Dioxomolybdenum(VI)-catalyzed reductive cyclization of nitroaromatics. Synthesis of carbazoles and indoles

Article abstract of DOI:10.1002/adsc.200600384

Reductive cyclization of nitrobiphenyls and nitrostyrenes to carbazoles and indoles, respectively, is carried out by triphenylphosphine under mild conditions catalyzed by a dichlorodioxomolybdenum(VI) complex. A one-pot procedure for the synthesis of regioselectively functionalized indoles has been developed from commercially available onitrobenzaldehydes and phosphoranes.

Full text of DOI:10.1002/adsc.200600384

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DOI: 10.1002/adsc.200600384
Dioxomolybdenum(VI)-Catalyzed Reductive Cyclization of Nitro-
aromatics. Synthesis of Carbazoles and Indoles
Roberto Sanz,a,* Jaime Escribano,a María R. Pedrosa,a Rafael Aguado,a
and Francisco J. Arnµiza,*
a
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael BaÇuelos s/n, 09001-Burgos, Spain
Fax : (+34)-947-258-831; e-mail: rsd@ubu.es or farnaiz@ubu.es
Received: July 27, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
À
Abstract: Reductive cyclization of nitrobiphenyls
and nitrostyrenes to carbazoles and indoles, respec-
tively, is carried out by triphenylphosphine under
mild conditions catalyzed by a dichlorodioxomolyb-
denum(VI) complex. A one-pot procedure for the
synthesis of regioselectively functionalized indoles
has been developed from commercially available o-
nitrobenzaldehydes and phosphoranes.
trene that undergoes C H insertion in a suitable side
chain.[9] Nevertheless, the isolation of N-hydroxy de-
rivatives[7a] along with computational studies[10] have
shown that an alternative 1,5-electrocyclization of the
corresponding nitroso intermediates to nitrones fol-
lowed by 1,5-H shift and tautomerization, may even
be competitive with nitrene formation. N-Ethylcarb-
azoles and N-ethoxy- or N-ethylindoles are usually
formed in these reactions as side products, probably
due to alkylation of the nitrogen by the generated
triethyl phosphate.[11] This problematic side reaction
could, in principle, be avoided by using PPh3 as a con-
venient alternative reducing agent due to the non-
electrophilic nature of its by-product, triphenylphos-
phine oxide. However, to the best of our knowledge,
Keywords: carbazoles; cyclization; indoles; molyb-
denum; nitro compounds; reduction
Indoles and carbazoles are ubiquitous components of only a single methodology has been developed using
both biologically active natural products and impor- PPh3 as a reductant in carbazole synthesis from nitro-
tant pharmaceuticals.[1] Also, in materials science car- biphenyls.[12] Freeman and co-workers have recently
bazoles are important building blocks.[2] So, the devel- described the synthesis of carbazoles by reductive cy-
opment of efficient synthetic routes to both core clization of 2-nitrobiphenyls using PPh3 in o-dichloro-
structures with a variety of substitution patterns is a benzene (o-DCB) at reflux (1808C).[13] Although with
current major objective in organic synthesis.[3] One this method the formation of undesired alkylated im-
important route to carbazoles and indoles is the re- purities is avoided, it still presents severe drawbacks
ductive cyclization of nitrobiphenyls and 2-nitrostyr- like the use of highly toxic solvents and the very high
enes, respectively.[4]
temperatures required.
Since its discovery in 1962,[5] the Cadogan reduction
On the other hand, it is known that some dioxo-
of 2-nitrobiphenyls by trivalent phosphorus reagents molybdenum(VI) complexes that mimic oxo-transfer-
has been recognized as a general route to carbazoles ases are efficient catalysts for oxo-transfer reac-
and other nitrogen-containing heterocycles,[6] and re- tions.[14] In this field, we have found that a number of
mains the most common method to effect deoxygena- addition compounds of dichlorodioxomolybdenum-
tive cyclizations. The reactions are usually conducted (VI) are able to catalyze a variety of oxo-transfer pro-
using an excess of P(OEt)3, as both the reductant and cesses, in particular the oxidation of thiols to disul-
G
solvent, at reflux (1568C). Also, Cadogan[5b] and fides with DMSO,[15] the deoxygenation of sulfoxides
Sundberg[7] reported that the deoxygenation of b-sub- to sulfides with phosphites,[16] and the reduction of N-
stituted o-nitrostyrenes with P
(OEt)3 afforded 2-sub- oxides with PPh3.[17] Herein, we report the synthesis
G
stituted (alkyl or aryl) indole derivatives. However, of carbazoles and indoles by the dichlorodioxomoly-
this method furnished very poor yields in the synthe- benum(VI)-catalyzed reductive cyclization of 2-nitro-
sis of 2-ethoxycarbonyl- and 2-acylindoles.[8] The biphenyls and 2-nitrostyrenes, respectively, with PPh3.
widely accepted mechanism for this transformation
Our choice of commercially available 2-nitrobi-
involved exhaustive deoxygenation to a singlet ni- phenyl 1a as a model substrate for deoxygenation was
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713

Roberto Sanz et al.
COMMUNICATION
prompted by the fact that the expected nitrene (or ni- oxide under air (Table 1, entries 4–6). Interestingly,
trenoid) intermediate, i.e., 2-biphenylnitrene 2a,[18]
(OEt)3, usually used under Cadogan cyclization con-
P
ACHTREUNG
would produce thermally stable and known products ditions, was less effective than PPh3 for deoxygena-
from relatively well-defined reaction modes: carb- tion of nitrobiphenyl 1a in the presence of the molyb-
À
azole 3a from a formal intramolecular C H bond in- denum complex (Table 1, entry 7). It is also interest-
sertion and/or 2-aminobiphenyl 4a from H abstraction ing to note that in the absence of catalyst (Table 1,
(Scheme 1).
As indicated in Scheme 1, deoxygenation is simply tected.[19]
achieved by refluxing a solution of 1a containing PPh3 In order to simplify the purification process, the
(2.4 equivs.) and a catalytic amount of MoO2Cl2(dmf)2 excess of PPh3 was easily transformed into the phos-
(5 mol%). Initially, 1a and PPh3 were taken upin tol- phine oxide by further addition of DMSO and a small
entry 8) only trace amounts of carbazole 3a were de-
AHCTREUNG
uene, MeCN, THF, DMF and refluxed overnight amount of the same catalyst (1 mol%) after the com-
(Table 1). As shown in Table 1 (entries 1–4) toluene plete conversion of the starting nitroaromatic.[20] So,
turned out to be the most suitable solvent in order to simple removal of the solvent and purification by
get a good conversion of nitrobiphenyl 1a. The use of silica gel column chromatography afforded carbazole
an inert atmosphere led to a better conversion, proba- 3a.
bly due to the catalyzed oxidation of PPh3 to the
With the conditions for the molybdenum-catalyzed
cyclization of 2-nitrobiphenyl 1a established, our next
goal was to test the scope and functional group toler-
ance of the method. Following known procedures for
the Suzuki–Miyaura cross-coupling reactions,[21] we
first synthesized a variety of 2-nitrobiphenyls 1b–i
having a range of usual functionalities. Nitroaromatics
1b–i were treated in the same reaction conditions as
described above for 1a: refluxing toluene
(10 mLmmolÀ1) for ca. 16 h in the presence of PPh3
Table 1. Conditions for the reductive cyclization of 1a.
Entry
Solvent
Time [h]
Conversion [%][a]
1
2
3
4
5
6
7
8
MeCN
24
16
16
16
16
16
16
16
55
DMF[b]
THF
0
67[c]
85
toluene[d]
toluene[e]
toluene[f]
toluene
toluene
90
(2.4 equivs.) and MoO2Cl2(dmf)2 (5 mol%). The re-
A
>95[g]
60[h]
<5[i]
sults are summarized in Table 2.
As seen in Table 2, our method tolerates a wide
range of functional groups such as alkyls, ethers, car-
bonyls, halogens, and carboxylic esters. In general,
good isolated yields were observed for this process
(Table 2, entries 1–7), although minor amounts of the
corresponding amines 4 were detected for substrates
bearing electron-donating substituents (Table 2,
entry 3). As previously noted by Freeman and co-
workers the only functional groups that appear to be
problematic for this reaction are those with free,
acidic protons, such as phenol 1h and carboxylic acid
1i.[13] Anyway, whereas Freeman reported no cycliza-
tion at all for 1h and 1i with PPh3 in refluxing o-DCB,
[a]
1
Estimated by H NMR analysis of the crude of the reac-
tion. The selectivity of the reaction for the formation of
3a from 1a was almost complete and only trace amounts
of 4a could be detected.
[b]
[c]
[d]
[e]
[f]
Carried out at 1108C.
15% of 4a was generated.
Synthesis grade.
Dried toluene under air atmosphere.
Dried toluene under nitrogen atmosphere.
83% isolated yield.
[g]
[h]
[i]
P
ACHTREUNG
Scheme 1. Optimization of the reductive cyclization of 2-nitrobiphenyl 1a to carbazole 3a. Reagents and conditions: i)
MoO2Cl2(dmf)2 (5 mol%), solvent, reflux, time (see Table 1).
ACHTREUNG
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Adv. Synth. Catal. 2007, 349, 713 – 718

Dioxomolybdenum(VI)-Catalyzed Reductive Cyclization of Nitroaromatics
COMMUNICATION
Table 2. Reductive cyclization of nitrobiphenyls 1 to carb-
azoles 3.
Table 3. Reductive cyclization of 2-nitrostyrenes 5 to indoles
6.
Entry Starting
material
R1
R2
H
Product Yield [%][a]
Entry Starting E/Z R1
R2 Product Yield [%][a]
material
73[b]
64
80
80
77
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
3a
86[b]
80
1
2
3
4
5
6
7
5a
5a
5a
5b
5c
5d
5e
4/1
1/0
0/1
Ph
Ph
Ph
H
H
H
H
H
H
6a
6a
6a
6b
6c
6d
t-Bu
OMe
CHO
COMe
F
CO2Et
OH
CO2H
t-Bu 3b
H
H
H
H
H
H
H
3c
3d
3e
3f
3g
3h
3i
78[c]
70
1/2.3 n-C5H11
1/2 Me
10/1 CO2Et
81
73
75
87
1.5/1 CO2Et Me 6e
84
33[d]
30
[a]
[b]
Isolated yield based on the starting nitrostyrene 5.
No reaction was observed without catalyst.
[a]
[b]
[c]
Isolated yield based on the starting nitrobiphenyl 1.
Carried out on a 10 mmol scale.
Small amounts (<10%) of the corresponding amine 4c
were detected.
tive 5e, with an additional substituent on the double
bond also underwent reductive cyclization to the 2,3-
disubstituted indole 6e in very good yield (Table 3,
entry 7).
[d]
20% of 1h and 10% of 4h were also isolated.
our procedure allows the synthesis of the correspond-
Among 2-substituted indoles, 2-acylindoles as well
ing carbazoles 3h and 3i in modest yields (Table 2, en- as indole 2-carboxylates constitute valuable building
tries 8 and 9). The low yields of these reactions could blocks for the synthesis of various heterocyclic com-
be due to the ability of nitrobiphenyls 1h and i with pounds. Also, regioselectively substituted indoles at
acidic protons, to generate alkoxo or carboxylate di- the carbocyclic ring are particularly difficult to access
oxomolybdenum(VI) complexes,[22] which would not following traditional methods due to the different
be active catalysts in the process.
electron-rich nature of each position.[23] In this con-
Once we had demonstrated the ability of our cata- text, we envisaged that this kind of interesting substi-
lytic method for the synthesis of carbazoles, we decid- tution pattern of indoles could be efficiently obtained
ed to explore the deoxygenation and subsequent cycli- in one-pot approach using our molybdenum-catalyzed
zation of o-nitrostyrenes as a method for the synthesis reductive cyclization. Hence, a Wittig reaction in tolu-
of indole derivatives. o-Nitrostilbene 5a was chosen as ene at room temperature of phosphoranes 8a (R=
a representative b-aryl-o-nitrostyrene. Its reductive OEt) or 8b (R=Me) with 2-nitrobenzaldehydes 7, all
cyclization with PPh3 under dioxomolybdenum cataly- of them commercially available, gave the correspond-
sis afforded 2-phenylindole 6a in good yield (Table 3, ing o-nitrostyrene derivatives.[24] Without isolation of
entry 1). It is interesting to note that both the cis- and these derivatives, subsequent addition of PPh3 and a
trans-isomers of 5a reacted, although a slightly higher catalytic amount of MoO2Cl2(dmf)2 (10 mol%) was
G
yield was obtained from the former (Table 3, entries 2 followed by refluxing of the mixture for 24 h.[25] As
and 3).[5b] Then, b-alkyl-o-nitrostyrenes 5b and c were mentioned above, oxidation of the excess of PPh3
prepared by Wittig reaction from 2-nitrobenzaldehyde with DMSO and removal of the solvent, followed by
and obtained in both cases as a mixture of geometri- simple column chromatography afforded interesting
cal isomers. When these substrates were subjected to regioselectively substituted indole derivatives 6f–o in
reductive cyclization under the same reaction condi- high to moderate overall yields referred to the start-
tions, the corresponding 2-alkylindoles 6b and c were ing o-nitrobenzaldehydes 7 (Table 4).[26]
isolated in good yields (Table 3, entries 4 and 5). In-
Finally, we checked whether 2-nitrobiphenyl 1a as
trigued by the low yields reported for the preparation well as 2-nitrostyrenes 5a and b would also undergo
of indole 2-carboxylates,[5b,7a] our next goal was to test the dioxomolybdenum-catalyzed reductive cyclization
our catalytic procedure in the reductive cyclization of to the corresponding heterocyclic derivatives using a
2-nitrocinnamates. Gratifyingly, treatment of ethyl 2- commercially available, polymer-bound triphenyl-
nitrocinnamate 5d under the established conditions phosphine (Scheme 2). The yields of the final com-
led to ethyl indole-2-carboxylate 6d in good yield pounds were comparable with those obtained using
(Table 3, entry 6). Moreover, 2-nitrocinnamate deriva- PPh3, whereas the isolation of the product by simple
Adv. Synth. Catal. 2007, 349, 713 – 718
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Roberto Sanz et al.
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Table 4. One-pot synthesis of 2-ethoxycarbonyl- and 2-
acetyl-substituted indoles 6 from 2-nitrobenzaldehydes 7.
ing to the corresponding nitroso derivatives 9. Since it
is known that the reductive cyclization of 2-nitrosobi-
phenyl compounds to carbazoles using PPh3 takes
place in benzene at low temperature,[28] we postulated
that the second deoxygenation may take place with-
out catalysis. Thus, nitroso intermediates 9 are rela-
tively rapid deoxygenated with a second equivalent of
Entry Starting R1[a]
material
R2
Product Yield [%][b] PPh3 to generate nitrenes (or nitrenoids) 2, which un-
À
dergo C H insertion to afford carbazoles 3 or indoles
6 (Scheme 3). Alternatively, as previously pointed
1
2
3
4
5
6
7
8
7a
H
OEt 6d
OEt 6f
OEt 6g
OEt 6h
71
85
15
50
81
45[d]
63
93
39
55
78
out,[10] nitroso derivatives 9 could undergo direct cyc-
lization before reduction to a nitrene, affording nitro-
nes 10 and finally N-hydroxy derivatives 11 which
would be further deoxygenated to 3 or 6 (Scheme 3).
In summary, we have developed a dioxomolybde-
num(VI)-catalyzed method for the reductive cycliza-
tion of nitroaromatics with PPh3 under milder condi-
tions than all previously reported. A wide range of in-
teresting functionalized carbazole and indole deriva-
tives have been prepared with this methodology
showing that it constitutes a synthetically competitive
alternative to already established methods for the
same kind of reactions.
7b
7c
4-Cl
5-Cl
6-Cl
7d[c]
7e
5,6-(OCH2O) OEt 6i
7-OMe
H
4-Cl
5-Cl
6-Cl
7f
7a
OEt 6j
Me 6k
Me 6l
Me 6m
Me 6n
7b
7c
9
10
11
7d[c]
7e
5,6-(OCH2O) Me 6o
[a]
[b]
[c]
Location of R1 on the final indole derivative 6.
Isolated yield based on the starting nitrobenzaldehyde 7.
Although it is commercially available (Sigma), it was syn-
thesized by oxidation of 4-chloro-2-nitrobenzylalcohol.
25% of the intermediate nitrocinnamate and 10% of
ethyl 2-amino-3-methoxycinnamate were also isolated.
[d]
Experimental Section
General Remarks
filtration of the solid-supported phosphine is much
easier. Under these conditions reaction times were a
bit longer.
All reactions were carried out under nitrogen atmosphere
unless otherwise specified. CH3CN, DMF, toluene and THF
were analytical grade and purchased from SDS. 1H and
13C NMR spectra were recorded on a Varian Mercury-Plus
300 or Varian Inova 400 spectrometers. 1H NMR spectra
(300 or 400 MHz) were recorded in CDCl3, DMSO-d6, or
acetone-d6 and chemical shifts (d) are reported in ppm from
TMS with the residual solvent resonance as internal stan-
dard. 13C NMR spectra (75.4 or 100.6 MHz) were measured
by using CDCl3, DMSO-d6, or acetone-d6 as solvents and in-
ternal standards. GC-MS was performed on an Agilent
6890N/5973 mass spectrometer. HR-MS was carried out on
a Micromass AutoSpect spectrometer. Na2MoO4·2H2O to
According with our previous reports in this
field,[15–17] we proposed that the process probably ini-
tiates with the rapid reduction of dioxomolybden-
um(VI) with PPh3. The resulting oxomolybdenum(IV)
reacts, as it is formed, with the remaining dioxomo-
lybdenum(VI) leading to a dinuclear, m-oxo, molybde-
num(V) complex,[27] as shown in Scheme 3. Then, the
mononuclear oxomolybdenum(IV), or the dinuclear
oxomolybdenum(V), or both species, are responsible
for the deoxygenation of nitroaromatics 1 and 5 lead-
Scheme 2. Dioxomolydenum-catalyzed reductive cyclization of 2-nitrobiphenyl 1a and 2-nitrostyrenes 5a and b with poly-
mer-bound PPh3.
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Dioxomolybdenum(VI)-Catalyzed Reductive Cyclization of Nitroaromatics
COMMUNICATION
Scheme 3. Proposed mechanims for the reductive cyclization of nitroaromatics 1 and 5.
prepare the catalyst was obtained from Acros Organics, and
Acknowledgements
polymer-bound triphenylphosphine (200–400 mesh, loading:
3 mmolgÀ1) was purchased from Fluka. Other chemicals
We thank the Ministerio de Educación y Ciencia and
FEDER (CTQ2004–08077-C02–02/BQU) and Junta de Cas-
tilla y León (BU012 A06 and BU033 A06) for financial sup-
port. J. Escribano thanks Junta de Castilla y León for a pre-
doctoral fellowship. Many thanks are due to Dr. F. Rodríguez
(Universidad de Oviedo) for helpful comments.
were purchased from Acros, Fluka and Aldrich and used as
received.
MoO2Cl2(dmf)2
G
The catalyst can be prepared as previously described[29] or
more readily as we have recently described in almost quanti-
tative yield from Na2MoO4·2H2O.[16]
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A
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AHCTREUNG
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azoles 3 and indoles 6 are listed in the Supporting Informa-
tion.
Adv. Synth. Catal. 2007, 349, 713 – 718
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717

Roberto Sanz et al.
COMMUNICATION
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DCB to get a good yield of carbazole derivatives, see
ref.[13]
[8] Later, it has been described that the use of a large
[20] Dioxomolybdenum(VI) complexes are efficient cata-
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A
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[9] A nitrene precursor or nitrenoid cannot be excluded;
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[10] I. W. Davies, V. A. Guner, K. N. Houk, Org. Lett. 2004,
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[24] The formation of the intermediates o-nitrocinnamates
or o-nitrochalcones was monitored by GC-MS and usu-
ally takes place in 1–2 h.
[25] It was added in two portions: 5 mol% of catalyst at the
beginning and further addition of another 5 mol% of
catalyst after 12 h.
[26] Although we have not an explanation for the lower
yields obtained for 5-chloroindoles 6g and 6m, we spec-
ulate that it could be due to a decreased efficacy of the
reductive deoxygenation [via electrophilic attack by the
oxomolybdenum(IV)complex] of the nitro group in
these cases.
[27] The tendency of oxomolybdenum(IV) and dioxomolyb-
denum(VI) to comproportionate is well documented:
R. H. Holm, Chem. Rev. 1987, 87, 1401–1449.
[28] P. J. Bunyan, J. I. G. Cadogan, J. Chem. Soc. 1963, 42–
49.
[11] See, for instance: a) I. Puskas, E. K. Fields, J. Org.
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[12] Nevertheless, Cadogan had reported a single example
in which 2-nitrobiphenyl affords carbazole in modest
yield using molten PPh3 in a sealed tube (see ref.[5b]).
Also, indolo[2,3-a]carbazole systems have been pre-
G
pared by double nitrene insertions using PPh3 in mod-
erate yields and in collidine at reflux, see: I. Hughes,
W. P. Nolan, R. A. Raphael, J. Chem. Soc., Perkin
Trans. 1 1990, 2475–2480.
[13] A. W. Freeman, M. Urvoy, M. E. Criswell, J. Org.
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[14] For a review about molybdenum and tungsten oxo-
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