Bronsted acid-catalyzed straightforward synthesis of benzo[b]carbazoles from 2,3-unsubstituted indoles

Article abstract of DOI:10.1002/adsc.201300868

Described is a general and efficient synthesis of valuable benzo[b]carbazoles by Bronsted acid-catalyzed reactions between simple C-2,C-3- unsubstituted indoles and ortho-[a-(hydroxy)benzyl] benzaldehyde acetals. Highly selective migration processes are i

Full text of DOI:10.1002/adsc.201300868

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DOI: 10.1002/adsc.201300868
Brønsted Acid-Catalyzed Straightforward Synthesis of
Benzo[b]carbazoles from 2,3-Unsubstituted Indoles
Anisley Suꢀrez,a Patricia Garcꢁa-Garcꢁa,a Manuel A. Fernꢀndez-Rodrꢁguez,a
and Roberto Sanza,*
a
ꢂrea de Quꢁmica Orgꢀnica, Departamento de Quꢁmica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael
BaÇuelos s/n, 09001 Burgos, Spain
Fax : (+34)-947-258-831; e-mail: rsd@ubu.es
Received: September 26, 2013; Revised: November 12, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300868.
Abstract: Described is a general and efficient syn-
thesis of valuable benzo[b]carbazoles by Brønsted
acid-catalyzed reactions between simple C-2,C-3-
unsubstituted indoles and ortho-[a-(hydroxy)ben-
zyl]benzaldehyde acetals. Highly selective migration
processes are involved as key steps in the overall
cascade sequence that involves the one-pot forma-
tion of two new bonds and a cycle in a regioselective
fashion.
On the other hand, the reaction of indoles with car-
bonyl derivatives, including acetals,[10] in the presence
of Lewis or protic acids is the most general method
for the synthesis of symmetrical 3,3’-bisindolylme-
thanes (3,3’-BIMs) (II). Their formation is proposed
to proceed through the intermediacy of an azafulveni-
um species such as I (with Nu=H) that undergoes
further addition of
a
second indole molecule
(Scheme 1).[11] When intermediates I are functional-
ized with an additional nucleophilic group such as an
electron-rich aromatic (Nu=Ar), a second Friedel–
Crafts alkylation process can take place affording
products like III (Scheme 1).[12] Alternatively, it is
well known that neutral alkylideneindolenine inter-
mediates related with I (Nu=H), commonly formed
from precursors having a suitable leaving group at the
benzylic position of 3-substituted indoles, are able to
Keywords: 1,2-alkyl shift; benzo[b]carbazoles;
Brønsted acid catalysis; heterocycles; synthetic
methods
Aryl- and heteroaryl-condensed carbazoles have at- add external nucleophiles in a conjugate fashion.[13]
tracted considerable interest because of their broad
Herein we wish to report our results on the Brønst-
spectrum of useful biological activities.[1] Among the ed acid-catalyzed reaction between indoles and aro-
benzocarbazole frameworks, annulated[b]carbazoles, matic aldehyde acetals possessing an a-(hydroxy)ben-
such as ellipticine and its derivatives,[2] are relevant zyl group at the ortho-position, which enables a facile
due to their interesting pharmacological activities[3] as entry into the synthesis of regioselectively functional-
well as their utility in the field of material chemistry.[4] ized benzo[b]carbazoles through an unprecedented
Different approaches for accessing this type of cascade sequence.
hetero
G
In the last years, we have been interested in the de-
though most of them imply multi-step sequences and velopment of new methodologies for the direct C-3
restricted substitution patterns. In this regard, ben- alkylation of indoles with alcohols.[14] As part of this
zo[b]carbazoles are commonly constructed from research, we studied the reaction between N-methyl-
either properly functionalized indoles or carbazoles,[5] indole
1a
and
[2-(diethoxymethyl)phenyl]-
substituted naphthalenes,[6] or more particularly from
ACHTUNGTRENNUNG
ketenimines and imidoyl selanides by radical cycliza- (Scheme 2). The use of selected s-Lewis acids, previ-
tions,[7] or from ynamides by dehydro Diels–Alder re- ously employed for the reaction of indoles with car-
actions.[8] However, to the best of our knowledge, bonyl derivatives, afforded isobenzofuran derivative
there are no general methodologies developed for the 3aa, obtained as a mixture of diastereoisomers, as the
direct synthesis of (hetero)aryl[b]carbazoles starting only product without formation of the corresponding
from
simple
C-2,C-3-unsubstituted
indoles 3,3’-BIM. Surprisingly, the same reaction under
Brønsted acid catalysis (20 mol% of PTSA) selective-
ly afforded a new product, the benzo[b]carbazole de-
(Figure 1).[9]
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Brønsted Acid-Catalyzed Straightforward Synthesis
Figure 1. Synthetic routes to benzo[b]carbazoles.
Scheme 1. Reported reactions of indoles and benzaldehyde derivatives: synthesis of 3,3’-BIMs (II) and C-3-carbocyclic-func-
tionalized indoles (III).
rivative 4aa, which was isolated in 78% yield.[16] Re- corresponding reactions with sp3-type acceptors like
markably, its formation formally involves two consec- halides or alcohols through the Ciamician–Plancher
utive and selective Friedel–Crafts-type reactions of rearrangement have been scarcely reported.[19]
a C-2,C-3-unsubstituted indole with a bis(electrophile)
Having found mild conditions to efficiently and di-
bearing an alcohol as sp3-type acceptor and an acetal rectly access 4aa from readily available N-methylin-
as carbonyl-type acceptor. Interestingly, whereas the dole we decided to check if this methodology could
preparation of annulated indolic frameworks by the be general for the synthesis of a variety of benzo[b]-
formal C-2-hydroarylation of indoles with sp2- or sp- carbazoles. First, N-methylindole 1a was treated with
type acceptors, such as Michael substrates[17] or gold- selected benzylic alcohols 2a–i, prepared from 2-lith-
activated alkynes,[18] has been well established, the iobenzaldehyde diethyl acetal and selected (hetero)ar-
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Anisley Suꢀrez et al.
Scheme 2. Acid-catalyzed reaction of N-methylindole 1a with diethyl acetal 2a. Selective formation of 3aa and 4aa.
Table 1. Synthesis of benzo[b]carbazoles 4.
Entry
1
R1
R2
2
Ar
t [h]
Product
Yield [%][a]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
NO2
Cl
CO2Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
2a
2d
2e
2f
2i
Ph
4-ClC6H4
4-BrC6H4
2-naphthyl
4-MeOC6H4
2,3,4-(MeO)3C6H2
2-thienyl
3-methyl-2-thienyl
5-methyl-2-furyl
Ph
16
24
16
3.5
16
0.5
2
1.5
2
5
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4ba
4bd
4be
4bf
4bi
4ce
4df
4ef
4ff
78
89
65
2[b]
3[b]
4[b]
5
58
85[c]
90
6
7
8
9
73
71
51[d]
65
10[b]
11[b]
12
13
14
15
16
17
18
2-naphthyl
4
50
92
4-MeOC6H4
2,3,4-(MeO)3C6H2
5-methyl-2-furyl
4-MeOC6H4
2,3,4-(MeO)3C6H2
2,3,4-(MeO)3C6H2
2,3,4-(MeO)3C6H2
16
0.5
3.5
4
1
1
98
68[d]
48
2e
2f
2f
2f
85
94
80
1
[a]
Yield of isolated products 4 based on the starting indole 1.
Carried out with 50 mol% of PTSA.
Same yield was obtained in a related reaction starting from alcohol 2’e bearing an ethylene acetal moiety instead of a di-
ethyl acetal one.
7–10% of the corresponding 6-arylbenzo[b]carbazole 5 was also isolated and characterized.
[b]
[c]
[d]
yl carboxaldehydes. As shown in Table 1, both EDG were obtained typically in high yields. Reactions with
and EWG substituents on the Ar group, as well as highly activated benzylic alcohols bearing EDG
heteroaromatics, were adequately tolerated in the groups proceed faster and with a lower amount of the
process and 11-aryl-5H-benzo[b]carbazoles 4aa–ai[20] Brønsted acid catalyst (entries 5–9 vs. 1–4). Interest-
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Brønsted Acid-Catalyzed Straightforward Synthesis
Table 2. Brønsted acid-catalyzed reaction of N-methylindole 1a with functionalized acetals 2j–n. Competitive formation of
benzo[b]carbazoles 4 vs. 4’ and 5.
Entry
2
Ar
Product(s)[a]
Yield [%][b]
1
2
3
4
5
2j
2k
2l
2m
2n
Ph
4-ClC6H4
4-MeOC6H4
2,3,4-(MeO)3C6H2
2-thienyl
4aj
4ak
4al
60[c]
68[c]
73[d]
82[e]
75[f]
4am+4’am (1/1.7)
4an+4’an (2/1)
When two regioisomers were generated, the ratio (in brackets) was determined by 1H NMR analysis of the crude reaction
mixture.
Yield of isolated product 4 based on the starting N-methylindole 1a.
Ca. 5% of the corresponding 6-arylbenzo[b]carbazole 5 was also isolated and characterized.
Trace amounts of 4’al and 5al were also formed.
[a]
[b]
[c]
[d]
[e]
[f]
Yield for the mixture of regioisomers. The major one was isolated and characterized.
56% of 4an and 19% of 4’an were isolated and characterized.
ingly, no influence in the process or yield was ob- ing neutral, moderately electron-rich, or electron-
served by varying the acetal moiety as we determined poor aryl substituents (entries 1–3), the corresponding
in the synthesis of benzo[b]carbazole 4ae from 2e and benzo[b]carbazoles 4 were almost exclusively ob-
2’e (entry 5). In addition, NH-indole 1b also reacted tained. However, in the case of highly activated hy-
with selected hydroxyacetals 2 to furnish benzocarba- droxyacetals 2m and 2n, with a 2-thienyl or a trime-
zole derivatives 4ba–bi in good yields (entries 10–14). thoxyphenyl group as Ar substituent, variable
Moreover, even the less nucleophilic 5-functionalized amounts of regioisomeric benzo[b]carbazoles 4’, dif-
indoles 1c–f are able to participate in this reaction al- fering on the final position of the methoxy group ini-
lowing the regioselective preparation of benzo[b]car- tially located at a defined position in the starting hy-
bazoles 4ce and 4df–ff in moderate to high yields (en- droxyacetal 2, were obtained (entries 4 and 5).
tries 15–18). However, the presence of an aromatic
With all these results in hand, a catalytic cycle that
group (Ar) as substituent in the starting alcohol 2 could account for the formation of benzo[b]carba-
seems to be mandatory for the success of the reaction zoles 4, 4’, and 5 is shown in Scheme 3. Initially, an
as substrates bearing alkyl (n-Bu), cyclopropyl, (E)-b- equilibrium between hydroxyacetal 2 and cyclized
ꢀ
styrenyl (CH=CHPh), or phenylethynyl (C CPh) acetal 6 is established in the acidic medium. Its reac-
only gave rise to decomposition products under the tion with the corresponding indole 1 would afford iso-
standard reaction conditions.
benzofuran derivatives 3, as it was observed when
Remarkably, all these reactions selectively occurred using several s-Lewis acids or lower amounts of
to form 11-aryl-5H-benzo[b]carbazoles 4 while the PTSA (see Table in the Supporting Information).[21]
corresponding regioisomeric 6-aryl-substituted ben- Probably favoured by the presence of the Brønsted
zo[b]carbazoles 5 were only observed in trace to acid, these isobenzofurans 3 are in equilibrium with
minor amounts in some cases (entries 9 and 14). In- the corresponding 3,3’-BIMs 8 through the iminium
trigued by these particular results, we decided to fur- intermediate 7 (path a).[22] This hypothesis was sup-
ther explore this process by using hydroxyacetals 2j–n ported by previous reports[12] and by isolation of bisin-
functionalized with a methoxy group at the aryl ring dole 8ab (Ar=4-ClC6H4; G=H), along with 3ab,
that contains the acetal group and with different aryl when carrying out the reaction with 5 mol% of PTSA
groups at the benzylic position. Their reactions with for 30 min. Reactions under the conditions reported
N-methylindole 1a under the standard conditions, in Table 1 (entry 2) of both isolated dihydroisobenzo-
PTSA (20 mol%) in MeCN at room temperature, furan 3ab and bisindole 8ab furnished benzo[b]carba-
mainly gave rise to the expected 11-aryl-5H-benzo[b]- zole 4ab. Having proved the intermediacy of 3, as
carbazoles 4 that could be isolated in synthetically well as its equilibrium with 8 in the reaction media,
useful yields (Table 2). With hydroxyacetals 2j–l bear- the formation of benzo[b]carbazole 4 would be ex-
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Anisley Suꢀrez et al.
Scheme 3. Proposed mechanism for the formation of benzo[b]carbazoles 4, 4’, and 5.
plained by an alternative path b which would imply er, both pathways do not account for the generation
a nucleophilic addition of C-3 of the indole that of benzo[b]carbazoles 4’, in which the relative posi-
would generate spiro species 9. This key intermediate tion of the G substituent and the Ar group have
could undergo two different 1,2-alkyl shifts (Ciami- changed with respect to the starting alcohol 2. So, we
cian–Plancher rearrangement) to recover aromaticity propose that the iminium intermediate 12 could also
after loss of a proton.[23] Migration of the hydroxyalk- evolve through an alternative pathway involving
yl group (path i) would lead to alcohol 10 that upon a [1,4]-aryl migration. Subsequent loss of a proton
loss of water would afford benzo[b]carbazole 4. On would explain the formation of benzo[b]carbazoles 4’.
the other hand, a competitive migration of the benzyl- This competitive process seems to be partially opera-
ic group (path ii) would lead to regioisomeric alcohol tive exclusively when the hydroxymethyl group is lo-
11 that would provide the corresponding benzo[b]car- cated at C-3 (intermediate 11 vs. 10), probably due to
bazole 5 after protonation and loss of water, probably the high stabilization of iminium intermediate 12. On
through the iminium intermediate 12, and subsequent the basis of this proposal the two 1,2-alkyl shifts
aromatization by further removal of a proton. Howev- (pathways i and ii) could not be distinguished for non-
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Brønsted Acid-Catalyzed Straightforward Synthesis
Scheme 4. Reactions of 1a with tertiary alcohols 13a–c. Synthesis of 6,11-disubstituted-5H-benzo[b]carbazoles 14.
functionalized hydroxyacetals 2 (G=H) as both of a proton (Scheme 4). Interestingly, the observed [1,4]-
them collapse to the same product (4’=4 for G=H). aryl or alkynyl shift has no precedent and opens the
From the results of Table 2 it seems that pathway i is door to future developments in this field. Specially
the preferred one whereas the benzyl migration (path- significant is the result of the migration of an alkynyl
way ii) resulted to be competitive only for highly acti- group in the formation of 14ac as the low migratory
vated substrates [G=OMe and Ar=2-thienyl or aptitude of these groups in carbocation rearrange-
2,3,4-(MeO)3C6H2] with an increased carbocation sta- ments is known.[25]
bilization ability at the benzylic position. Also, the
subsequent [1,4]-aryl migration on intermediate spe- also useful for the synthesis of heteroaryl-fused carba-
cies 12 is favoured for electron-rich aromatics as Ar zoles. So, 10-aryl-5H-thieno[3,2-b]carbazoles 18 were
substituents. In the other cases, only trace amounts of selectively prepared under the standard Brønsted acid
regioisomers 5 are formed. catalysis from thiophene-based hydroxyacetals 17a
Moreover, the reported methodology resulted to be
AHCTUNGTRENNUNG
Based in our proposed mechanism we envisioned and 17b (Scheme 5). Interestingly, starting from re-
that acetal derivatives 13 bearing a tertiary benzylic gioisomeric hydroxyacetal 19, the corresponding
hydroxy group could be potential precursors of 6,11- thieno
disubstituted benzo[b]carbazoles thus expanding the formed (Scheme 5). In addition, benzo
scope of the reported benzocarbazole synthesis. Grati- b]carbazole 22 as well as benzofuro[2,3-b]carbazole
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
fyingly, treatment of indole 1a with hydroxyacetals 24 could also be prepared with this methodology from
13a–c under the standard Brønsted acid catalysis se- a properly functionalized benzo[b]thiophene 21 and
lectively afforded the aimed 6,11-disubstitued ben- benzo[b]furan 23, respectively (Scheme 5). The for-
zo[b]carbazole derivatives 14 (that correspond with 4’ mation of all of these carbazole derivatives could be
in the general mechanism depicted in Scheme 3) in understood in the same way as benzo[b]carbazoles 4,
good yields (Scheme 4).[24] It is interesting to note thus involving initial hydroxyalkyl shift (pathway i in
that for these acetals 13 the scope of the substitution Scheme 3) followed by loss of water. Furthermore,
at the benzylic carbon bearing the hydroxy group is the synthesis of these adducts was completely selec-
not limited to aromatic substituents, like in secondary tive with the exception of carbazole derivative 24 the
alcohols 2, as shown for 13ac having an alkynyl group formation of which was accompanied with the regioi-
that affords the corresponding benzo[b]carbazole someric benzofuroACTHNUGTRNEUNG[2,3-b]carbazole 25 in a ca. 1.6:1
14ac. As we anticipated, by increasing the migratory ratio (Scheme 5).[26] On the contrary, hydroxyacetals
aptitude of the benzylic carbon in intermediate 15 bearing N-heterocycles such as pyridines or indoles
(tertiary in 15 vs. secondary in 9) an initial selective led to no reaction or decomposition under the estab-
migration of the tert-alkyl group (pathway ii in lished conditions (Figure 2).[27]
Scheme 3) occurred to form iminium species 16.
In conclusion, we have described a straightforward
These intermediates, in contrast with related ones 12 and regioselective synthesis of aryl-functionalized
in Scheme 3, could only evolve by a formal [1,4]-mi- (hetero)aryl-annulated[b]carbazoles from easily avail-
gration to recover the aromaticity after loss of able starting materials such as indoles and ortho-[a-
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Anisley Suꢀrez et al.
Scheme 5. Synthesis of heteroaryl[b]carbazoles 18, 20, 22, 24 and 25.
Experimental Section
General Remarks
All reactions involving air-sensitive compounds were carried
out under an N2 atmosphere (99.99%). All glassware was
oven-dried (1208C), evacuated and purged with nitrogen.
All common reagents and solvents were obtained from com-
mercial suppliers (VWR, Alfa and Aldrich) and used with-
out any further purification. Solvents were dried by standard
methods. Hexane and ethyl acetate were purchased as extra
pure grade reagents and used as received. For the prepara-
tion of starting alcohols see the Supporting Information.
TLC was performed on aluminum-backed plates coated
with silica gel 60 with F254 indicator; the chromatograms
were visualized under ultraviolet light and/or by staining
with a Ce/Mo reagent and subsequent heating. Rf values are
reported on silica gel. Flash column chromatography was
carried out on silica gel 60, 230–240 mesh. NMR spectra
were measured on Varian Mercury-Plus 300 MHz and
Varian Inova-400 MHz spectrometers. High resolution-mass
spectra (HR-MS) were recorded on a Micromass Autospec
spectrometer using EI at 70 eV. Melting points were mea-
sured on a Gallenkamp apparatus using open capillary tubes
and are uncorrected. GC-MS and low resolution mass spec-
tra (LR-MS) measurements were recorded on an Agilent
Figure 2. Not successful N-heterocycles-functionalized hy-
droxyacetals.
(hydroxy)benzyl]benzaldehyde acetals under simple
Brønsted acid catalysis through a new cascade se-
quence. This efficient and metal-free methodology
complements the current synthetic scenario for the
preparation of benzo[b]carbazoles by adding a new
strategy that allows the direct use of C-2,C-3-unsubsti-
tuted indoles. Further studies to prove the proposed
mechanism of this new transformation and to extend
its synthetic scope are currently in progress in our lab-
oratory.
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6890N/5973 Network GC System, equipped with an HP-
5 MS column.
5744–5747; c) J.-Y. Balandier, N. Henry, J.-B. Arlin, L.
Sanguinet, V. Lemaur, C. Niebel, B. Chattopadhyay,
A. R. Kennedy, P. Leriche, P. Blanchard, J. Cornil,
Y. H. Geerts, Org. Lett. 2013, 15, 302–305.
General Procedure for the PTSA-Catalyzed Synthesis
[5] a) G. W. Gribble, D. J. Keavy, D. A. Davis, M. G. Saul-
nier, B. Pelcman, T. C. Barden, M. P. Sibi, E. R. Olson,
J. J. Belbruno, J. Org. Chem. 1992, 57, 5878–5891;
b) H. L. Fraser, G. W. Gribble, Can. J. Chem. 2001, 79,
1515–1521; c) N. Haider, J. Kꢅferbçck, Tetrahedron
2004, 60, 6495–6507; d) P. Balczewski, A. Bodzioch, E.
of Benzo[b]carbazoles 4, 4’, and 5
To a mixture of the corresponding acetal derivative 2
(1 mmol) and the corresponding indole 1 (1 mmol) in
MeCN (1 mL) was added PTSA (20 mol%, 38 mg). The re-
action mixture was stirred at room temperature until com-
plete disappearance of the acetal derivative was observed by
TLC (0.5–24 h), then it was quenched with a 0.5M aqueous
solution of NaOH, and extracted with EtOAc (3ꢄ15 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and solvent was removed under reduced pressure.
The remaining residue was purified by flash chromatography
on silica gel using mixtures of hexane/EtOAc as eluents.
The corresponding benzo[b]carbazoles 4, 4ꢀ, and 5 were iso-
lated in the yields reported in the text. Characterization
data and NMR spectra are presented in the Supporting In-
formation.
´
Rꢆzycka-Sokolowska, B. Marciniak, P. Uznanski,
Chem. Eur. J. 2010, 16, 2392–2400; e) R. Sureshbabu,
V. Saravanan, V. Dhalayan, A. K. Mohanakrishnan,
Eur. J. Org. Chem. 2011, 922–935; f) V. Dhalayan, R.
Sureshbabu, A. K. Mohanakrishnan, Indian J. Chem.
B: 2011, 50B, 843–857; g) K. S. Prakash, R. Nagarajan,
Adv. Synth. Catal. 2012, 354, 1566–1578.
[6] a) M. E. Budꢇn, V. A. Vaillard, S. E. Martin, R. A.
Rossi, J. Org. Chem. 2009, 74, 4490–4498; b) P. Appuk-
kuttan, E. van der Eycken, W. Dehaen, Synlett 2005,
127–133.
[7] a) M. Schmittel, J.-P. Steffen, M. A. W. ꢂngel, B.
Engels, C. Lennartz, M. Hanrath, Angew. Chem. 1998,
110, 1633–1635; Angew. Chem. Int. Ed. 1998, 37, 1562–
1564; b) C. Shi, K. K. Wang, J. Org. Chem. 1998, 63,
3517–3520; c) Y. Xing, B. Hu, Q. Yao, P. Lu, Y. Wang,
Chem. Eur. J. 2013, 19, 12788–12793. See also ref.[2d]
[8] M. F. Martꢁnez-Esperꢆn, D. Rodrꢁguez, L. Castedo, C.
Saꢀ, Tetrahedron 2008, 64, 3674–3686.
[9] Few particular examples have been reported: a) R.-Y.
Tang, J.-H. Li, Chem. Eur. J. 2010, 16, 4733–4738; b) Y.
Nagase, T. Miyamura, K. Inoue, T. Tsuchimoto, Chem.
Lett. 2013, 42, 1170–1172.
[10] T. M. Kubczyk, S. M. Williams, J. R. Kean, T. E. Davies,
S. H. Taylor, A. E. Graham, Green Chem. 2011, 13,
2320–2325.
[11] For a recent review, see: M. Shiri, M. A. Zolfigol, H. G.
Kruger, Z. Tanbakouchian, Chem. Rev. 2010, 110,
2250–2293. Aryl(3-indolyl)carbenium ions I have been
recently isolated as stable ortho-benzenedisulfonamide
salts and fully characterized. See: M. Barbero, S. Cada-
muro, F. Cauda, S. Dughera, G. Gervasio, P. Venturello,
J. Org. Chem. 2012, 77, 4278–4287.
[12] a) F.-L. Sun, M. Zeng, Q. Gu, S.-L. You, Chem. Eur. J.
2009, 15, 8709–8712; b) H. Li, J. Yang, Y. Liu, Y. Li, J.
Org. Chem. 2009, 74, 6797–6801.
[13] For a review, see: A. Palmieri, M. Petrini, R. R.
Shaikh, Org. Biomol. Chem. 2010, 8, 1259–1270.
[14] a) R. Sanz, D. Miguel, J. ꢂlvarez-Gutiꢇrrez, F. Rodrꢁ-
guez, Synlett 2008, 975–978; b) R. Sanz, D. Miguel, A.
Martꢁnez, M. Gohain, P. Garcꢁa-Garcꢁa, M. A. Fernꢀn-
dez-Rodrꢁguez, E. ꢂlvarez, F. Rodrꢁguez, Eur. J. Org.
Chem. 2010, 7027–7039.
[15] Prepared from commercially available 2-bromobenzal-
dehyde diethyl acetal by Br–Li exchange and further
reaction with benzaldehyde. See the Supporting Infor-
mation.
[16] For detailed optimization studies, see the Supporting
Information.
Acknowledgements
We gratefully acknowledge the Ministerio de Economꢀa y
Competitividad (MINECO) and FEDER (CTQ2010-15358)
for financial suꢁport. P.G.-G. and M. A.F.-R. thank
MINECO for “Juan de la Cierva” and “Ramꢂn y Cajal”
contracts.
References
[1] For selected reviews, see: a) G. H. Kirsch, Curr. Org.
Chem. 2001, 5, 507–518; b) H.-J. Knçlker, D. R. Reddy,
Chem. Rev. 2002, 102, 4303–4427; c) T. Janosik, N.
Wahlstrçm, J. Bergman, Tetrahedron 2008, 64, 9159–
9180; d) A. W. Schmidt, K. R. Reddy, H.-J. Knçlker,
Chem. Rev. 2012, 112, 3193–3328.
[2] Isolation: a) S. Goodwin, A. F. Smith, E. C. Horning, J.
Am. Chem. Soc. 1959, 81, 1903–1908; anticancer activi-
ty: b) P.-L. Kuo, Y.-L. Hsu, C.-H. Chang, C.-C. Lin,
Cancer Lett. 2005, 223, 293–301; synthesis: c) G. W.
Gribble, M. G. Saulnier, J. A. Obaza-Nutaitis, D. M.
Ketcha, J. Org. Chem. 1992, 57, 5891–5899; d) J. M.
Pedersen, W. R. Bowman, M. R. J. Elsegood, A. J.
Fletcher, P. J. Lovell, J. Org. Chem. 2005, 70, 10615–
10618, and references cited therein.
[3] For selected reports, see: a) G. W. Gribble, M. G. Saul-
nier, J. Chem. Soc. Chem. Commun. 1984, 168–169;
b) C. Asche, W. Frank, A. Albert, U. Kucklaender,
Bioorg. Med. Chem. 2005, 13, 819–837; c) K. Kinoshita,
T. Kobayashi, K. Asoh, N. Furuichi, T. Ito, H. Kawada,
S. Hara, J. Ohwada, K. Hattori, T. Miyagi, W.-S. Hong,
M.-J. Park, K. Takanashi, T. Tsukaguchi, H. Sakamoto,
T. Tsukuda, N. Oikawa, J. Med. Chem. 2011, 54, 6286–
6294.
[4] See, for example: a) N.-X. Hu, S. Xie, Z. Popovic, B.
Ong, A.-M. Hor, J. Am. Chem. Soc. 1999, 121, 5097–
5098; b) M. T. Levick, S. C. Coote, I. Grace, C. Lam-
bert, M. L. Turner, D. J. Procter, Org. Lett. 2012, 14,
[17] See, for example: A. C. Silvanus, S. J. Heffernan, D. J.
Liptrot, G. Kociok-Kçhn, B. I. Andrews, D. R. Carbery,
Org. Lett. 2009, 11, 1175–1178.
Adv. Synth. Catal. 2014, 356, 374 – 382
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
381

COMMUNICATIONS
Anisley Suꢀrez et al.
[18] For pioneering work, see: C. Ferrer, A. M. Echavarren,
Angew. Chem. 2006, 118, 1123–1127; Angew. Chem. Int.
Ed. 2006, 45, 1105–1109. See, also: Y. Lu, X. Du, X.
Jia, Y. Liu, Adv. Synth. Catal. 2009, 351, 1517–1522.
[19] For a recent report, see: C. C. J. Loh, G. Raabe, D.
Enders, Chem. Eur. J. 2012, 18, 13250–13254, and refer-
ences cited therein.
b) A. S. K. Hashmi, W. Yang, F. Rominger, Adv. Synth.
Catal. 2012, 354, 1273–1279; c) C.-X. Zhuo, Q.-F. Wu,
Q. Zhao, Q.-L. Xu, S.-L. You, J. Am. Chem. Soc. 2013,
135, 8169–8172. For stereospecific migrations promoted
by PTSA on spiroindolenines, see: d) Q.-F. Wu, C.
Zheng, S.-L. You, Angew. Chem. 2012, 124, 1712–1715;
Angew. Chem. Int. Ed. 2012, 51, 1680–1683; e) C.
Zheng, Q.-F. Wu, S.-L. You, J. Org. Chem. 2013, 78,
4357–4365.
[20] The structure of all the new compounds 4, 4’, 5, 14, 18,
20, 22, 24 and 25 were determined by NMR techniques
1
including COSY, NOESY and H-13C 2D experiments.
[24] The structure of 14aa was further confirmed by X-ray
analysis. CCDC 959146 contains the supplementary
crystallographic data for this compound. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[25] G. E. Salnikov, A. M. Genaev, V. A. Bushmelev, V. G.
Shubin, Org. Biomol. Chem. 2013, 11, 1498–1501.
[26] Whereas the formation of major regioisomer 24 would
involve the expected pathway, that is, hydroxyalkyl
shift followed by loss of water, the minor product 25
seems to arise from a competitive hydroxyalkyl shift
followed by [1,4]-aryl migration, probably due to the
effect of the oxygen atom.
In addition, the substitution at C-6 or C-11 of the ben-
zo[b]carbazole moiety could be easily established as
the substituent at C-11 is significantly deshielded by
the indole benzene ring. See refs.[5b,7b]
[21] The initial formation of isobenzofuran derivatives 3
precludes the possibility of an alternative mechanism
involving a prior direct substitution of the hydroxy
group by the indole through C-3 and further direct cy-
ACHTUNGTRENNUNGclization by attack of C-2 to the carbonyl.
À
[22] Indolation by Lewis acid-catalyzed C O bond cleavage,
see: a) J. Barluenga, A. Fernꢀndez, F. Rodrꢁguez, F. J.
FaÇanꢀs, J. Organomet. Chem. 2009, 694, 546–550;
b) X. Guo, S. Pan, J. Liu, Z. Li, J. Org. Chem. 2009, 74,
8848–8851.
[27] Treatment of 1a with pyridine- or indole-functionalized
hydroxyacetal (Figure 2) led to no reaction under cata-
lytic (20 mol%) or excess (120 mol%) amounts of
PTSA.
[23] For selective 1,2-migration processes on spiroindole-
nine intermediates, see: a) G. Broggini, V. Barbera,
E. M. Beccalli, E. Borsini, S. Galli, G. Lanza, G.
Zecchi, Adv. Synth. Catal. 2012, 354, 159–170;
382
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Adv. Synth. Catal. 2014, 356, 374 – 382