An original route to newly-functionalized indoles and carbazoles starting from the ring-opening of nitrothiophenes

Article abstract of DOI:10.1016/j.tetlet.2011.11.137

The multifaceted behavior of nitrobutadienes deriving from the initial ring-opening of nitrothiophenes finds a further clear-cut example in their Michael-type acceptor reactivity towards indole. Thus, depending on the starting diene, either newly-function

Full text of DOI:10.1016/j.tetlet.2011.11.137

Tetrahedron Letters 53 (2012) 752–757
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An original route to newly-functionalized indoles and carbazoles starting
from the ring-opening of nitrothiophenes
Lara Bianchi a, , Gianluca Giorgi b, Massimo Maccagno a, Giovanni Petrillo a, Carlo Scapolla a,
⇑
Cinzia Tavani a
a Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
b Dipartimento di Chimica, Università di Siena, Via A. Moro, I-53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The multifaceted behavior of nitrobutadienes deriving from the initial ring-opening of nitrothiophenes
finds a further clear-cut example in their Michael-type acceptor reactivity towards indole. Thus, depend-
ing on the starting diene, either newly-functionalized indoles or carbazoles are produced, the latter as the
result of an appealing double (intermolecular + intramolecular) Michael-type addition to a nitrovinylic
moiety. The outcome encompasses motifs for both mechanistic and synthetic interest in the field of het-
erocycles endowed with possible pharmacological activity.
Received 16 August 2011
Revised 25 November 2011
Accepted 29 November 2011
Available online 8 December 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Nitrobutadienes
Nitrogen heterocycles
Indoles
Carbazoles
Michael-type additions
The highly functionalized aminobutadienes 2, 5, and 9,
smoothly originating from the ring-opening of 3,4-dinitrothioph-
ene 1,1 3-nitrothiophene 42 or 2-nitrothiophene 8,3 respectively,
with secondary amines (Scheme 1), represent valuable building
blocks in the field of organic synthesis.4–21 In the last two decades
we have reported a number of interesting applications of both the
dinitro-4–11 and nitro-butadienes12–21 3, 6, 7, 10, and 11, which
mainly exploit proper preliminary modifications of the functional-
ities deriving from the initial ring-opening.
A preliminary screening of reported experimental conditions26
for the nucleophilic addition of indole to nitroolefins, carried out
on the non-symmetric diene 10a (Ar = Ph), has provided the results
reported in Table 1. When detected, the isolated product (Exp. 1
and 2) was structurally in agreement with the expected Michael-
type adduct (Scheme 2, 13a), obtained, due to the generation of
two chiral carbons, as a ca. 1.5:1 mixture of diastereoisomers (each
as a racemic couple), with retention of the original configuration of
the remaining double bond.
In particular, within a multifaceted reactivity endowed with
potentialities which cannot be offered by, for example, simple nitro-
alkenes,22 a manifold production of homo- and heterocyclic deriva-
tives7,19 significantly widens the application field of such conjugated
systems. In this context, the effectiveness of the intramolecular Mi-
chael-type addition to the nitrovinyl moiety has more recently led to
interesting novel S-heterocycles,15,20,21,23 thus providing new pre-
cursors to target molecules with potential pharmacological activity.
In order to widen their synthetic scope, we have now turned to
the behavior of our nitro- and dinitro-butadienes as Michael-type
acceptors in intermolecular conjugate additions,24 and herein
report on some particularly rewarding preliminary results stem-
ming from the employment of the biologically ubiquitous25 indole
(12) as the electron-rich nucleophilic partner.
As a matter of facts, 10a did not prove to be in general very reac-
tive, leading at most to low substrate conversions: most likely the
electron-donor effect of sulfur counteracts the electron-withdraw-
ing one of the nitro group, resulting in an overall poor reactivity of
the double bond(s) of 10a as Michael-acceptor(s). Nevertheless, on
the grounds of results obtained with an ‘unfavorable’ model system,
we decided to extend the conditions of Exp. 227 to 11a (Ar = Ph)
(Scheme 3), that is, to a substrate for which we would expect a reac-
tivity increase, thanks to the concomitant favorable effects of NO2
and SO2Me on the electrophilicity of the C(2) and/or C(4) carbon
atoms.
The system immediately appeared much more rewarding, lead-
ing, in the smooth conditions applied, to the disappearance of sub-
strate (3.5 h) and allowing the isolation of a more than satisfactory
yield (77%) of the expected 14a (Scheme 3), again as a mixture (ca.
1:1) of diastereoisomers27 and retention of the double bond
configuration.
⇑
Corresponding author.
E-mail address: lara.bianchi@unige.it (L. Bianchi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.137

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 752–757
753
NO2
NO2
O2N
NO2
NRR'
R''
i)
ii)
R'RN
R''
S
1
O2N
2
O2N
3
i) Et2NH (excess), EtOH, 0 °C, overnight; ii) ArMgBr (2.2 mol equiv.), THF, 0 °C, 15'-45', then acidic quenching.
NO2
NO2
NO2
NO2
i)
ii)
iii)
iv)
SMe
SMe
SO2Me
R'RN
Ar
Ar
S
6
7
5
4
i) Pyrrolidine (2 mol equiv.), AgNO3 (2 mol equiv.), EtOH, rt, overnight; ii) excess MeI, 0°C to rt, 2 h;
iii) ArMgBr (1.1 mol equiv.), THF, -78°C, 15–45 min., then acidic quenching; iv) MCPBA (2 mol equiv.), CH2Cl2, rt.
NO2
NO2
SMe
NO2
SMe
i)
iv)
ii)
iii)
SO2Me
NO2
S
8
Ar
R'RN
Ar
9
11
10
i) Pyrrolidine (9 mol equiv.), AgNO3 (1 mol equiv.), EtOH, rt, overnight; ii) excess MeI, 0°C to rt, 2 h;
iii) ArMgBr (1.1 mol equiv.), THF, -30°C, 15–45 min., then acidic quenching; iv) MCPBA (2 mol equiv.), CH2Cl2, rt.
Scheme 1. Nitrobutadienic building-blocks from the ring-opening of nitrothiophenes 1, 4, 8.
Table 1
Results from a preliminary screening of experimental conditions for the reaction between 10a (Ar = Ph) and indole (12)
Exp.
12 (mol equiva)
Catalyst (mol equiva)
Solvent
T (°C)
Time (days)
10a (recovered)
13ab
1
2
3
4
5
1.3
1
4
1
1
NBS (0.1)
Zn(OAc)2 (0.2)
I2 (0.3)
—
—
CH2Cl2
EtOH
Et2O
H2O
CF3CH2OH
40
25
25
Reflux
25
5
4
4
4
4
80%
70%
14%c
21%c
—
—
Traces
100%
0%d
ca. 100%
a
b
c
With respect to 10a.
Ca. 1.5:1 diastereomeric mixture (see Ref. 27).
Absolute yield.
d
Extensive 10a decomposition with no isolation of the expected product.
stabilized carbanion by indole from the main product can only be
hypothesized at this stage. The formation of 15, whose yield could
conceivably be improved by a proper modulation of the reaction
conditions, is surely not trivial, as it provides access to new exam-
ples of a class of bis(indolyl)-based molecules which are under
investigation for their pharmacological/biological properties.29,30
As shown in Scheme 3, very similar, rewarding results were
obtained when extending the reaction to the p-tolyl (11b) and
p-chlorophenyl (11c) derivatives, allowing to foresee a rather wide
applicability range for our original approach.
H
N
NO2
NO2
SMe
(cat.)
+
SMe
N
H
Ph
Ph
10a
12
13a
(ca. 1.5 : 1 mixture
of two diastereoisomers)
In the context of our preliminary screening, butadienes 6 and 7,
deriving from the initial ring-opening of 3-nitrothiophene, issue
different challenges, represented by (a) any propensity to react of
the former (where an electronically unfavorable methylthio func-
tion is present, much alike 10), or (b) the behavior of the latter,
which holds good structural reasons for a regioselectivity issue
relevant to the nucleophilic attack to either activated double bond.
Scheme 2. Michael-type addition of indole to the nitrobutadiene from ring-opening
of 8.
Moreover, interestingly enough, the main product was accom-
panied by small amounts (6%) of a secondary one whose structure,
based on both 1H and 13C NMR analysis, corresponds to the
bis(3-indolyl)methane derivative 15a: replacement of a highly
H
N
H
N
NO2
NO2
Zn(OAc)2
EtOH
NH
+
+
SO2Me
N
H
SO2Me
Ar
Ar
Ar
12
Ar = Ph: 11a
15a: 6%
14a: 77%
14b: 76%
15b
Ar = p-Tol: 11b
Ar = p-ClC6H4:
: 10%
11c
15c: 7%
14c
: 55%
Scheme 3. Products from the reaction between indole and nitrosulfonylbutadienes 11.

754
L. Bianchi et al. / Tetrahedron Letters 53 (2012) 752–757
H
N
H
N
NO2
SO2Me
indole
NO2
NH
+
p-Tol
Zn(OAc)2, EtOH
p-Tol
17b
p-Tol
16b: 49%
CH2SO2Me
7b
: 19%
Scheme 4. Products from the reaction between indole and nitrosulfonylbutadiene 7b.
As a matter of facts, 6b (Ar = p-Tol) showed, in ethanol, a very low
different products, the two main ones being the isomeric nitrocar-
bazoles 19b and 20b (Scheme 6).
The unambiguous assignment of the 3-nitro-1,4-bis(p-tolyl)-9H-
carbazole structure to 19b was obtained by means of a single-crys-
tal X-ray analysis after crystallization from ethanol, the relevant
ORTEP drawing being reported in Figure 1.33
reactivity at room temperature while yielding a very complex final
mixture at 50 °C, most likely as the result of extensive decom-
position.
On the other hand, the outcome of the reaction with 7b (Scheme
4) was quite intriguing, whereby the main product 16b, isolated
after 24 h in a 49% yield as a ca. 4:1 Z:E mixture (as judged on the
grounds of chemical shifts in the 1H NMR spectrum),27 is the result
of a 1,4-addition to the dienic system: this requires that protonation
of the delocalized anion 18 (Scheme 5), originated by selective
nucleophilic addition to the nitrovinyl moiety, occurs at the carbon
that binds the sulfonyl group rather than the nitro group.
The 1,4-addition is probably favored as it leads to a more substi-
tuted double bond and/or as it restores a thermodynamically stable
nitrovinyl functionality: an outcome undoubtedly of particular
interest from a synthetic point of view. As a matter of facts, we
have already reported a similar outcome elsewhere.15,20,21
Besides to the main product, also in this case a bis(3-indo-
lyl)methane derivative (17b)27 was isolated: again, a nucleophilic
displacement of a stabilized carbanion by a second molecule of
indole is likely at play.
As far as dinitrobutadienes 3 are concerned, while structurally
simpler because of their molecular symmetry, in our hands they
have so far proved to be rather awkward and unpredictable
systems, as reaction can affect just one nitrovinyl moiety11 or both
of them,8,9,31 which could in turn behave independently9 or coop-
eratively.8,31 For the tests herein, we chose to use two molar equiv-
alents of indole in order to cope with a foreseeable concurrent
pathway represented by a double Michael addition.8 Very first
attempts also suggested mild heating (40 °C) and the use of non-
catalytic amounts of zinc acetate in order to favor the reactivity.32
Much to our surprise, starting from the bis(p-tolyl) derivative 3b
we could isolate, from a relatively complex final mixture, three
A reasonable mechanistic hypothesis, still awaiting experimen-
tal substantiation, is formulated in Scheme 7, where an initial,
intermolecular, Michael addition to a nitrovinylic moiety to give
21 is followed by a second, intramolecular, nucleophilic attack onto
the remaining nitrovinyl, again followed by restoration of the aro-
maticity of indole and eventually leading to the double addition
product 22: the neat result so far being a double electrophilic aro-
matic substitution at positions 3 and 2 of the indole nucleus, the
diene acting as a double Michael acceptor and the indole as a dou-
ble nucleophile. It is worth mentioning, at this regard, that, as
recently reported in similar cases, a second participation of the in-
dole nucleus as a nucleophile could involve the same C(3) position,
to generate a spiro-type intermediate which would subsequently
transform, in acidic media, into the final condensed system:36 pos-
sibility which cannot be ruled out for our system, although not
supported by any experimental data so far. As already noticed in
previous studies of ours,6,8 molecular arrays such as 22, possessing
two nitro groups on adjacent saturated carbon atoms, easily
remove nitrous acid: in this case, given the nature of the tricyclic
system, two different regioisomers can be originated, namely the
intermediate cyclohexadiene derivatives 23 and 24. Finally, via
oxidation either by air or by the just released nitrous acid, both
dienes could aromatize to the isolated carbazoles 19 and 20.
Actually, so far we have not managed to obtain a suitable single
crystal of the secondary product (i.e., 20); nonetheless, the structure
of 2-nitro-1,4-bis(p-tolyl)-9H-carbazole can be rather straightfor-
wardly guessed on the grounds of the mechanistic hypothesis
advanced. More reliable confirmation definitely comes from the
spectral (1H NMR, 13C NMR, IR, UV–vis and GC–MS) analogies be-
tween 19b and 20b, as well as from some quantum mechanical
calculations.
O
Nu
Ar
Nu
Ar
Nu
Ar
Surprisingly enough, the third (minor: 7%) product isolable
from the reaction on 3b is represented by the dinitrocarbazole
25b (Scheme 8), whose identification again rests, at the moment,
on spectroscopic evidences.32 One must admit, in this case, a dou-
ble oxidation of intermediate 22b, strongly driven by the thermo-
dynamic advantage of full aromatization, for which the system
N
O
NO2
NO2
SO2Me
SO2Me
SO2Me
18
Scheme 5. Charge delocalization in the anionic intermediate 18.
Ar
Ar
NO2
NO2
Ar
indole
Zn(OAc)2, EtOH
+
NO2
Ar
N
H
N
H
O2N
Ar
Ar
3a
19a
: 48%
20a: 24%
Ar = Ph:
20b
Ar = p-Tol: 3b
19b: 48%
19c
: 27%
3c
20c
Ar = m-ClC6H4:
: 29%
: 14%
Scheme 6. Isomeric nitrocarbazoles from the reaction between indole and dinitrobutadienes 3.

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 752–757
755
p-Tol
p-Tol
NO2
NO2
two-step
oxidative aromatization
NO2
p-Tol
NO2
p-Tol
N
H
N
H
25b
22b
Scheme 8. Oxidative pathway to dinitrocarbazole 25b.
Table 2
Results for the reaction between 3b and indole (12) in EtOH at 40 °C with or without
added DDQ
Exp. 12 (mol equiva) DDQ (mol equiva) Time (h) 19bc 20bc 25bc
1
2
3
2
2
2
—
3
5
24
48%
31%
32%
27%
7%
50%
49%
24 + 2b
24 + 2b
a
b
c
With respect to 3b.
Additional time after DDQ addition, before water quenching.
Absolute yield.
In conclusion, we feel that the preliminary results reported
herein provide further valuable examples of the very interesting
behavior, from the standpoint of both synthetic and mechanistic
aspects, of the nitrosubstituted conjugated butadienes of Scheme
1. It is surely worth recalling that much interest is attached to
the synthesis and/or functionalization of nitrogen heterocycles
such as indoles25 or carbazoles,37 that is, molecules which, because
of biological/pharmacological activity studies and/or technological
applications, fill everyday’s literature with papers and review
articles.
Figure 1. ORTEP drawing of carbazole 19b. Ellipsoids enclose 50% probability.
Anyway, besides the general interest attached to the functional-
ized heterocycles obtained, it seems in particular worth noting that
from the reaction on dinitrobutadienes 3 only carbazoles (19, 20 or
25) could be isolated and identified: that is, products deriving from
a double (intermolecular + intramolecular) Michael-type addition.
Actually, the absence of substituted indoles deriving from a single
intermolecular conjugate addition as well as of bis(3-indo-
lyl)butanes deriving from a double intermolecular Michael addi-
tion (26) strongly suggests that 21, initially formed by ‘clipping’
of the 4-carbon chain onto indole, is ‘forced’ to cyclize most likely
by a concomitance of structural, electronic, and/or geometric fac-
tors. On the other hand, the overall cyclization seems precluded
(most likely for different reasons) to the systems of both Schemes
3 and 4, which could, at least in principle, build a five-member
most likely exploits the ‘home-made’ HNO2 oxidant formed along
the main pathway of Scheme 7.
On the grounds of the discussion above, the possibility to favor
the formation of carbazoles by means of external oxidants has also
been addressed. As a matter of fact, although the easy oxidability of
indole itself heavily limits the use of an oxidant in the starting mix-
ture, for the model 3b we have preliminarily found that, in other-
wise standard conditions,32 the addition of DDQ after the standard
reaction time (24 h) and before quenching with water actually
increases the relative yield of the most oxidized product 25b (Table
2). Optimization will presumably lead to even more enhanced
selectivities.
O2N
Ar
Ar
NO2
NO2
NO2
Ar
Ar
indole
Zn(OAc)2, EtOH
NO2
Ar
O2N
N
H
N
H
Ar
21
3
22
- HNO2
Ar
Ar
Ar
Ar
NO2
+
NO2
+
aromatization
NO2
NO2
N
H
N
H
N
H
N
H
Ar
Ar
Ar
Ar
19
20
23
24
Scheme 7. Proposed mechanism for the synthesis of nitrocarbazoles 19 and 20.

756
L. Bianchi et al. / Tetrahedron Letters 53 (2012) 752–757
24. (a) Rai, V.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2006, 4693–4703; (b) Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–1894.
carbon-ring fused to the indole heteroring, with no possibility,
though, of complete aromatization.
25. (a) Sundberg, R. J. Pyrroles and their Benzoderivatives: Synthesis and
Applications In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 313–376; (b) Kochanowska-
Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489–4497;
(c)Fattorusso, E., Taglialatela-Scafati, O., Eds.Modern Alkaloids. Structure,
H
N
Isolation, Synthesis and Biology; Wiley-VCH Verlag GmbH
Weinheim, Germany, 2008.
& Co. KGaA:
O2N
Ar
26. (a) Bandini, M.; Eichhlozer, A. Angew. Chem., Int. Ed. Engl. 2009, 48, 9608–9644.
and references therein; (b) Kuo, C. W.; Wang, C. C.; Fang, H. L.; Raju, B. R.;
Kavala, V.; Habib, P. M.; Yao, C. F. Molecules 2009, 14, 3952–3963; (c)
Harshadas, M. M.; Dachepally, A. K.; Bandi, C. R. Helv. Chim. Acta 2009, 92,
1002–1006.
27. Typical procedure for the reaction of nitrobutadienes 6, 7, 10 and 11 with indole:
To a stirred suspension of substrate (0.5 mmol) in ethanol (2.5 mL), indole
(0.5 mmol) and zinc acetate (0.025 mmol) were added. The mixture was stirred
at room temperature until the reaction was complete (TLC), the solvent was
evaporated and the residue was purified by column chromatography using
hexane/ethyl acetate (5:1) to collect 13 and hexane/ethyl acetate (3:1) to
collect derivatives 14–17.
Ar
NO2
N
H
26
Acknowledgements
(E)-3-[1-(Methylthio)-1-nitro-4-phenylbut-3-en-2-yl]-1H-indole (13a): isolated
as a 1.5:1 mixture of diastereoisomers (A and B, respectively). 1H NMR (CDCl3,
300 MHz): d (ppm) 2.17 (s, 3H of A), 2.30 (s, 3H of B), 4.52 (dd, J = 9.6, 7.8 Hz,
1H of A), 4.62 (dd, J = 9.8, 7.7 Hz, 1H of B), 5.77 (d, J = 9.9 Hz, 1H of B), 5.78 (d,
J = 9.6 Hz, 1H of A), 6.49 (dd, J = 15.6, 7.7 Hz, 1H of B), 6.50 (dd, J = 15.6, 7.8 Hz,
1H of A), 6.59 (d, J = 15.7 Hz, 1H of A + 1H of B), 7.11–7.42 (m, 9H of A + 9H of
B), 7.69 (d, J = 7.7 Hz, 1H of A + 1H of B), 8.15 (br s, 1H of B), 8.20 (br s, 1H of A).
13C NMR (75 MHz, CDCl3): d (ppm) 14.86, 15.26, 43.58, 44.06, 95.18, 96.07,
111.56, 111.70, 118.78, 118.91, 120.05, 120.10, 122.35, 122.59, 122.61, 122.64,
125.38, 125.64, 125.89, 126.51, 126.59, 127.82, 127.88, 128.40, 128.49, 128.53,
128.76, 133.40, 133.54, 136.24, 136.29, 136.45 (two pairs of carbons are
accidentally isochronous).
The authors wish to thank Mr. A. Sciutto for skilful contribution
to the experimental work. Financial support was provided by
Grants from Ministero dell’Istruzione, dell’Università e della Ric-
erca (MIUR-Roma, PRIN 20085E2LXC).
References and notes
1. Dell’Erba, C.; Spinelli, D.; Leandri, G. J. Chem. Soc., Chem. Commun. 1969, 549.
2. Surange, S. S.; Kumaran, G.; Rajappa, S.; Rajalakshmi, K.; Pattabhi, V.
Tetrahedron 1997, 53, 8531–8540.
3. Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin Trans. 1 1974,
2357–2360.
4. Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron Lett. 1990,
31, 4933–4936.
5. Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron 1992, 48,
4407–4418.
(E)-3-(1-(Methylsulfonyl)-1-nitro-4-(p-tolyl)but-3-en-2-yl)-1H-indole
(14b):
isolated as ca. 1:1 mixture of diastereoisomers; two series of signals are
present in the NMR spectra, although no assignment to either diastereoisomer
is, at the moment, possible. 1H NMR (300 MHz, CDCl3): d (ppm) 2.31 (s, 6H),
2.67 (s, 3H), 3.16 (s, 3H), 4.91 (dd, J = 8.4, 10.5 Hz, 1H), 4.93 (t, J = 8.9 Hz, 1H),
5.95 (d, J = 10.0 Hz, 1H), 5.98 (d, J = 8.8 Hz, 1H), 6.44 (dd, J = 15.5, 8.6 Hz, 1H),
6.54 (dd, J = 15.6, 8.4 Hz, 1H), 6.65 (d, J = 10.1 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H),
7.10 (d, J = 7.8 Hz, 4H), 7.14–7.33 (m, 10H), 7.35–7.41 (m, 1H), 7.41–7.47 (m,
1H), 7.70 (t, J = 8.6 Hz, 2H), 8.20 (br s, 1H), 8.30 (br s, 1H). 13C NMR (75 MHz,
CDCl3): d (ppm) 21.20, 39.44, 40.88, 42.45, 42.79, 103.32, 103.79, 109.15,
110.54, 111.81, 112.13, 118.34, 118.53, 120.41, 120.71, 121.80, 122.52, 122.55,
122.89, 123.05, 124.02, 124.97, 125.05, 126.56, 126.59, 129.29, 129.34, 132.94,
133.07, 134.12, 134.12, 136.18, 136.21, 138.28, 138.32 (a pair of carbons are
accidentally isochronous). MS (ESI): m/z 385 [M+H]+.
(E)-3,3-Bis(1H-3-indolyl)-1-(p-tolyl)propene (15b). Red-brownish solid, mp
127–128 °C (diethyl ether/petroleum ether). 1H NMR (300 MHz, CDCl3): d
(ppm) 2.30 (s, 3H), 5.38 (dd, J = 7.1, 1.2 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 6.74
(dd, J = 15.8, 7.0 Hz, 1H), 6.91 (dd, J = 2.5, 0.9 Hz, 2H), 6.96–7.13 (m, 4H), 7.13–
7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 2H), 7.23–7.31 (m, 2H), 7.35 (dt, J = 8.1, 0.9 Hz,
2H), 7.59 (dd, J = 7.8, 1.1 Hz, 2H), 7.92 (br s, 2H). 13C NMR (75 MHz, CDCl3): d
(ppm) 21.15, 37.42, 111.05, 118.51, 119.21, 120.00, 121.87, 122.53, 126.20,
126.95, 129.10, 129.77, 131.29, 134.87, 136.62, 136.70. MS (ESI): m/z 363
[M+H]+.
6. Dell’Erba, C.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron Lett. 1992, 33, 7047–
7048.
7. (a) Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.; Tavani, C.
2,3-Dinitro-1,3-butadienes: Versatile Building Blocks from the Ring Opening of
3,4-Dinitrothiophene In Targets in Heterocyclic Systems: Chemistry and
Properties; Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana: Rome,
2006; Vol. 10, pp 1–23; (b) DellErba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Synthetic Exploitation of the Ring-Opening of 3,4-Dinitrothiophene In Topics in
Heterocyclic Systems: Synthesis Reactions and Properties; Attanasi, O. A., Spinelli,
D., Eds.; Research Signpost: Trivandrum, India, 1996; Vol. 1, pp 1–12.
8. Dell’Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J. Org.
Chem. 2000, 903–912.
9. Armaroli, T.; Dell’Erba, C.; Gabellini, A.; Gasparrini, F.; Mugnoli, A.; Novi, M.;
Petrillo, G.; Tavani, C. Eur. J. Org. Chem. 2002, 1284–1291.
10. Bianchi, L.; Dell’Erba, C.; Gasparrini, F.; Novi, M.; Petrillo, G.; Sancassan, F.;
Tavani, C. Arkivoc 2002, ix, 142–158.
11. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Spinelli, D.; Stenta,
M.; Tavani, C. Lett. Org. Chem. 2007, 4, 268–272.
12. Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.;
Spinelli, D. Tetrahedron 2001, 57, 8159–8165.
13. Bianchi, L.; Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.
Tetrahedron 2002, 58, 3379–3385.
14. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.;
Sancassan, F.; Tavani, C. J. Org. Chem. 2003, 68, 5254–5260.
15. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Novi, M.; Petrillo, G.;
Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Tetrahedron 2004, 60,
4967–4973.
16. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.;
Severi, E.; Tavani, C. J. Org. Chem. 2005, 70, 8734–8738.
17. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Petrillo, G.; Rizzato, E.;
Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Arkivoc 2006, vii, 169–185.
18. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Rocca, V.; Sancassan, F.;
Scapolla, C.; Severi, E.; Tavani, C. J. Org. Chem. 2007, 72, 9067–9073.
19. Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
Spinelli, D.; Tavani, C.; Viale, M. Versatile Nitrobutadienic Building-Blocks from
the Ring-Opening of 2- and 3-Nitrothiophenes In Targets in Heterocyclic
Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Società
Chimica Italiana: Rome, 2007; Vol. 11, pp 1–20.
20. Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
Spinelli, D.; Stenta, M.; Galatini, A.; Tavani, C. Tetrahedron 2009, 65, 336–343.
21. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Severi, E.;
Spinelli, D.; Stenta, M.; Tavani, C. Chem. Eur. J. 2010, 16, 1312–1318.
22. Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Eur J. Org. Chem. 2009,
4091–4101. and references therein.
3-[4-(Methylsulfonyl)-2-nitro-1-(p-tolyl)but-2-en-1-yl)-1H-indole (16b): isolated
as
a brown-solid ca. 4:1 Z:E mixture after crystallization from toluene/
petroleum ether: only the NMR signals for the main (Z)-isomer are completely
described. 1H NMR (CDCl3, 300 MHz): d (ppm) 2.35 (s, 3H), 2.85 (s, 3H), 3.98
(dd, J = 14.7, 7.8 Hz, 1H), 4.12 (dd, J = 14.7, 8.4 Hz, 1H), 5.73 (td, J = 8.3, 1.3 Hz,
1H), 5.82 (s, 1H), 6.72 (dd, J = 2.5, 0.9 Hz, 1H), 7.08–7.29 (m, 6H), 7.34–7.46 (m,
1H), 7.49 (d, J = 7.3 Hz, 1H), 8.13 (s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm)
21.1, 40.7, 45.4, 53.7, 111.7, 113.9, 118.1, 118.6, 120.1, 122.8, 124.6, 125.7,
128.2, 129.7, 134.4, 136.7, 137.7, 159.2.MS (ESI): m/z 385 [M+H]+. For the
minor (E)-isomer, only a few signals in the 1H NMR spectrum can be clearly
identified: d (ppm) 2.24 (s, 3H), 2.36 (s, 3H), 3.42–3.60 (m, 2H), 6.16 (s, 1H),
6.75 (dd, J = 2.5, 1.1, 1H), 8.20 (s, 1H); the multiplet (td) for the vinylic proton is
covered by the aromatic signals, well above 7 ppm, clearly indicating its cis
relationship with the adjacent nitrogroup.28
Bis(1H-3-indolyl)(p-tolyl)methane (17b). Pink solid, mp 88.0–90.0 °C (toluene/
petroleum ether); lit.29a mp 87.0–87.3 °C (benzene). 1H NMR (CDCl3,
300 MHz): d (ppm) 2.32 (s, 3H), 5.85 (s, 1H), 6.67 (s, 2H), 7.00 (t, J = 7.5 Hz,
2H), 7.08 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.36
(d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.91 (br s, 2H). 13C NMR (75 MHz,
CDCl3): d (ppm) 21.09, 39.72, 110.98, 119.15, 119.85, 119.93, 121.84, 123.53,
127.04, 128.53, 128.89, 135.47, 136.63, 140.92.
28. Bianchi, L.; Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.
Tetrahedron 2002, 58, 3379–3385. and references therein.
29. (a) Maciejewska, D.; Rasztawicka, M.; Wolska, I.; Anuszewska, E.; Gruber, B.
Eur. J. Med. Chem. 2009, 44, 4136–4147; (b) Chintharlapalli, S.; Papineni, S.;
Safe, S. Mol. Pharmacol. 2007, 71, 558–569.
30. (a) Chao, W.-R.; Yean, D.; Amin, K.; Green, C.; Jong, L. J. Med. Chem. 2007, 50,
3412–3415; (b) Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Tetrahedron 2004, 60,
2051–2055.
23. Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Spinelli, D.;
Tavani, C. Tetrahedron 2011, 67, 8160–8169.

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 752–757
757
31. Dell’Erba, C.; Giglio, A.; Mugnoli, A.; Novi, M.; Petrillo, G.; Stagnaro, P.
Tetrahedron 1995, 51, 5181–5192.
(dichloromethane/petroleum ether). 1H NMR (CDCl3, 300 MHz): d (ppm) 2.49
(s, 3H), 2.52 (s, 3H), 6.90 (d, J = 8.3 Hz, 1H), 7.09–7.00 (m, 1H), 7.41–7.48 (m,
10H), 8.40 (br s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 21.61, 21.71, 111.50,
118.88, 121.43, 122.82, 123.30, 128.07, 128.38, 128.74, 128.82, 129.96, 130.37,
130.64, 131.25, 137.74, 139.47, 140.14, 141.27 (three pairs of carbons are
accidentally isochronous). EI (relative intensity): m/z 437(100) [M+ꢀ], 407(7),
374(9), 361(20), 345(20), 332(17), 316(12), 255(9), 171(16), 164(63), 158(51),
151(34), 146 (28), 138(14), 119(10), 91(12).
32. Typical procedure for the reaction of dinitrobutadienes 3 with indole. To a stirred
suspension of 3 (0.5 mmol) in ethanol (8 mL) at 40 °C, indole (1.1 mmol) and
zinc acetate (0.5 mmol) were added. The mixture was stirred at 40 °C for 24 h
to ensure completion of reaction and then poured into water and extracted
with dichloromethane; the organic extracts were dried over Na2SO4 and the
solvent was removed under reduced pressure. The residue was purified by
column chromatography using hexane/ethyl acetate (10:1) to give 19, 20 and
25.
33. X-ray crystallography. Single crystals of 19b were submitted to X-ray data
collection on an Oxford-Diffraction Xcalibur Sapphire 3 diffractometer with a
3-Nitro-1,4-bis(p-tolyl)-9H-carbazole (19b). Yellow solid, mp 213–214 °C
(dichloromethane/petroleum ether). 1H NMR (CDCl3, 300 MHz): d (ppm) 2.49
(s, 3H), 2.53 (s, 3H), 6.74 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 5.1 Hz, 1H), 7.48–7.29 (m,
8H), 7.62 (d, J = 8.0 Hz, 2H), 8.16 (s, 1H), 8.60 (br s, 1H). 13C NMR (75 MHz,
CDCl3): d (ppm) 21.59, 21.81, 111.20, 120.78, 122.16, 123.11, 123.23, 123.97,
124.34, 127.16, 128.36, 128.48, 129.89, 130.57, 132.44, 133.64, 133.96, 138.13,
138.85, 139.43, 140.52, 142.22. EI (relative intensity): m/z 392(100) [M+ꢀ],
375(9), 362(13), 347(14), 331(34), 316(9), 254(12), 171(19), 164(48), 158(48),
151(22), 145(13), 139(13), 119(9), 91(5). UV–vis (CHCl3) kmax 230, 281, 306,
344 nm.
2-Nitro-1,4-bis(p-tolyl)-9H-carbazole (20b). Yellow solid, mp 124–125 °C
(dichloromethane/petroleum ether). 1H NMR (CDCl3, 300 MHz): d (ppm) 2.49
(s, 3H), 2.52 (s, 3H), 7.05 (t, J = 7.5 Hz, 1H), 7.47–7.32 (m, 8H), 7.65–7.53 (m,
3H), 7.77 (s, 1H), 8.19 (br s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 21.57,
111.07, 117.14, 119.17, 120.17, 122.34, 123.47, 124.02, 127.59, 128.77, 129.07,
129.57, 130.28, 130.99, 136.29, 137.11, 138.39, 138.65, 138.83, 141.39, 145.36
(a pair of carbons are accidentally isochronous). EI (relative intensity): m/z
392(100) [M+ꢀ], 375(6), 362(14), 347(17), 331(23), 316(7), 254(12), 171(10),
164(52), 158(46), 151(25), 145 (15), 139(13), 119(8), 91(5). UV–vis (CHCl3)
kmax 242, 260, 346 nm.
graphite monochromated Mo-Ka radiation (k = 0.71073 Å) at 293 K. The
structure was solved by direct methods implemented in SHELXS-97
program.34 The refinement was carried out by full-matrix anisotropic least-
squares on F2 for all reflections for non-H atoms by means of the SHELXL-97
program.35 Crystallographic data (excluding structure factors) for structure
19b have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC-836410. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
34. Sheldrick, G. M. SHELXS-97, Rel. 97-2, A Program for Automatic Solution of
Crystal Structures, University of Göttingen, Göttingen (Germany), 1997.
35. Sheldrick, G. M. SHELXL-97, Rel. 97-2,
A Program for Crystal Structure
Refinement, University of Göttingen, Göttingen (Germany), 1997.
36. (a) Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Köhn, G.; Andrews, B. I.;
Carbery, D. R. Org. Lett. 2009, 11, 1175–1178; (b) Liu, K. G.; Robichaud, A. J.; Lo,
J. R.; Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769–5771.
37. (a) Takeuchi, T.; Oishi, S.; Watanabe, T.; Ohno, H.; Sawada, J.; Matsuno, K.; Asai,
A.; Asada, N.; Kitaura, K.; Fujii, N. J. Med. Chem. 2011, 54, 4839–4846; (b) Rosini,
M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D.
W.; Tarozzi, A.; Bolognesi, M. L.; Minarini, A.; Tumiatti, V.; Andrisano, V.;
Mellor, I. R.; Melchiorre, C. J. Med. Chem. 2008, 51, 4381–4384.
2,3-Dinitro-1,4-bis(p-tolyl)-9H-carbazole (25b). Yellow solid, mp 267–268 °C