An acid-promoted novel skeletal rearrangement initiated by intramolecular ipso-Friedel-Crafts-type addition to 3-alkylidene indolenium cations

Article abstract of DOI:10.1039/c2cc31699d

An acid-promoted novel skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel-Crafts-type addition of phenols to 3-alkylidene indolenium cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and intramolecular Pictet-Spengler reaction proceeded sequentially, producing tricyclic indole derivatives.

Full text of DOI:10.1039/c2cc31699d

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COMMUNICATION
An acid-promoted novel skeletal rearrangement initiated by
intramolecular ipso-Friedel–Crafts-type addition to 3-alkylidene
indolenium cationsw
Takuya Yokosaka, Tetsuhiro Nemoto and Yasumasa Hamada*
Received 7th March 2012, Accepted 10th April 2012
DOI: 10.1039/c2cc31699d
An acid-promoted novel skeletal rearrangement is described. Using
trifluoroacetic acid as the acid promoter, an intramolecular ipso-
Friedel–Crafts-type addition of phenols to 3-alkylidene indolenium
cations, formation of iminium cations through rearomatization of the
spirocyclohexadienone units, and intramolecular Pictet–Spengler
reaction proceeded sequentially, producing tricyclic indole derivatives.
Polycyclic molecular frameworks with indole units are attractive
synthetic targets in medicinal chemistry because of their potential
for diverse biological activities.1 Therefore, considerable effort has
been devoted to the development of an efficient synthetic method
of such indole derivatives. Recently, 3-alkylidene indolenium
cations have been attracting attention as versatile synthetic inter-
mediates. Various functionalized molecules with indole units have
been synthesized based on acid-promoted generation of this class
of reactive species.2
Scheme 1 Initial sequential reaction design.
IV via a rearomatization process. While investigating this synthetic
scheme, however, we obtained an unexpected finding. Herein
we report our results.
Our investigation began with the preparation of a model
substrate (Scheme 2). After chlorination of p-benzyloxybenzyl
alcohol 1, the resulting benzyl chloride derivative 2 was
coupled with Weinreb amide 3, affording 4 in 72% overall
yield (2 steps). Compound 4 was transformed into the corre-
sponding aldehyde 5 by treatment with LiAlH4. Subsequent
C–C bond formation using a Grignard reagent 6, followed by
deprotection of the benzyl group, afforded the model substrate
7a in 38% yield over three steps. To verify the feasibility of the
designed reaction sequence, compound 7a was first treated
with trifluoroacetic acid (TFA) in CH2Cl2 at 0 1C. The
postulated reaction adducts like compound III or IV were,
however, not obtained at all, and the tryptoline derivative 8a
was unexpectedly produced in 79% yield.5
As part of our ongoing studies aimed at developing novel
synthetic methods for multi-cyclic molecules, we recently
reported a Pd-catalyzed intramolecular ipso-Friedel–Crafts
allylic alkylation of phenols that provides spirocyclohexadienones
through a nucleophilic dearomatization.3,4 We envisioned that
utilization of 3-alkylidene indolenium cations as electrophiles in
the intramolecular ipso-Friedel–Crafts reaction of phenols would
lead to characteristic sequential processes. The initial reaction
design based on this working hypothesis is outlined in Scheme 1.
Treatment of indole derivative I with an acid promoter should
lead to the formation of a 3-alkylidene indolenium cation.
An intramolecular ipso-Friedel–Crafts-type addition of para-
substituted phenol to the indolenium cation would subsequently
occur to give spirocyclohexadienone II, in which the nucleophilic
indole exists near the electrophilic cyclohexadienone. An intra-
molecular conjugate addition of the indole would then be expected
to proceed sequentially, producing pentacyclic adduct III.
A sequential dienone–phenol rearrangement of II might be
another possible pathway, which would afford indole derivative
This finding led us to optimize the reaction conditions using
compound 7a as the substrate (Table 1). Reactivity gradually
Graduate School of Pharmaceutical Sciences, Chiba University,
1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.
E-mail: hamada@p.chiba-u.ac.jp; Fax: +81-43-226-2920;
Tel: +81-43-226-2920
w Electronic supplementary information (ESI) available: Experimental
procedures, additional data, compound characterization, and NMR
charts. See DOI: 10.1039/c2cc31699d
Scheme 2 TFA-promoted unexpected skeletal rearrangement.
Chem. Commun., 2012, 48, 5431–5433 5431
c
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Table 1 Optimization of the reaction conditions for the transformation
of 7a into 8a in CH2Cl2
Table 2 Substrate scopea
Entry
Substrate
Product (Yield)
Entry Acid (equiv.)
Conc./M Temp./1C Time/h Yield (%)
1
2
3
4
5
6
7
8
TFA (8)
TFA (4)
TFA (2)
TFA (1)
TFA (8)
CF3SO3H (1)
TsOHÁH2O (1) 0.1
Sc(OTf)3 (0.2) 0.1
Yb(OTf)3 (0.2) 0.1
In(OTf)3 (0.2) 0.1
B(C6F5)3 (0.2) 0.1
B(C6F5)3 (0.5) 0.1
0.1
0.1
0.1
0.1
0.025
0.1
0
0
0
0
0
0
0
rt
rt
rt
rt
rt
2
9
24
24
3
79
68
43
8
91
Messy
11
25
5
0.2
24
24
24
24
24
24
9
10
11
12
32
49
65
decreased when the reaction was performed using less than
8 equiv. of TFA (entries 1–4). On the other hand, the yield
improved to 91% when the reaction was performed using
8 equiv. of TFA under diluted conditions (0.025 M) (entry 5).
Use of more acidic promoters resulted in a messy reaction
(entries 6 and 7). The same reaction was also examined using
several Lewis acid catalysts. Among the examined Lewis acids,
B(C6F5)3 gave the best results. Using 20 mol% of B(C6F5)3,
the reaction proceeded slowly at room temperature to provide
8a in 49% yield (entry 11). This yield improved to 65% when
50 mol% of B(C6F5)3 was used (entry 12). For practical
reasons, TFA was selected as the optimal reaction promoter.
We next evaluated the scope and limitations of different
substrates (Table 2). In addition to para-substituted phenol
derivative 7a (entry 1), O-methyl and O-benzyl derivatives 7b
and 7c were applicable to this reaction, and the corresponding
tricyclic adducts 8b and 8c were obtained in 90% yield and
98% yield, respectively (entries 2 and 3). Moreover, the
reaction using an ortho-substituted methyl ether derivative
7d proceeded smoothly to give the corresponding product 8d
in good yield (entry 4). This reaction system was also effective
for N-Z-protected indole derivative 7e as well as N-Ts-protected
indole derivative 7f (entries 5 and 6). In addition, compounds 7g
and 7h, bearing electron-withdrawing and electron-donating
functionalities on the indole ring, were tolerant to this reaction,
giving the products 8g and 8h in 90% yield and 84% yield,
respectively (entries 7 and 8). Aniline-tethered substrates 7i–7k
were also applicable to this reaction, and the corresponding
products were obtained with good conversion (entries 9–11).
Substrates with a longer tether were also examined under the
same reaction conditions. When substrate 7l, bearing a CH2
unit-longer tether than 7b, was treated with 8 equiv. of TFA, the
reaction proceeded smoothly to give the product with the
7-membered ring 8l in 88% yield (entry 12). Although there is
still room for improvement in the yield, the present method
could be extended to an 8-membered ring synthesis (entry 13).6
To gain insight into the reaction mechanism of this skeletal
rearrangement, deuterium-labelled substrates 7b-d1 and 7b-d2
were synthesized7 and subjected to the developed reaction
conditions (Scheme 3). Deuterium-labelled products 8b-d1
and 8b-d2 were obtained, respectively, with the complete
incorporation of deuterium atoms. These experimental data
led us to propose a plausible mechanism for this skeletal
rearrangement (Scheme 4).
a
b
Reaction conditions: TFA (8 equiv.), CH2Cl2 (0.025 M), 0 1C.
equiv. of TFA was used. Reaction was performed at room tempera-
5
c
d
ture. 11% of 7i was recovered (76% yield based on the recovered 7i).
e
33% of 7j was recovered (93% yield based on the recovered 7j).
13% of 7k was recovered (57% yield based on the recovered 7k).
f
Scheme 3 Deuterium labelling studies.
First, 3-alkylidene indolenium cation A is formed by the acid-
promoted dehydration of 7b. Subsequently, intramolecular
ipso-Friedel–Crafts-type addition of a para-substituted phenol
c
5432 Chem. Commun., 2012, 48, 5431–5433
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Angew. Chem., Int. Ed., 2009, 48, 1313; (g) T. Liang, Z. Zhang and
J. C. Antilla, Angew. Chem., Int. Ed., 2010, 49, 9734; (h) F.-L. Sun,
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Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng and Q.-X. Guo,
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3 T. Nemoto, Y. Ishige, M. Yoshida, Y. Kohno, M. Kanematsu and
Y. Hamada, Org. Lett., 2010, 12, 5020.
4 For representative synthetic methods for spirocyclohexadienones,
see: Oxidation of phenols with hypervalent iodine reagents;
(a) T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto,
H. Tohma and Y. Kita, Angew. Chem., Int. Ed., 2005, 44, 6193;
(b) T. Dohi, A. Maruyama, Y. Minamitsuji, N. Takenaga and
Y. Kita, Chem. Commun., 2007, 1224; (c) T. Dohi, A. Minamitsuji,
S. Maruyama, S. Hirose and Y. Kita, Org. Lett., 2008, 10, 3559.
Reviews: (d) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008,
108, 5299; (e) T. Dohi, Chem. Pharm. Bull., 2010, 58, 135. Radical
cyclization: (f) F. Gonzalez-Lopez de Turiso and D. P. Curran,
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Org. Lett., 2005, 7, 151; (g) T. Lanza, R. Leardini, M. Minozzi,
D. Nanni, P. Spagnolo and G. Zanardi, Angew. Chem., Int. Ed.,
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E. Fanghanel, Eur. J. Org. Chem., 2003, 47; (i) X. Zhang and
¨
Scheme 4 Reaction pathway.
derivative to the indolenium cation proceeds to give dearoma-
tized cationic species B. Sequential rearomatization of the
spirocyclohexadienone moiety accompanying the C–C bond
cleavage results in the formation of iminium cation C. An
intramolecular Pictet–Spengler reaction of the intermediate C
finally occurs to give tricyclic indole derivative 8b. Cationic
species such as intermediate C are generated by the retro-
Mannich process of azaspiroindolenines.8 To the best of our
knowledge, this is a novel method for generating such iminium
cation intermediates through a cascade reaction process based
on the ipso-Friedel–Crafts-type addition of phenol derivatives
to 3-alkylidene indolenium cations.9,10
R. C. Larock, J. Am. Chem. Soc., 2005, 127, 12230; (j) B.-X. Tang,
Q. Yin, R.-Y. Tang and J.-H. Li, J. Org. Chem., 2008, 73, 9008.
Arene–Ru complex-mediated dearomatization; (k) F. C. Pigge,
J. J. Coniglio and N. P. Rath, Org. Lett., 2003, 5, 2011;
(l) F. C. Pigge, R. Dhanya and E. R. Hoefgen, Angew. Chem.,
Int. Ed., 2007, 46, 2887. Cu-catalyzed oxygenation of a-azido-N-
arylamides; (m) S. Chiba, L. Zhang and J.-Y. Lee, J. Am. Chem.
Soc., 2010, 132, 7266. Nucleophilic dearomatization of phenols:
(n) Q.-F. Wu, W.-B. Liu, C.-X. Zhuo, Z.-Q. Rong, K.-Y. Ye and
S.-L. You, Angew. Chem., Int. Ed., 2011, 50, 4455;
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´
and S. L. Buchwald, J. Am. Chem. Soc., 2011, 133, 9282.
5 Deprotection of the Boc group of 7a did not occur under these
acidic conditions. The Boc group of 7a could be removed under
basic conditions (K2CO3, MeOH–THF, 60 1C). Treatment of the
non-protected substrate with 8 equiv. of TFA, however, gave
complex mixtures.
In conclusion, we developed an innovative method for
synthesizing tricyclic indole derivatives through an acid-
promoted novel skeletal rearrangement. The method is based on
the intramolecular ipso-Friedel–Crafts-type addition of phenol
derivatives to 3-alkylidene indolenium cations, followed by the
formation of iminium cations through rearomatization of spiro-
cyclohexadienone units. Structurally diverse indole derivatives were
obtained in good yield under mild and simple reaction conditions.
Deuterium labelling studies revealed the mechanistically interesting
reaction pathway. The present method provides access to polycyclic
molecular frameworks that are of potential interest as scaffolds for
drug design.
6 In addition to 8m, a pyrrolidine derivative 9 shown below was
obtained as the major by-product.
7 For the preparation of deuterium-labelled substrates 7b-d1 and
7b-d2, see the ESIw.
8 (a) J. P. Brennan and J. E. Saxton, Tetrahedron, 1986, 42, 6719;
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This work was financially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, and the Research
Foundation for Pharmaceutical Sciences.
9 For a similar reaction initiated by epoxide opening reaction with
anisole derivative, see: R. Marcos, C. Rodriguez-Escrich,
C. I. Herrerias and M. A. Pericas, J. Am. Chem. Soc., 2008,
130, 16838.
10 For examples of Pictet–Spengler reaction based on the generation
of iminium cations through a cascade reaction process, see:
Notes and references
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This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5431–5433 5433