Intramolecular fischer indole synthesis in combination with alkyne hydroarylation: Synthesis of tetracyclic chromeno-indoles

Article abstract of DOI:10.1021/ol4031638

Aryl hydrazides bearing a carbonyl function connected through an alkyne tether underwent an intramolecular Fischer indolization and alkyne hydroarylation in a tandem fashion to afford novel tetracyclic chromeno-indoles. The accompanying isomerization of the 2H-chromene double bond can be avoided by stopping the tandem process at the indolophane stage and conducting the alkyne-hydroarylation reaction separately in the absence of a proton source.

Full text of DOI:10.1021/ol4031638

Letter
pubs.acs.org/OrgLett
Intramolecular Fischer Indole Synthesis in Combination with Alkyne
Hydroarylation: Synthesis of Tetracyclic Chromeno-indoles
Jun Park, Sun-Young Kim, Ji-Eun Kim, and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul 131-791, Korea
S
* Supporting Information
ABSTRACT: Aryl hydrazides bearing a carbonyl function
connected through an alkyne tether underwent an intra-
molecular Fischer indolization and alkyne hydroarylation in a
tandem fashion to afford novel tetracyclic chromeno-indoles.
The accompanying isomerization of the 2H-chromene double
bond can be avoided by stopping the tandem process at the
indolophane stage and conducting the alkyne-hydroarylation
reaction separately in the absence of a proton source.
Scheme 1. Tandem IMFIS/ortho-Claisen Rearrangement vs
IMFIS/Alkyne Hydroarylation
ndole is arguably the most frequently found structural motif
1
Iin nature.
The intriguing biological properties and
molecular architechtures of indole based natural products
continue to pose challenges and motivations for the synthesis.2
Recently, polycyclic indole alkaloids with a 3,4-fused tricyclic
indole core have emerged as the target system of interest in the
same vein (Figure 1).3
Figure 1. Selected examples of polycyclic indole alkaloids with a 3,4-
fused tricyclic indole core.
indole 6.6 Ozonolysis or an equivalent reaction of the 2H-
chromene double bond would then provide ketone function in
the center ring for further derivatization.
However, their synthesis can often be difficult due to the lack
of a general synthetic method that paves the way to such 3,4-
fused tricyclic indoles. We have previously demonstrated that
the intramolecular Fischer indole synthesis (IMFIS)4 coupled
with an aromatic [3,3]-sigmatropic rearrangement can be an
effective synthetic entry to the 3,4-fused tricyclic indole 3
(Scheme 1).5 In this reaction sequence, aryl hydrazide 1 with a
carbonyl function attached to the para-position of the aryl
hydrazide undergoes an intramolecular Fischer indolization to
first give indolophane intermediate 2. Subsequent engagement
with an aromatic [3,3]-sigmatropic rearrangement reaction
affords 3,4-fused tricyclic indole 3 due to the deliberate
insertion of the C−C double bond in the tether. As an
extension, we set out to investigate the similar tandem reaction
of aryl hydrazide incorporating a C−C triple bond in the tether.
In this contest, the aromatic [3,3]-sigmatropic rearrangement
would be followed by aromatization, a [1,5]-hydrogen shift, and
6π-electrocyclization to give novel tetracyclic 2H-chromeno-
At the outset of its synthetic utility, this elaboration raises a
few fundamental questions such as whether IMFIS would ever
be possible, as it needs to go through indolophane 5 that has a
much higher strain energy than indolophane 2, and whether the
indolophane 5, even if formed, can undergo an intramolecular
alkyne-hydroarylation reaction that usually requires an
extremely high reaction temperature (200−250 °C)7 or a
metal catalyst.8 Also, the effect of tether length on this tandem
process needs to be addressed. The potential synthetic value
together with the aforementioned basic issues prompted us to
investigate the tandem IMFIS/alkyne-hydroarylation reactions
of aryl hydrazides 4 with alkyne tethers of varying lengths.
Received: November 2, 2013
Published: December 5, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
Aryl hydrazides 4a−4d were prepared from TBS propargyl
ether 7 via the route described in Scheme 2. Deprotonation
Table 1. Tandem Reactions of Aryl Hydrazides 4a−4d
Scheme 2. Synthesis of Aryl Hydrazide 4a−4d
yield after 4 h (entry 4). Increasing the reaction time up to 3
days had little effect on the reaction (entry 5). Apparently, this
tandem process is strongly dependent on the tether length, and
the tethers employed in aryl hydrazides 4b and 4c (n = 2 and
3) appeared to be adequate. Evidently, the alkyne tether in aryl
hydrazide 4a (n = 1) is too short to furnish the required
indolophane intermediate 5a. On the other hand, the tether in
aryl hydrazide 4d (n = 4) would be too long to give the
conformation needed for the ensuing aromatic [3,3]-sigma-
tropic rearrangement, after the formation of the indolophane
intermediate 5d. It is worth noting that the reactions described
in entries 2 and 3 represent the first nonmetal catalyzed
intramolecular alkyne-hydroarylation reaction of aryl propargyl
ether to proceed at temperatures as low as the refluxing
temperature for n-propyl alcohol. The ring strain in the
corresponding indolophane intermediate 5b and 5c is believed
to be the main driving force. With the above-mentioned results
in hand, we set out to investigate the tandem IMFIS/alkyne-
hydroarylation process of the aryl hydrazide that contains a
substituent next to the phenolic oxygen of the aromatic ring
(Table 2).
with n-BuLi and the substitution reaction with alkyl bromides
8a−8d furnished silyl propargyl ethers 9a−9d which were
desilylated with TBAF to give alcohols 10a−10d in good
overall yield (70%−83%). The resulting alcohols 10a−10d
were then mesylated into 11a−11d for the reaction with p-
iodophenol 12a. Simple mixing in the presence of potassium
carbonate at rt afforded aryl propargyl ethers 13a−13d in good
overall yields (70%−89%). Finally, Cu(I)-catalyzed coupling
reactions with ethyl carbazate were conducted on iodides 13a−
13d to provide the corresponding aryl hydrazides 4a−4d.9 Aryl
hydrazides 4a−4d were then heated under reflux in n-PrOH
containing a small amount of HCl (aq), with the conditions
previously optimized for the tandem process of 1 (Table 1).
As shown above, aryl hydrazide 4a (n = 1) afforded no
desired product, but a complex mixture of unidentifiable
products (entry 1). Varying the reaction conditions (temper-
ature, solvent) or the type of acid catalyst gave no
improvement. Fortunately, the desired tandem IMFIS/alkyne-
hydroarylation reaction was realized when the tether was
elongated by one carbon unit. Thus, aryl hydrazide 4b (n = 2)
gave an inseparable mixture of tetracyclic 2H-chromeno-indole
6b and its double bond isomerization product 14b (1:10) in
88% total yield after 24 h (entry 2). Aryl hydrazide 4c with a
one-carbon longer tether (n = 3) also underwent the tandem
reaction at a much faster rate. In this case, the initially formed
tandem product was completely isomerized into 14c in 83%
yield after 4 h (entry 4). However, aryl hydrazide with one-
carbon further extended tether 4d (n = 4) gave no tandem
reaction products (6d or 14d). The reaction was found to stop
at the Fischer indole stage, furnishing indolophane 5d in 81%
Incorporation of the substituent R makes the aryl hydrazide
unsymmetrical and thus may invoke a regioselectivity issue
depending on the direction the Fischer indolization proceeds
Table 2. Tandem Reactions of Substituted Aryl Hydrazides
entry
4
time (h)
14 (yield)
a
1
2
3
4
5
6
7
4e (R = Me)
4f (R = OMe)
4g (R = Ph)
4h (R = F)
13
13
13
13
13
13
14
14e (73%)
b
14f (50%)
14g (74%)
14h (70%)
14i (89%)
14j (78%)
14k (40%)
4i (R = Cl)
4j (R = Br)
4k (R = CO2Pr)
a
Yield was calculated from iodide 13e (two steps), because hydrazide
b
4e was difficult to purify. Yield was calculated from iodide 13f (two
steps), because hydrazide 4f was difficult to purify.
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Organic Letters
Letter
(clockwise vs counter-clockwise). Despite the concern,
however, all the alkyne tethered substituted aryl hydrazides
were wrapped around one direction (clockwise) to afford
tetracyclic chromeno-indoles 6, in good yield, after double
bond isomerization. The substituent R appeared to provide
sufficient steric bias forcing the intramolecular Fischer
indolization reaction at a distance. The electronic nature of
the substituent R has little effect on the reaction, as the product
yield for the aryl hydrazide 4f bearing an electron-donating
methoxy group (entry 2) is essentially identical to that for 4h
with an electron-withdrawing fluorine group (entry 4).
However, a significant drop in the product yield was observed
with the aryl hydrazide 4k that contains strongly electron-
withdrawing ester functionality (entry 7).
For the installation of the ketone function in the central ring,
we need to suppress the double bond migration process.
Toward this, we opted to disintegrate the tandem process into
the individual reactions by stopping the reaction at the
indolophane intermediate stage and conducting the intra-
molecular alkyne-hydroarylation reaction separately in the
absence of proton sources. Thus, the intramolecular Fischer
indolization reactions were carried out at lower temperatures
(Table 3). In the case of aryl hydrazide 4b (n = 2), lowering the
Table 4. Alkyne Hydroarylation Reactions of 5c and 5d
entry
5
conditions
results
1
2
3
4
5
6
5c (n = 3)
5c (n = 3)
5c (n = 3)
5c (n = 3)
5d (n = 4)
5d (n = 4)
xylene, reflux, 1 h
6c (99%)
6c (83%)
6c (32%)
6c (99%)
toluene, reflux, 22 h
benzene, reflux, 8 d
InI3, CH2CI2, 0 °C, 10 min
xylene, reflux, 1 h
a
decomposition
no reaction
InI3, CH2CI2, rt, 5 d
a
Starting indolophane 5c was recovered in 65% yield.
embedded in the indolophane 5c together with the favorable
entropy effect enabled the reaction to proceed at temperatures
much lower than required for the acyclic cases. In the presence
of InI3,8a the reaction went to completion within 10 min at 0 °C
to provide 6c in essentially quantitaive yield (entry 3).
Unfortunately, 5d gave no hydroarylation product under either
thermal or metal-catalyzed conditions (entries 4 and 5). A
simple molecular modeling study indicated that the distance
between the two reacting carbon temini (C3 and C3′) is a little
too far (3.09 Å for 5c vs 3.20 Å for 5d) for appropriate orbital
overlapping to occur.
Table 3. Interruption of the Tandem Reaction at the Fischer
Indolization Stage
In summary, we have found that aryl hydrazide connected to
the carbonyl function through an alkyne tether can undergo an
intramolecular Fischer indolization and cycloisomerization
reaction to afford novel tetracyclic 2H-chromeno-indoles. The
accompanying double bond migration can be avoided by
stopping the tandem process at the Fischer indolization stage
and conducting the alkyne-hydroarylation reaction separately in
the absence of a proton source. This conceptually new
approach may find further uses in the synthesis of macrocyclic
or polycyclic indoles of pharmacological interest.
entry
4
conditions
5
a
b
1
2
3
4b (n = 2)
4b (n = 2)
4c (n = 3)
60 °C, 3 h
rt, 24 h
trace
trace
60 °C, 12 h
5c, 88%
a
b
A mixture of 6b and 14b (1:10) was obtained in 62% total yield. A
mixture of 6b and 14b (1:10) was obtainedin 5% total yield.
ASSOCIATED CONTENT
* Supporting Information
■
reaction temperature to 60 °C had little influence as the
reaction proceeded all the way to afford a mixture of 6b and
14b (1:10) in 62% total yield after 3 h (entry 1). When
performed at room temperature, the reaction slowed down
quite a bit to give a mixture of 6b and 14b (ratio: 1:10) in 5%
total yield after 24 h. At this low conversion, there was no
noticeable indolophane 5b formed (entry 2). On the other
hand, the reaction of aryl hydrazide 4c (n = 3) effectively
stopped at the Fischer indolization stage, when performed at 60
°C, providing the indolophane 5c in 88% yield after 12 h (entry
3).
S
Experimental details and spectral data for new polycyclic indole
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ccho@hanyang.ac.kr.
Notes
The authors declare no competing financial interest.
The isolated Fischer product 5c was then subjected to the
various conditions to execute the intramolecular alkyne-
hydroarylation reaction (Table 4). When heated in xylene
under reflux, 5c was cleanly converted into tetracyclic 2H-
chromeno-indole 6c in quantitative yield after 1 h, with no
detectable double bond isomerization product 14c (entry 1).
The reaction was also found to proceed at lower temperature,
affording the same product 6c in 83% yield after 22 h in
refluxing toluene (entry 2). Running the reaction in lower
boiling benzene resulted in a substantial decrease in the
conversion (32% yield after 8 days, entry 3). The strain
ACKNOWLEDGMENTS
This work was supported by a grant from the National
Research Foundation of Korea (2011-0022343).
■
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