A photochemical route to benzo[a]carbazoles via domino elimination/ electrocyclization of 2-aryl-3-(1-tosylalkyl)indoles

Article abstract of DOI:10.1002/adsc.201201051

The photochemical synthesis of benzo[a]carbazoles from easily synthesizable 2-aryl-3-(1-tosylalkyl)indoles is presented. Irradiation of these substrates in polar aprotic solvents (acetone or THF) gives selectively the target products in satisfactory yields. This versatile and efficient procedure promises to be a useful alternative to the multistep strategies reported in the literature. Copyright

Full text of DOI:10.1002/adsc.201201051

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DOI: 10.1002/adsc.201201051
A Photochemical Route to Benzo[a]carbazoles via Domino
Elimination/Electrocyclization of 2-Aryl-3-(1-tosylalkyl)indoles
Stefano Protti,a,* Alessandro Palmieri,b,* Marino Petrini,b Maurizio Fagnoni,a
Roberto Ballini,b and Angelo Albinia
a
PhotoGreen Lab, Department of Chemistry, University of Pavia, V. Le Taramelli 12, 27100 Pavia, Italy
Fax : (+39)-038-298-7323; phone: (+39)-038-298-7316; e-mail: prottistefano@gmail.com
Green Chemistry Group, School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino
b
1, 62032 Camerino (MC), Italy
E-mail: alessandro.palmieri@unicam.it
Received: November 28, 2012; Published online: February 22, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201051.
Abstract: The photochemical synthesis of benzo[a]-
carbazoles from easily synthesizable 2-aryl-3-(1-tos-
ACHTUNGTRENNUNGylalkyl)indoles is presented. Irradiation of these
substrates in polar aprotic solvents (acetone or
THF) gives selectively the target products in satis-
factory yields. This versatile and efficient procedure
promises to be a useful alternative to the multistep
strategies reported in the literature.
ence of complex hydrides (e.g., lithium aluminum hy-
dride) has likewise been reported.[4] Another conceiv-
able elimination of the sulfonyl group was homolysis.
We reasoned that the indolylmethyl radical formed in
this case had no addition path available and thus was
expected to undergo either reduction or elimination.
A heteroanalogue of stilbene would be formed in
the latter case that could in turn be a useful inter-
mediate, e.g., for addition processes (given the polar-
ized structure) or for cyclization reactions to yield
benzo[a]carbazoles (D) (Scheme 1, path c). These
compounds are rare in nature,[5] but are of considera-
ble interest in view of their biological activity.[5,6] Ben-
zo[a]carbazoles have also found extensive applica-
tions as photographic[5a] and photorefractive[7] materi-
als. Despite these multifaceted applications, the large-
À
Keywords: benzo[a]carbazoles; C S bond homolyt-
ic cleavage; domino reaction; 6pe electrocycliza-
tion; photochemical activation
Functionalization of indoles at C-3 is a key synthetic scope syntheses of these heterocycles are limited in
process acting as a launching pad for the preparation number and the development of an efficient proce-
of more complex structural entities. The Friedel– dure to achieve this structural entity is desirable.[5,8]
Crafts process involving Lewis acid-catalyzed electro- Among the possible methods to achieve the homoly-
philic substitutions with electron-poor alkenes and sis of the sulfone moiety,[9] photochemistry seemed
carbonyl derivatives is certainly the most exploited a reasonable choice in view of the literature prece-
process to attain this goal.[1] In this context, a useful dent.[10]
starting point is offered by 3-(1-tosylalkyl)indoles A
(Scheme 1) that were recently demonstrated to be
easily available by an acid-promoted three-compo-
nent coupling of an indole and an aldehyde in the
presence of p-toluenesulfinic acid.[2]
These are promising compounds for building a side
chain in indole derivatives since the arylsulfonyl
group can be easily removed under basic or acid con-
ditions (path a) affording a vinylogous imine B (or its
iminium ion analogue). The thus generated electro-
philic species have been found to react efficiently
with various s- and p-bond nucleophiles Nu leading
to the corresponding addition products C (path b).[2,3]
À
The reductive cleavage of the C S bond in the pres- Scheme 1. General behaviour of 3-(1-tosylalkyl)indoles.
Adv. Synth. Catal. 2013, 355, 643 – 646
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643

Stefano Protti et al.
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Table 1. Irradiation of 2-phenyl-3-(1-tosylpropyl)indole (1)
With this target in mind we embarked on an explor-
atory study of the photochemistry of a model com-
pound, 2-phenyl-3-(1-tosylpropyl)indole (1). This
compound shows two maxima at 226 and 298 nm, re-
in neat solvents.[a]
spectively, (for the latter with an
e of 1.2ꢁ
104 LmolÀ1 cmÀ1) and was conveniently irradiated by
phosphor-coated lamps (emission centered at
366 nm). HPLC monitoring of the changes occurring
upon irradiation of a nitrogen-flushed 10À2 M solution
in acetonitrile showed the formation of a single main
peak and when the reaction was completed a single
product was isolated. To our surprise, spectroscopic
characterization demonstrated that this was benzo[a]-
carbazole 10. Apparently, loss of the sulfone moiety
led directly to cyclization. In order to distinguish the
sequence of events, UV monitoring was added.
Entry
Solvent
10[b] Yield [%]
1
2
3
4
5
6
7
MeCN
MeOH
i-PrOH
t-BuOH
MeCN/H2O 5/1
THF
35
22
40
0
8[c]
54
acetone
49 (0)[d]
The course of the photolysis of a 4ꢁ10À5 M solution
of 1 (Optical Bench, lirr > 280 nm) showed the gradu-
al decrease of the absorption maxima at 226 and
298 nm concomitant with the rise of new absorption
bands located at 254, 283, 308 and a shoulder at
360 nm (see Figure 1 for details). The end spectrum
was practically coincident with that of 10, whereas the
non-univocal profile at different wavelengths (see
Inset) demonstrated that further intermediates were
involved. The reaction was examined in various sol-
[a]
Conditions:
A
nitrogen-equilibrated solution of
1 (10À2 M) in the chosen solvent, irradiated at 366 nm (10
lamps) for 18 h.
[b]
[c]
[d]
A complete conversion of 1 was observed, except where
indicated.
40% conversion of 1, yield based on the consumption of
the indole.
Oxygen-saturated solution.
vents (Table 1). Product 10 was formed in methanol photolyzed solution in acetone showed that, along
and isopropyl alcohol with a yield similar to that in with the formation of 10, p-toluenesulfinic acid was
MeCN, but was not observed in t-BuOH. Addition of generated in a comparable yield (60%).
water to acetonitrile strongly depressed the yield. The
Nitrogen flushing was required, since indole 1 react-
best results were obtained in acetone and THF, where ed only sluggishly and no carbazole was formed in an
it reached and slightly exceeded 50% (entries 6 and oxygen-saturated solution. The above data give some
7). Furthermore, ionic chromatography analysis of the indication about the conditions under which a ben-
zo[a]carbazole may be obtained and, on this basis, the
exploration was extended to further substituted
indole derivatives (2–9). As reported in Table 2, irra-
diation of 2 afforded the corresponding benzo[a]car-
bazole (11) in both acetone and THF (55 and 65%
yields, respectively) after 16 h of irradiation. Similar
satisfactory results have been obtained in the case of
3 where the formation of 5-hexylbenzo[a]carbazole
(12, 57% yield) was accompanied by a small amount
of the desulfonylated indole 3H (2% in acetone).
As for indole 4, the corresponding 5-benzyl deriva-
tive 13 was isolated in acetone (56%) and, although
with lower efficiency, in THF. Furthermore, a longer
irradiation time (30 h) was required to achieve a com-
plete consumption of 4. Benzo[a]carbazoles have like-
wise been obtained starting from substrates that con-
tain a substituent at the 4-position of the phenyl ring.
Thus, 3,5-dialkyl derivatives 14 and 15 have been iso-
lated in good yields after 24 h irradiation of the pre-
cursors 5 and 6. Likewise, the 4-methoxyphenyl-sub-
Figure 1. UV-monitoring of a 4ꢁ10À5 M solution of 1 in
MeCN (lirr >280 nm) from 0 (black dotted line) to 400 s
(black continuous line). Inset: absorbance profiles recorded
at 226, 254, 320 and 360 nm.
stituted indole (7) was found to generate, under irra-
diation, the corresponding 3-methoxybenzo[a]carba-
zole (16) both in acetone and THF with satisfactory
yields (62 and 55% yields, respectively) and the tri-
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A Photochemical Route to Benzo[a]carbazoles via Domino Elimination/Electrocyclization
Table 2. Synthesis of benzo[a]carbazole 10–18.[a]
Indole R1
R2
G
tirr
[h]
Product,[b,c] (Yield
[%])
1
2
3
CH3
C4H9
C6H13
H
H
H
H
H
H
16
16
16
10, 49 (54)
11, 55 (65)
12, 57 (53)
3H, 2 (<1)
13, 56 (37)
14, 46 (45)
15, 54 (69)
16, 62 (55)
17, 61 (75)
18, 54 (35)
9H, 4 (<1)
Scheme 2. Photochemistry of 2-phenyl-3-(1-tosylalkyl)in-
doles (1–9) in polar solvents.
4
5
6
7
8
9
CH2C6H5
C2H5
C6H13
C2H5
C3H10
C7H15
H
H
H
H
H
CH3
H
CH3
CH3
OCH3 24
CF3
H
30
24
24
30
30
E/Z isomer, path b). This is not isolated and under-
goes 6pe electrocyclization, apparently a process too
fast for allowing accumulation of sufficient materia
for isolation. This probably corresponds to the inter-
mediate indicated by UV monitoring (see inset in
Figure 1). Sparse evidence for cyclization of com-
pounds containing the 3-styrylindole moiety under
both photochemical[11] and thermal conditions[12] has
been reported in the literature. In particular, the pho-
tochemical rearrangement of 3H-indole-spirocyclo-
[a]
Conditions: 1–9 (10À2 M) in acetone or THF, lirr =366 nm
(10 lamps), 18 h.
Irradiation carried out in acetone (isolated yield).
In parentheses the reaction carried out in THF; yield de-
termined by HPLC analysis.
[b]
[c]
fluoromethylphenyl derivative 8 gave a somewhat propanes followed by photocyclization of the ob-
better yield (75% in THF, Table 2). Finally, we found tained 2-phenyl-3-styrylindole has been found to
that the alkylation of the indole nitrogen did not afford, among other products, a mixture of the corre-
affect the reaction, and 11-methylbenzo[a]carbazole sponding benzo[a]carbazole (about 30% yield) and
18 was obtained in a satisfactory yield (54% in ace- 6,11-dihydrobenzo[a]carbazole.[11a] In the present case,
tone), again accompanied by some desulfonylated 9H. the reaction appears to involve an efficient photo-
As for the mechanism, the above indoles are char- chemical reaction that gives dihydrocarbazole III
acterized by a broad fluorescence with a discrete
ACHTUNGTREN(NGNU path d). Chemoselective aromatization of systems
Stokes shift (lem at 360 and 460 nm, respectively, for like III (presumably preceded by a [1,5]-hydride
compound 1) that is little affected in air- vs. nitrogen- shift)[11a] has been reported in the literature both in
equilibrated solution. Oxygen-quenching of the pho- the presence[11c] and in the absence of oxygen[11b]and
tochemical reaction thus suggests that this proceeds is supposed to occur in the formation of the final ben-
from the triplet state. The positive identification of p- zocarbazoles 10–18 (path e).
toluenesulfinic acid along with the literature prece-
In conclusion, we have found a general synthesis of
dent for some benzyl sulfones,[10b] supports that homo- benzo[a]carbazoles that proceeds as a one-pot process
À
À
lytic cleavage of the C S bond with the generation of involving both photochemical (initial C S bond ho-
a benzyl/sulfonyl radical pair occurs (Scheme 2, path molysis, and 6pe electrocyclization) as well as thermal
a) and is followed by b-hydrogen abstraction from I steps. Along with the above-mentioned facile access
by the sulfonyl radical. The reduction of I (path c) to to sulfonylmethyl derivatives of 2-arylindoles, the
give desulfonylated 3H and 9H observed as minor present method represents an annelation procedure
products in two cases is likewise well explained by the with large scope (in particular electron-donating or
homolytic cleavage and the role of radical intermedi- withdrawing substituents do not affect the reaction)
ates. The main product is however alkenylindole (II, that gives novel access to this family of heterocycles.
Adv. Synth. Catal. 2013, 355, 643 – 646
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Experimental Section
Typical Procedure for the Synthesis of 10–18
A nitrogen-equilibrated solution of the chosen compound
(1–9, 0.4 mmol, 10À2 M) in acetone or THF (40 mL) was irra-
diated in a multilamp reactor equipped with 10 phosphor
coated lamps (emission centered at 366 nm) until the com-
plete consumption of the substrates. Work-up of the reaction
and purification of the obtained products involved concen-
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chloroform mixture as eluant.
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Acknowledgements
The authors thank the Universities of Pavia and Camerino
and MIUR-Italy (FIRB National Project “Metodologie di
nuova generazione nella formazione di legami carbonio-car-
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