258 (100), 184, 91. Anal. Calcd for
C22H23NO3 (349.42): C, 75.62; H, 6.63; N, 4.01. Found: C, 75.93; H,
6.69; N, 4.07.

R. Ballini et al. / Tetrahedron 64 (2008) 5435–5441
5441
Uenishi, J. Tetrahedron 2007, 63, 4172–4177; (e) Blay, G.; Ferna´ndez, I.; Pedro, J. R.;
Vila, C. Org. Lett. 2007, 9, 2601–2604.
2. Adamo, M. F. A.; Konda, V. Org. Lett. 2007, 9, 303–305.
4.5. Ethyl 2-(5-methoxy-1H-3-indolyl)-2-tetrahydro-2-
furanylacetate 16
3. (a) Mahboobi, S.; Wiegrebe, W.; Popp, A. J. Nat. Prod. 1999, 62, 577–579; (b)
Koike, T.; Takeuchi, N.; Hagiwara, M.; Yamazaki, K.; Tobinaga, S. Heterocycles
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Heterocycles 1997, 45, 1271–1280.
4. (a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479–500; (b)
Czarnocki, Z.; Siwicka, A.; Szawka1o, J. Curr. Org. Synth. 2005, 2, 301–331; (c)
Ballini, R.; Marcantoni, E.; Petrini, M. Nitroalkenes as Amination Tools. In Amino
Group Chemistry; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008; pp 93–148; (d)
Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1996; (e)
Harada, H.; Hirokawa, Y.; Suzuki, K.; Hiyama, Y.; Oue, M.; Kawashima, H.; Kato,
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Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
6576–6579.
Sodium metal (5 mmol, 0.115 g) was dissolved in dry EtOH
(7 mL) and then diester 15e (1 mmol, 0.34 g) dissolved in 2 mL of
EtOH was added dropwise at room temperature. After stirring for
3 h at room temperature, 1 M HCl (7 mL) was added and the solu-
tion was concentrated under reduced pressure. The resulting
aqueous layer was extracted with CH2Cl2 (3ꢁ15 mL), and the
combined organic extracts were dried over Na2SO4. The crude
product obtained after removal of the solvent at reduced pressure
was purified by flash chromatography (hexanes/ethyl acetate 95:5)
giving 0.25 g of ester derivative 16 as a white solid (yield 84%), mp
132–135 (d.r¼93:7, major diastereomer): IR (cmꢂ1, Nujol): 1217,
5. Lewandowska, E. Tetrahedron 2007, 63, 2107–2122.
6. (a) Lewandowska, E. Tetrahedron 2006, 62, 4879–4883; (b) Ballini, R.; Fiorini,
D.; Palmieri, A. Tetrahedron Lett. 2005, 46, 1245–1246.
7. (a) Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. Adv. Synth. Catal. 2006,
348, 191–196; For related processes using acidic activators in the reaction of
1621, 1715, 3350. 1H NMR (CDCl3, 400 MHz)
d: 1.23 (t, 3H, J¼7.3 Hz),
1.50–1.62 (m, 1H), 1.74–1.95 (m, 3H), 3.73–3.89 (m, 2H), 3.87 (s, 3H),
3.93–4.00 (m, 1H), 4.08–4.26 (m, 2H), 4.54–4.69 (m, 1H), 6.86 (dd,
1H, J¼2.6, 9.0 Hz), 7.16–7.27 (m, 3H), 8.12 (br s, 1H). 13C NMR (CDCl3,
indoles with methyl
b-nitroacrylate see: (b) Bartoli, G.; Bosco, M.; Giuli, S.;
Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem.
2005, 70, 1941–1944; (c) Murugan, R.; Karthikeyan, M.; Perumal, P. T.; Reddy, B.
S. R. Tetrahedron 2005, 61, 12275–12281.
100 MHz) d: 14.4, 25.7, 30.1, 49.4, 56.1, 61.1, 68.7, 80.7, 101.2, 110.8,
8. (a) Luzzio, F. A. Tetrahedron 2001, 57, 915–945; (b) Rosini, G. Comphehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2, pp 321–340;
(c) Rosini, G.; Ballini, R.; Sorrenti, P. Synthesis 1983, 1014–1016; (d) Rosini, G.;
Ballini, R.; Petrini, M.; Sorrenti, P. Synthesis 1985, 515–517; For a recent paper
see: (e) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Synthesis 2004, 1938–1940.
9. Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem. 1992, 57, 2160–2162.
10. (a) Woo, Y.; Lai, D. Y.; Argus, M. F.; Arcos, J. C. Toxicol. Lett. 1995, 79, 219–228; (b)
Talalay, P.; De Long, M. J.; Prochaska, H. J. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
8261–8265.
112.3, 112.8, 123.7, 127.4, 131.4, 154.4, 173.6. GC–MS (70 eV): m/z:
303 (Mþ), 233 (100), 204, 187, 160, 71, 43, 29. Anal. Calcd for
C
17H21NO4 (303.35): C, 67.31; H, 6.98; N, 4.62. Found: C, 67.59; H,
7.05; N, 4.55.
4.6. Ethyl (E)-6-hydroxy-2-(5-methoxy-1H-3-indolyl)-2-
hexenoate 17
11. (a) Rueck-Braun, K.; Freysoldt, T. H. E.; Wierschem, F. Chem. Soc. Rev. 2005, 34,
507–516; (b) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P.
Chem. Rev. 2004, 104, 199–250; (c) Chung, C.; Wan, Y.; Toy, P. H. Tetrahedron:
Asymmetry 2004, 15, 387–399; (d) Valkenberg, M. H.; de Castro, C.; Hoelder-
ich, W. F. Green Chem. 2002, 4, 88–93; (e) Clark, J. H. Acc. Chem. Res. 2002, 35,
791–797.
12. (a) Swiderska, M. A.; Stewart, J. D. Org. Lett. 2006, 8, 6131–6133; (b) Addo, J. K.;
Teesdale-Spittle, P.; Hoberg, J. O. Synthesis 2005, 1923–1925; (c) Ballini, R.;
Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004, 45, 7027–7029.
13. (a) Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K.
Chem. Asian J. 2007, 2, 1150–1160; (b) Tosaki, S.; Hara, K.; Gnanadesikan, V.;
Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 11776–11777.
14. (a) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006, 71, 5737–5742; (b)
Woodcock, S. R.; Marwitz, A. J. V.; Bruno, P.; Branchaud, B. P. Org. Lett. 2006, 8,
3931–3934; (c) Denmark, S. E.; Baiazitov, R. Y. J. Org. Chem. 2006, 71, 593–605.
15. Pollini, G. P.; Baricordi, N.; Benetti, S.; De Risi, C.; Zanirato, V. Tetrahedron Lett.
2005, 46, 3699–3701.
A solution of diester 15e (0.5 mmol, 0.17 g) in THF/water (11 mL,
1:10) was cooled at 0 ꢀC and 0.25 N NaOH (4 mL) was added under
stirring. After stirring for 7 h at 0 ꢀC, 1 M HCl was added dropwise
until pH¼4 and then the solution was extracted with EtOAc
(3ꢁ20 mL). The combined organic extracts were dried over Na2SO4
and the crude product obtained after filtration and removal of the
solvent at reduced pressure was purified by flash chromatography
(hexanes/ethyl acetate 95:5) giving 0.083 g of hydroxyester de-
rivative 17 as a yellow waxy solid (yield 55%, d.r¼94:6, major di-
astereomer): IR (cmꢂ1, Nujol): 1621, 1701, 3420. 1H NMR (CDCl3,
400 MHz)
d
: 1.26 (t, 3H, J¼7.3 Hz), 1.59–1.70 (m, 2H),1.79–1.99 (br s,
1H), 2.23 (q, 2H, J¼7.3 Hz), 3.51 (t, 2H, J¼6.4 Hz), 3.79 (s, 3H), 4.23
(q, 2H, J¼7.3 Hz), 6.78 (d, 1H, J¼2.6 Hz), 6.81 (dd, 1H, J¼2.6, 9.0 Hz),
6.95 (d, 1H, J¼2.6 Hz), 7.11 (t, 1H, J¼7.7 Hz), 7.16 (d, 1H, J¼9.0 Hz),
16. Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52, 1677–1684.
17. Ethyl acetate has been recently included among environmentally preferred
solvents because of its relatively low volatility and scanty toxicity: (a) Alfonsi,
K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.;
Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31–36;
For a related paper see also: (b) Capello, C.; Fisher, U.; Hungerbu¨ hler, K. Green
Chem. 2007, 9, 927–934.
8.58 (br s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 14.5, 26.5, 31.9, 56.0,
61.1, 62.1, 101.5, 109.7, 112.3, 112.4, 125.3, 127.3, 127.6, 131.0, 144.7,
154.2, 168.3. GC–MS (70 eV): m/z: 303 (Mþ), 257 (100), 230, 212,
198, 184, 154, 128, 115, 29. Anal. Calcd for C17H21NO4 (303.35): C,
67.31; H, 6.98; N, 4.62. Found: C, 66.98; H, 6.89; N, 4.54.
18. (a) Youn, S. W. Org. Prep. Proc. Int. 2006, 38, 505–591; (b) Cox, E. D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797–1842.
19. (a) Ballini, R.; Rinaldi, A. Tetrahedron Lett. 1994, 35, 9247–9250; (b) Ballini, R.;
Bosica, G. Tetrahedron 1995, 51, 4213–4222; (c) Ballini, R.; Bosica, G.; Petrelli, L.;
Petrini, M. Synthesis 1999, 1236–1240; (d) Ballini, R.; Bosica, G.; Cioci, G.; Fiorini,
D.; Petrini, M. Tetrahedron 2003, 59, 3603–3608.
20. Review: (a) Kabalka, G. W.; Pagni, R. M. Tetrahedron 1997, 53, 7999–8065; For
some recent examples see: (b) Ge, Y.; Hu, L. Tetrahedron Lett. 2007, 48, 4885–
4888; (c) Sharifi, A.; Salimi, R.; Mirzaei, M.; Abaee, M. S. Synth. Commun. 2007,
37, 1825–1832.
Acknowledgements
Financial support from University of Camerino and MIUR (Na-
tional Project ‘‘Sintesi organiche ecosostenibili mediate da nuovi
sistemi catalitici’’) is gratefully acknowledged.
21. Kopinski, R. P.; Pinhey, J. T. Aust. J. Chem. 1983, 36, 311–316.
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Costa, H.; Me´rour, J.-Y.; Le´once, S. Tetrahedron 2000, 56, 3189–3196; (c) Simoji,
Y.; Saito, F.; Tomita, K.; Morisawa, Y. Heterocycles 1991, 32, 2389–2397.
23. Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2004, 69, 6907–6908.
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