A cycloisomerization/Friedel-Crafts alkylation strategy for the synthesis of pyrano[3,4- b ]indoles

Article abstract of DOI:10.1021/ol201532k

The synthesis of pyrano[3,4-b]indoles is described. The reaction sequence involves Sonogashira coupling of dihydropyran propargyl ether scaffolds with iodoanilines to afford intermediate indoles. Lewis acid-catalyzed ionization of the dihydropyrans, followed by intramolecular C3 alkylation of the indole, provides the title compounds.

Full text of DOI:10.1021/ol201532k

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4012–4015
A Cycloisomerization/FriedelꢀCrafts
Alkylation Strategy for the Synthesis
of Pyrano[3,4-b]indoles
Matthew R. Medeiros, Scott E. Schaus,* and John A. Porco Jr.*
Chemistry Department, Center for Chemical Methodology and Library Development,
Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
seschaus@bu.edu; porco@bu.edu
Received June 8, 2011
ABSTRACT
The synthesis of pyrano[3,4-b]indoles is described. The reaction sequence involves Sonogashira coupling of dihydropyran propargyl ether
scaffolds with iodoanilines to afford intermediate indoles. Lewis acid-catalyzed ionization of the dihydropyrans, followed by intramolecular C3
alkylation of the indole, provides the title compounds.
It is well established that compounds containing the
“privileged” indole motif exhibit a myriad of biological
activities.1 Building upon our recently reported study of
dihydropyran rearrangements,2 we developed a program
focused on the synthesis of molecules comprising the
pyrano[3,4-b]indole framework. Compounds having this
skeleton have been used as anti-inflammatory and analge-
sic agents as exemplified by etodolac (1) and pemedolac (2)
(Figure 1).3 More recently these compounds have shown
promise as inhibitors of hepatitis C virus (HCV) NS5B
polymerase (3)4 and as potential treatments for lymphoma.5
A SciFinder search6 of known compounds having the
pyrano[3,4-b]indole skeleton revealed 2726 structures with
only 55 (2%) bearing substitution at C3 and C4 (cf. 1,
Figure 1). Accordingly, methodology providing functio-
nalization at these positions will serve to increase the
diversity of this chemotype. Herein, we describe a cycloi-
somerization/alkylation strategy that affords pyrano[3,4-
b]indoles exhibiting both stereochemistry and useful func-
tional groups at C3 and C4.
We envisioned a strategy to pyranoindoles of the type
4 involving intramolecular FriedelꢀCrafts cyclization
of indole 5 (Scheme 1a). Alkylation of allylic alcohol 6
with a substituted bromomethylindole (7) would pro-
vide the desired cyclization precursor. Considering
our interest in library synthesis, and identifying the
indole fragment as a diversity element, we were
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(6) A structure search for the pyrano[3,4-b]indole skeleton was
conducted on March 14, 2011 using the web-based SciFinder Scholar
Database.
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r
10.1021/ol201532k
Published on Web 07/08/2011
2011 American Chemical Society

alkyne 11 and 2-iodoaniline to provide o-alkynylaniline 12
(Scheme 2).10 A variety of conditions havebeenreportedto
effect cycloisomerization of o-alkynylanilines.8,11 Our de-
sire to conduct a tandem process and prior experience with
related rearrangements2 led us to explore conditions that
would allow both alkyne activation and ringopening ofthe
dihydropyran. A preliminary screen revealed PtCl2 and
Ph3PAuCl/AgSbF6 as candidate catalysts for the transfor-
mation. However, upon further investigation, we did not
observe the desired pyranoindole. Rather, we isolated both
indole 13 and alcohol 14, the latter presumably arising
from β-elimination. Furthermore, exposure of indole 13 to
Sc(OTf)3 in CH3NO2 resulted in exclusive formation of
elimination product 14.
Figure 1. Biologically active pyrano[3,4-b]indoles.
concerned with the availability and preparation of diverse
bromomethylindoles.7
Scheme 2. Attempted Cycloisomerization/Alkylation Using an
Unprotected o-Alkynylaniline
Alternatively, reports of the intermolecular, electrophilic
alkylation of the intermediate metal vinylidenes resulting
Scheme 1. Proposed (a) Intramolecular Indole Alkylation and
(b) Cycloisomerization/Alkylation Strategies
Encouraged by the isolation of indole 13, we anticipated
that deactivation of the indole moiety with an electron-
withdrawing group on the nitrogen would abrogate the
formation of alcohol 14. Accordingly, sulfonylation of
aniline 12 under standard conditions provided sulfona-
mide 15 (Scheme 3). A brief catalyst screen revealed a
marked dependence of product formation on catalyst choice.
Use of π-philic catalysts such as PtCl2 and Ph3PAuCl12
generated the desired pyranoindole 16 along with a small
amount of the intermediate indole 17 (entries 1 and 2).
Alternatively, treatment of 15 with Sc(OTf)3 and In(OTf)3,
both known to be oxophilic Lewis acids,13 provided tetra-
hydrofuran 18 (stereochemistry not determined).10 Pre-
sumably, tetrahydrofuran 18 arises from initial ionization
of the dihydropyran followed by nucleophilic attack by the
pendant alkyne to form the C3ꢀC8 bond. The resulting
vinyl carbocation may finally be quenched by water present
from metal-catalyzed cycloisomerization of o-alkynylanilines8
inspired us to pursue an intramolecular cycloisomeriza-
tion/alkylation strategy employing o-alkynylanilines (8)
(Scheme 1b). Sonogashira coupling9 of terminal alkynes
(9) with readily available iodoanilines (10) would serve to
generate the desired cycloisomerization precursors.
Investigation of our proposed cycloisomerization ap-
proach commenced with Sonogashira coupling of terminal
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
ꢀ
€
1975, 16, 4467–4470. (b) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
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(10) See Supporting Information for complete experimental details.
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(14) See SupportingInformation for a graphical representation of the
proposed mechanism.
Org. Lett., Vol. 13, No. 15, 2011
4013

protected derivative confirmed the stereochemistry of the
major isomer.10 Due to the convenience and high yield of
the two-step procedure, we pursued this strategy for the
remainder of our study.
Scheme 3. Catalyst Role in the Tandem Cycloisomerization/
FriedelꢀCrafts Rearrangementa
An investigation of the scope of the reaction revealed
that indoles containing electron-withdrawing (Table 1,
entries 1ꢀ5) or electron-donating groups (entry 6) provided
the desired pyranoindoles in good yields. The reaction
conditions were tolerant of both azide and bromide sub-
stituents at R2 (entries 7ꢀ8). Furthermore, use of iodo-
phenols as coupling partners in the Sonogashira reaction
provided intermediate benzofurans, which were smoothly
transformed to pyrano[3,4-b]benzofurans16 using identical
conditions (entries 9ꢀ10).
Table 1. Scope of the Sc(OTf)3-Catalyzed Cyclizationa
a Conditions: substrate (0.10 mmol), catalyst (0.010 mmol), CH3NO2
(1 mL), 3 h. bStarting material recovered.
in the reaction medium. Tautomerization of the intermedi-
ate enol affords the C9 ketone.14
We desired to streamline the synthesis of the cycloisome-
rization precursors (15) in order to provide a route amen-
able to library preparation. Accordingly, we considered
protection of the iodoaniline prior to the Sonogashira
coupling in order to provide a more convergent process
and to increase the flexibility of protecting groups (Scheme
4). However, we did not observe any of the expected
protected alkynyl aniline after Sonogashira coupling of
alkyne 11 and sulfonamide 19. Instead, we only observed
formation of indole 20 arising from cycloisomerization.15
substrate
yield
(%)
entry
(20,23)
X
R1
R2
drb
1
2
20
23a
b
NHTS
H
OMe
OMe
OMe
OMe
OMe
OMe
Br
90
95
95
88
77
49
74
44
80
60
13:1
4:1
NHMS 5-F
3
NHTS
NHTS
5-CF3
5-NO2
2:1
4
c
1:1
5
d
NHMS 6-Cl
4:1
6
e
NHTS
NHTS
NHMS
O
5-OMe
>20:1
17:1
5:1
7
f
H
H
H
8
g
N3
9
h
i
OMe
3:1
Scheme 4. Synthesis of Pyranoindoles 21 and 22
10
O
5-CO2Me OMe
1:1
a See Supporting Information for detailed experimental procedures.
b Determined by 1H NMR analysis of the crude reaction mixture.
An investigation of the reaction scope revealed an inter-
esting relationship between the electronic nature of the
indole and the diastereoselectivity of the reaction. Analysis
of the results in Table 1 reveals that a decrease in the
electron density of the indole is accompanied by a decrease
in the diastereoselectivity of the reaction. Our rationale for
this trend is illustrated in Scheme 5. We envision two initial
pathways for the reaction. Lewis acid mediated ionization
of the dihydropyran may afford the open intermediate 26
(pathway a). Alternatively, SN20 attack of the indole on the
activated dihydropyran would lead to iminium 27
(pathway b). Bond rotation in 26 to relieve A1,3-strain
would provide 28, which upon ring closure and rearoma-
tization would yield trans-pyranoindole 21. Iminium 27
could also undergo two possible reaction pathways, the
Subsequent exposure of indole 20 to Sc(OTf)3 in CH3NO2
provided pyranoindoles 21 and 22 in 90% combined yield
and 13:1 diastereomeric ratio favoring the trans isomer. An
X-ray crystal structure of the analogous methanesulfonyl-
(15) (a) Xiong, X.; Pirrung, M. C. Org. Lett. 2008, 10, 1151–1154. (b)
For examples of cycloisomerization occuring under Sonogashira con-
ditions, see: Chen, Y.; Markina, N. A.; Larock, R. C. Tetrahedron 2009,
65, 8908–8915. (c) Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65,
7761–7775.
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Chem. Lett. 2006, 16, 457–460.
4014
Org. Lett., Vol. 13, No. 15, 2011

first being CꢀC bond cleavage to return to the open
intermediate 26 (pathway c). A second reaction manifold
(pathway d) involves deprotonation to furnish cis-pyra-
noindole 22. We hypothesize that the electron deficiency of
the aromatic ring decreases the pKa of the indolic proton
prior to rearomatization making pathway d more favor-
able in these cases, thereby, increasing the proportion of
the cis-isomer. Increasing electron density of the indole
may favor SN20 pathway b. However, based on our results
webelievethatstereodifferentiation toaccesscis-pyranoin-
dole isomers (cf. 22) occurs during pathways c and d.
Reports of the oxidative rearrangement of 2,3-sub-
stituted indoles prompted our investigation of the
oxidation of pyranoindole 30 (Scheme 6b).18 We antici-
pated that selective epoxidation of the indole 2,3-π
bond, followed by ring contraction, would provide a
rearranged spirooxindole. Indeed, subjection of pyra-
noindole 30 to mCPBA in CH2Cl2 produced spiroox-
indole 31 in 49% yield.
Scheme 6. (a) Etherification and (b) Oxidative Rearrangement
of Pyranoindoles
Scheme 5. Proposed Mechanism for Pyranoindole Formation
In conclusion, we have developed syntheses of pyrano-
[3,4-b]indolesand pyrano[3,4-b]benzofurans containing an
uncommon C3ꢀC4 substitution pattern. The two-step
procedureinvolvesSonogashiracouplingof dihydropyran
propargyl ether scaffolds with iodoanilines followed by
FriedelꢀCrafts alkylation. Conditions to convert pyra-
noindoles into other scaffolds, including a bis-pyran and
a spirooxindole, were also devised. Further studies using
the methodology to access diverse chemical architectures
are currently underway and will be reported in due course.
In order to increase the diversity of structures accessed
using this methodology, we proceeded to investigate
further reactions of the pyranoindole scaffolds. Precedent
for the etherification of alkenols using metal triflates
prompted us to investigate further cyclization of 24d
(Scheme 6a).17 Indeed, microwave heating of 24d in the
presence of a catalytic amount of Sc(OTf)3 in 1,2-dichlo-
roethane provided bis-pyran 29 in 93% yield as a single
diastereomer. The corresponding cis-isomer (25d) did not
cyclize under these conditions and decomposed upon
increasing the temperature and catalyst loading.
Acknowledgment. We gratefully acknowledge financial
support from the NIGMS CMLD initiative (P50-
GM67041). We also thank Drs. Paul Ralifo and Norman
Lee (Boston University) for assistance with instrumenta-
tion and Dr. Jeffrey W. Bacon (Boston University) for
X-ray crystallographic analysis.
~
(17) (a) Coulombel, L.; Weıwer, M.; Dunach, E. Eur. J. Org. Chem.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2009, 5788–5795. (b) Dzudza, A.; Marks, T. Chem.;Eur. J. 2010, 16,
3403–3422.
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hedron 2006, 62, 5195–5200. (b) Movassaghi, M.; Schmidt, M. A.;
Ashenhurst, J. A. Org. Lett. 2008, 10, 4009–4010.
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