Intramolecular Didehydro-Diels-Alder Reaction for the Synthesis of Benzo- and Dihydrobenzo-Fused Heterocycles

Article abstract of DOI:10.1021/acs.orglett.7b00155

Using an intramolecular didehydro-Diels-Alder reaction, ene-yne substituted pyrroles, thiophenes, and furans afford functionalized indoles, benzothiophenes, and benzofurans and the corresponding dihydroaromatic products. Product selectivity for the aromatic or dihydroaromatic product is controlled by the reaction conditions, which vary depending upon the substrate.

Full text of DOI:10.1021/acs.orglett.7b00155

Letter
pubs.acs.org/OrgLett
Intramolecular Didehydro-Diels−Alder Reaction for the Synthesis of
Benzo- and Dihydrobenzo-Fused Heterocycles
Ashley E. Bober, Justin T. Proto, and Kay M. Brummond*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Using an intramolecular didehydro-Diels−Alder reaction, ene−yne
substituted pyrroles, thiophenes, and furans afford functionalized indoles,
benzothiophenes, and benzofurans and the corresponding dihydroaromatic
products. Product selectivity for the aromatic or dihydroaromatic product is
controlled by the reaction conditions, which vary depending upon the substrate.
enzo- and dihydrobenzo-fused heterocycles are a diverse
Bclass of compounds that play important roles in
pharmaceuticals, biological probes, and electronic materials.1
Naturally occurring benzo-fused heterocycles exhibit biological
activity in a wide range of therapeutic applications. Indole
represents the most prominent of these heterocyclic moieties
and is found in many pharmaceuticals and biologically active
natural products.1a,2 Benzothiophenes and benzofurans,
although less common, have been the subject of growing
attention. For example, colchicine derivative 1 is a lead anticancer
compound that displays antiproliferative activity at nanomolar
concentrations (Figure 1).3 Benzothiophene 2 acts as an
antithrombotic agent that deactivates plasminogen activator
inhibitor-1 during the coagulation process.4 (−)-Nodulisporic
acid C (3), an indole derivative, is an orally available antiflea
agent used to treat domestic animals.5 Tetrahydrocarbazole 4 is a
promising candidate as a treatment for obesity in rat models.6
Rising interest has led to an increased number of synthetic
approaches to efficiently generate functionalized benzo-fused
heterocycles.1b,7 Most of these synthetic methods, especially
those performed on large scale, begin by constructing the
heterocyclic ring from benzene-containing precursors, due to
their availability and ease of functionalization.2a,8 The hetero-
cyclic portion is often formed via condensation reactions,1a such
as the Fischer indole synthesis, and the conversion of α-
haloketones to form benzofurans and benzothiophenes.1a,9
Modern transition-metal-catalyzed reactions provide alternative
conditions for the synthesis of indoles, yet they employ aniline-
derived precursors seen in classical reactions that result in the
same substitution patterns.10 In 2014, Njardarson et al. mapped
the functionalization patterns of indoles in FDA-approved
drugs.11 Of 17 drugs containing indole scaffolds, 15 contained
substitution at the 3-position, and 12 were substituted at the 5-
position. In contrast, only one drug incorporated substituents at
either the 4- or 7-positions; no drugs were substituted at the 6-
position. Structure 5 highlights substitution patterns under-
represented in pharmaceuticals.
Figure 1. Biologically relevant fused heterocycles. Structure 5 illustrates
common substitution patterns in FDA-approved indole drugs, adapted
with permission from ref 11. Copyright 2014 American Chemical
Society.11
The intramolecular didehydro-Diels−Alder (IMDDA) reac-
tion was previously established as a method to efficiently
generate naphthalene- and dihydronaphthalene-containing
frameworks from the same diene−yne precursors; this divergent
method requires only subtle changes to the reaction con-
ditions.12 Herein, we explore the feasibility of utilizing the
IMDDA reaction to prepare benzo-fused heterocycles as an
alternate synthetic approach to access more challenging
substitution patterns (Scheme 1). The benzo- and dihydro-
Received: January 16, 2017
© XXXX American Chemical Society
A
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Organic Letters
Letter
the IMDDA precursor, phenyl- and TMS-substituted propiolic
acids were converted to acid chlorides using oxalyl chloride and a
catalytic amount of dimethylformamide (DMF). Each acid
chloride was added dropwise to the allylamine to provide amides
9 and 10.
Scheme 1. Heterocyclic Scaffolds via the IMDDA Reaction
Pyrrole derivatives were also synthesized with incorporation of
ketones into the diene−yne tethers (eq 3, Scheme 2). After
addition of vinylmagnesium bromide to pyrrole-2-carboxalde-
hyde,14 an Eschenmoser−Claisen rearrangement15 of allyl
alcohol 11 afforded dimethyl amide 12 in good yield. Installation
of the alkyne moiety was achieved following Trost’s procedure.16
When the alkyne terminus was phenyl-substituted, addition of
the alkyne proceeded in 76% yield to generate diene−yne 13.
Comparable yields were observed for TMS and TIPS
substitution of the alkyne (14 and 15). A poor yield was
obtained for the addition of 4-methylpentyne due to the
formation of uncharacterized byproducts (16, 11% yield).
With the heterocyclic diene−ynes in hand, the IMDDA
reaction was tested. Nitrobenzene (PhNO2) as the reaction
solvent delivered exclusively the benzothiophene and benzofuran
products when ester-containing tethers were installed at the C2-
positions (entries 1 and 3, Table 1). On the basis of previous
fused heterocyclic cores each offer a unique reactivity profiles for
subsequent potential applications. The benzo-fused heterocycles
show immediate similarity to pharmaceuticals, and the
dihydrobenzo-fused heterocycles offer many sites for additional
functionality and complexity to be introduced.
To examine the utility of the IMDDA reaction for the
preparation of heterocyclic scaffolds, a variety of diene−yne
precursors were synthesized. We chose to explore several
heterocycles, including thiophene, furan, and pyrrole, as well as
a range of tether functionalities. Scheme 2 depicts a
Scheme 2. Representative Syntheses of IMDDA Precursors
Table 1. C2-Substituted Aromatic Selectivity
%
time
(min)
%
yield
a
b
entry
X
Y
R
PhNO2
Ar/DH
c
1
S
S
O
Ph
100
3
20
3
100:0
100:0
100:0
100:0
90
86
65
42
94
94
74
90
99
69
41
2
O
TMS
Ph
10
c
3
O
O
100
4
O
O
TMS
Ph
10
10
20
50
100
50
50
50
20
3
5
NTs
NTs
NTs
NTs
NTs
NTs
NTs
O
50:50
83:17
97:3
6
O
Ph
3
7
O
Ph
3
8
O
Ph
3
100:0
88:12
93:7
9
CH2
CH2
Ph
3
10
11
TMS
3
CH2
TIPS
10
78:22
a
b
c
1H NMR ratios Isolated yield, 0.06−0.13 mmol. Lower conc. not
tested.
representative synthesis of a heterocyclic substrate equipped
with an ester-containing tether. Allylic alcohol 6 was prepared via
the Wittig reaction of pyrrole-2-carboxaldehyde (98% yield)13
and subsequent DIBAL reduction (98% yield; see the Supporting
Information (SI)). To form the alkynoate tether, the carboxyl-
activating reagent EDCI·HCl was used to couple 6 with
phenylpropiolic acid to generate 7 in moderate yield (67%; eq
1, Scheme 2). The same process was used to synthesize IMDDA
precursors containing tethers at the C3-position of the pyrrole as
well as for the thiophene and furan analogues (see the SI).
In addition to IMDDA precursors incorporating ester
functionality within the diene−yne tether, thiophenes featuring
amide moieties were also synthesized via the Gabriel synthesis
(eq 2, Scheme 2). Phosphorus tribromide was used to convert
allylic alcohol 8 to the corresponding allyl bromide, which was
further reacted with potassium phthalimide to deliver the allylic
phthalimide in good yield (83%, two steps). Refluxing with
hydrazine in ethanol delivered the free amine (72%). To prepare
studies of styrenyl substrates, 10% PhNO2 in o-dichlorobenzene
(o-DCB) was sufficient to exclusively generate the aromatic
product.12b These optimized conditions proved successful when
alkynoate tethers were incorporated at the C2-positions of
thiophene and furan, affording exclusively aromatic products
(entries 2 and 4). When the IMDDA reaction of a pyrrole with an
alkynoate tether was conducted using 10% PhNO2, the aromatic
product was formed in a 50:50 mixture with the dihydroaromatic
product (entry 5). Increasing the concentration of PhNO2
increased the ratio of aromatic to dihydroaromatic product, yet
it was not until neat PhNO2 was employed that the aromatic
indole was solely formed (entries 5−8). Moving forward, o-DCB
containing 50% PhNO2 was selected as the medium to generate
indoles in IMDDA reactions, as these conditions would minimize
the amount of PhNO2 but still allow for enhanced product
selectivity (entries 9−10). However, with a TIPS group at the
alkyne terminus of the IMDDA precursor, selectivity and yield
decreased appreciably (entry 11). The marked decrease in yield is
B
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Letter
attributed to steric interactions between the pyrrole and the
isopropyl groups on silicon.
Table 3. C2-Substituted Dihydroaromatic Selectivity
Conditions to provide aromatic product selectivity were also
explored for heterocycles with tethers at the C3 position.
Thiophene substrates containing ester and amide tethers showed
high selectivity for the aromatic products when 10% PhNO2 in o-
DCB was employed as the reaction solvent (entries 1−5, Table
2). Neat PhNO2 delivered the benzofuran product exclusively in
Table 2. C3-Substituted Aromatic Selectivity
%
time
(min)
%
yield
a
b
entry
X
Y
R
PhNO2
Ar/DH
1
2
3
4
5
6
7
8
S
S
S
S
S
O
Ph
10
10
10
10
10
20
20
80
30
30
3
96:4
99:1
99:1
95:5
99:1
100:0
86
71
71
82
74
78
O
TMS
CH2Cy
Ph
O
NH
NH
O
TMS
Ph
c
O
100
d
e
NTs
NTs
O
Ph
50
5
4:96
57
a
b
c
1H NMR ratios. Isolated yield, 0.06−0.09 mmol. Reaction conc.
e
CH2
Ph
100
5
81:19
57
d
e
0.10−0.12 M. No products detected, only decomposition. 63%
recovery SM.
a
b
c
1H NMR ratios. Isolated yield, 0.05−0.11 mmol. Lower conc. not
tested. Anomalous result under investigation. Decomposition by
TLC.
d
e
was successfully oxidized to the corresponding indole via
manganese(IV) oxide (see the SI).17
the reaction of a precursor featuring an ester-containing tether
(entry 6). When a pyrrole precursor with an ester-containing
tether was reacted in 50% PhNO2, only trace aromatic product
Conditions to provide the dihydroaromatic product selectively
were also explored for heterocycles with tethers at the C3-
position. The thiophene precursor containing an alkynoate
tether yielded the dihydroaromatic product selectively in DMF at
180 °C (entry 1, Table 4). Reaction of a TMS-substituted
thiophene precursor in DMF at 225 °C produced a 12:88 ratio of
the aromatic to dihydroaromatic products in 48% yield; however,
the TMS group was cleaved in situ (entry 2). Alkyl substitution of
the alkyne terminus positively impacted selectivity, which was
increased to 7:93 in favor of the dihydroaromatic product (entry
1
was detected by H NMR (entry 7). PhNO2 provided the
aromatic product in an 81:19 ratio with the dihydroaromatic
product for the reaction of a pyrrole precursor with an alkynone
tether (entry 8). Significant decomposition was observed by
TLC in these cases (entries 7−8).
Reaction in DMF provided dihydroaromatic products with
high selectivity for phenyl-substituted alkynes of C2-substituted
thiophene and furan systems (entries 1 and 3, Table 3). The
dihydroindole lactone product was generated with good
selectivity at higher concentrations and temperatures as low as
120 °C (entry 5). For pyrroles with alkynone tethers, high
concentrations of the substrate in DMF provided less selectivity,
resulting in an 11:89 ratio of the aromatic to dihydroaromatic
products (entry 6). Reaction of the same substrate in o-DCB at
higher temperature and lower concentration afforded an 8:92
ratio of products in excellent yield (99%, entry 7). DCE, although
similar in polarity and easier to remove than o-DCB, did not
deliver the same selectivity for the dihydroaromatic product
(entry 8). Reaction in DMF at higher concentration gave the
aromatic product in a 60:40 ratio with its dihydroaromatic
counterpart for pyrrole featuring a TMS-substituted alkynone
tether (entry 9). Changing the solvent to DCE and lowering the
reaction temperature yielded exclusively the dihydroindole
product (entry 10). Increasing reaction concentration led to
decreased selectivity (entry 11). TIPS substitution at the alkyne
terminus decreased the reaction rate significantly as well as the
selectivity and yield (entry 12).
Table 4. C3-Substitued Dihydroaromatic Selectivity
The dihydroindole examples featuring ketone tethers slowly
oxidized to the fully aromatic indole products under air (entries
6−11, Table 3; see the SI). Spontaneous oxidation was not
observed for other dihydroaromatic products. However, a
dihydroindole with a lactone tether and phenyl substitution
a
b
c
1H NMR ratios. Isolated yield, 0.03−0.1 mmol. Reaction conc.
d
e
f
0.10−0.12 M. Crude yield. TMS cleaved. Decomposition by TLC.
g
Not isolated.
C
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3). Reaction of the substrate with an amide tether and Ph
substitution at the alkyne terminus gave a 34:66 ratio of aromatic
to dihydroaromatic products (entry 4). A TMS-substituted
analogue had a comparable product ratio (38:62, entry 5). The
reaction of a furanyl alkynoate precursor in DMF achieved fair
selectivity for the dihydroaromatic product in low yield (entry 6).
Mild selectivity for the dihydroaromatic product and low yield
was observed for the reaction of a pyrrole alkynoate precursor in
DMF at 150 °C (entry 7). Changing the solvent to o-DCB and
raising the temperature to 180 °C gave complete selectivity for
the dihydroindole and a slightly improved yield (entry 8).
Decreasing the concentration to 0.03 M and raising the reaction
temperature to 225 °C maintained exclusive selectivity for the
dihydroindole while significantly improving the yield to 75%
(entry 9). High reaction temperatures were required to drive the
reaction to completion and circumvent decomposition of the
starting material. In contrast, reaction of a pyrrole precursor
containing an alkynone tether afforded exclusively the
dihydroindole in 95% yield (entry 10).
Using the conditions described within, the IMDDA reaction
provides a useful alternative route to thiophene-yl and pyrrolyl
systems. While the product selectivities for the furanyl
heterocycles are high, the yields for these transformations are
lower than for the thiophene-yl and pyrrolyl systems. For most
cases examined, product selectivity is controlled by the IMDDA
reaction conditions, as predicted by previous studies in our
laboratory on naphthalenes and dihydronaphthalenes. However,
the heterocyclic substrates also play a role in product selectivities,
showing different propensities to form the dihydroaromatic and
aromatic products as compared to the corresponding styrenyl
substrates.12,18 The thiophene substrates give better selectivity
for the aromatic product than the pyrrole compounds. On the
other hand, the pyrrole precursors selectively deliver dihydroar-
omatic products at relatively low temperatures and in higher
yields. Yields for C2-substituted IMDDA reactions are margin-
ally higher than for the analogous C3-substituted heterocycles,
although the reaction times are consistent where comparable.
The substituent on the terminus of the alkyne markedly affects
the yield of the IMDDA reaction, with phenyl-substituted
alkynes affording higher yields than the silyl- or alkyl-substituted
examples.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kbrummon@pitt.edu.
ORCID
Kay M. Brummond: 0000-0003-3595-6806
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the NSF (CHE-1465032) for financial
support.
■
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ASSOCIATED CONTENT
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