Three-Component Cascade Reactions with 2,3-Diketoesters: A Novel Metal-Free Synthesis of 5-Vinyl-pyrrole and 4-Hydroxy-indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b01855

5-Vinyl-pyrrole and 4-hydroxy-indole derivatives are synthesized by metal-free aldol/cyclization/aromatization cascade reactions of in situ generated enamines with 2,3-diketoesters. This convenient atom-economical process produces multifunctional pyrrole and indole products in moderate to good yields.

Full text of DOI:10.1021/acs.orglett.5b01855

Letter
pubs.acs.org/OrgLett
Three-Component Cascade Reactions with 2,3-Diketoesters: A Novel
Metal-Free Synthesis of 5‑Vinyl-pyrrole and 4‑Hydroxy-indole
Derivatives
Qiang Sha,†,‡ Hadi Arman,‡ and Michael P. Doyle*,‡
†School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, 210094, P. R. of China
‡Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: 5-Vinyl-pyrrole and 4-hydroxy-indole derivatives are synthesized by metal-free aldol/cyclization/aromatization
cascade reactions of in situ generated enamines with 2,3-diketoesters. This convenient atom-economical process produces
multifunctional pyrrole and indole products in moderate to good yields.
Scheme 1. General Routes towards Pyrroles or Indoles
Involving Enamine Formation
yrroles and indoles are two of the most abundant classes of
Pheterocycles found in natural products and pharmaceut-
icals.1 Extensive methods have been developed for their synthesis
and further modification,2 and those that employ enamines have
played a prominent role. Three general routes involving enamine
formation exemplify those that have been developed for their
synthesis: (1) multicomponent enamine reactions with ketones
and amines that form pyrroles via condensation reactions
(Scheme 1, eq 1);3 (2) metal-catalyzed cycloaddition reactions of
stable enamines with alkynes or vicinal diols (Scheme 1, eq 2);4
and (3) the synthesis of pyrroles or indoles by intramolecular
cyclization reactions in the presence of a catalyst and oxidant
during which C−H activation occurs (Scheme 1, eq 3).5
Individually, these methods have their unique advantages, and
they complement each other to broaden applications for pyrrole
and indole synthesis. However, their shortcomings, such as a
narrow substrate scope and the use of heavy metal catalysts, are
also obvious, and they suggest the need for new methods to
prepare functionalized pyrroles.
Vicinal tricarbonyl (VTC) compounds are important
intermediates for organic synthesis. The pioneering work by
Wasserman and co-workers provided examples demonstrating
wide applications of VTCs in the synthesis of natural products
and synthetic intermediates.6 Lash and co-workers have used
them in the synthesis of pyrrole derivatives.7 Our group has
applied them to synthesize highly functionalized furans8 and 3-
aminopyrroles.9
carbon of VTC compounds. The highly active nature of the
middle carbonyl group makes them very receptive to participate
in many kinds of nucleophilic addition reactions.12 During our
We also reported the first diastereoselective10 and enantiose-
lective11 nucleophilic addition reactions that occur at the central
Received: June 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01855
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Organic Letters
Letter
attempts to combine VTC chemistry with aldol chemistry by
generating enamines in situ, we uncovered a novel three-
component cascade methodology for the synthesis of 5-vinyl-
pyrrole and 4-hydroxy-indole derivatives. This methodology
includes tandem aldol condensation, cyclization, and dehydra-
tion/aromatization (Scheme 1, eq 4).
We have previously reported that 2,3-diketoesters are
conveniently formed by oxidation of the corresponding α-
diazo-β-ketoesters,8−11 and there are multiple methods that
directly access these diazo compounds. 2,3-Diketoesters exist as
monohydrates, the dehydration of which can be achieved by
gentle warming under reduced pressure. However, although use
of the hydrate of VTCs decreases the reaction rate of subsequent
reactions, convenience in handling VTC hydrates makes them
the primary target for investigation. Initially, we chose 2,2-
dihydroxy-3-oxobutanoate (1a), aniline (2a), and cyclohexanone
(3a) as starting materials to examine pyrrole formation. The
reaction was performed at 65 °C for 24 h using THF as the
solvent, and 5-vinyl-pyrrole 4a was obtained, albeit in only 21%
yield (Table 1, entry 1). Although these reaction conditions gave
benzoic acid gave 4a in the highest yield (Table 1, entry 13).
Performing this reaction under the optimized conditions at
temperatures lower or higher than 65 °C significantly decreased
the yield of 4a (Table 1, entries 17−18).
With the optimal reaction conditions in hand, we investigated
the substrate scope with various 2,3-diketoesters and aliphatic
monoketones (Scheme 2). Two representative 2,3-diketoesters
Scheme 2. Substrate Scope of Three-Component Reactions of
a
2,3-Diketoesters with Aniline and Aliphatic Monoketones
Table 1. Optimization of Three-Component Reaction of
Benzyl 2,2-Dihydroxy-3-oxobutanoate with Aniline and
a
Cyclohexanone
a
Reaction conditions: 1 (0.20 mmol), 2a (0.22 mmol), 3 (0.40 mmol),
benzoic acid (0.04 mmol), toluene (1 mL), 65 °C, 36 or 60 h; yields
b
refer to isolated yields. 110 °C for 16 h.
were investigated (R1 = Me, Ph). Good yields were obtained by
using different ester groups (Scheme 2, 4a−4c) and with cyclic
monoketones having ring sizes of six or larger (Scheme 2, 4f−4j).
However, when cyclopentanone was used, the desired product
was obtained in only 10% yield; the sharp drop in yield may be
due to ring tension of the five-membered ring which made the
cyclization reaction less competitive (Scheme 2, 4e).4b,7b Also
dihydro-2H-thiopyran-4(3H)-one gave 4i in 28% yield. Interest-
ingly, 3-pentanone gave 4u in 53% yield, but a higher
temperature (refluxing toluene) was required to make this
reaction occur smoothly.
Various anilines were used for the formation of 4 to evaluate
their electronic influences in the three-component process.
Halide substituted anilines gave 5-vinyl-pyrroles in moderate to
good yields (Scheme 3, 4k−4n), but strong electron-donating
groups obviously favored the process. Anilines with electron-
donating methoxy, methyl, or aryl groups either in the ortho or
para positions gave 4 in good yields (Scheme 3, 4i−4l).
However, anilines with electron-withdrawing groups on the
phenyl ring gave the pyrrole derivatives in only moderate yield
(Scheme 2, 4s−4t). The use of an aliphatic amine further
demonstrates the generality of this methodology (Scheme 3, 4u).
The structure of 5-vinyl-pyrrole product 4m was confirmed by X-
ray diffraction analysis.13 In gram scale syntheses of 4m we
obtained the same yield as in the small scale reaction, suggesting
the potential of this process for large scale production.
a
b
yield
entry
solvent
additive
temp
1
THF
−
−
−
−
−
−
−
−
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
65 °C
rt
21
2
toluene
methanol
DCM
35
3
8
4
20
5
DCE
21
6
CHCl3
MeCN
Et2O
32
7
12
8
36
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
TFA
trace
16
d
10
11
12
13
14
15
16
17
18
PTSA
Zn(OTf)2
Et3N
trace
trace
c
benzoic acid
57(55 )
49
4-isopropylbenzoic acid
4-nitrobenzoic acid
(CF3)2CHOH
42
41
benzoic acid
trace
30
benzoic acid
110 °C
a
Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), 3a (0.20
mmol), additive (0.02 mmol), at indicated temperature for 24 h.
b
Yield was determined by 1H NMR spectroscopy of the reaction
c
mixture using CH2I2 as internal standard. Isolated yield, average of
two runs. PTSA refers to p-toluenesulfonic acid.
d
a mixture of unidentified materials in addition to 4a, we were
encouraged with the potential synthetic efficiency of this three-
component reaction. Attempted optimization by changing the
solvent (Table 1, entries 2−8) identified toluene as the best with
4a formed in 35% yield (Table 1, entry 2). Sensing that acid or
base catalyst might increase the product yield, Bronsted acids,
zinc triflate as a representative of a Lewis acid, and triethylamine
were used as additives (Table 1, entries 9−16). Of these additives
To exemplify the ease with which these pyrrole products can
be converted to indoles, we used one reported procedure to
perform the indole formation reaction by using 4m as starting
material (Scheme 4). By using a Pd/C as catalyst and acetic acid
as solvent,14 4m′ was obtained in 56% yield without
optimization.
With the observed generality of this methodology for 5-vinyl-
pyrrole formation with aliphatic monoketones, the use of
B
DOI: 10.1021/acs.orglett.5b01855
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Organic Letters
Letter
Scheme 3. Substrate Scope of Three-Component Reactions of
Ethyl 2,2-Dihydroxy-3-oxo-3-phenylpropanoate 1d with
Substituted Anilines and Cyclohexanone 3a
Scheme 5. Substrate Scope of Three-Component Reactions of
2,3-Diketoesters with Anilines and 1,3-Cyclohexanediones
a
a
a
Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), 5 (0.40 mmol),
TFA (0.02 mmol), DCE (1 mL), 65 °C, 16 h; yields refer to isolated
product yields.
Scheme 6. Studies on the Reaction Mechanism
a
Reaction conditions: 1d (0.20 mmol), 2 (0.22 mmol), 3a (0.40
mmol), benzoic acid (0.04 mmol), toluene (1 mL), 65 °C, 36 h; yields
b
refer to isolated yields. 4 mmol scale.
Scheme 4. Oxidative Aromatization of 4m
a
Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), benzoic acid
(0.04 mmol), toluene (1 mL), 65 °C, 3 h; then 3a (0.4 mmol), 65 °C,
b
36 h. Reaction conditions: 3a (0.40 mmol), 2a (0.22 mmol), benzoic
acid (0.04 mmol), toluene (1 mL), 65 °C, 3 h; then 2a (0.20 mmol),
65°C, 36 h. Reaction conditions: 1a (1.50 mmol), 3a (3.0 mmol), L-
aliphatic 1,3-diketones was investigated. We envisioned that 1,3-
diketones could form 4-hydroxyindole derivatives following
aromatization. We chose 2,2-dihydroxy-3-oxobutanoate (1a, R1
= Me), aniline (2a), and 1,3-cyclohexanedione (5a) as a model
system to study this reaction. However, the desired indole
product 6a was obtained in only 6% yield by using the optimized
reaction conditions employed for the synthesis of 5-vinyl-pyrrole
derivatives in Table 1 (Scheme 5, 6a). The reaction conditions
for this transformation were optimized,14 and after screening of
various solvents and additives, we obtained 4-hydroxyindole 6a
in 53% yield by using trifluoroacetic acid as an additive and 1,2-
dichloroethane as solvent. We then investigated other substrates
to reveal the broad applications of this reaction (Scheme 5, 6b−
6f). Similar to observations of reactivities of anilines in 5-vinyl-
pyrrole forming reactions, anilines with electron-donating groups
were favored in this transformation.
To better understand the mechanistic pathway of this complex
transformation we focused on addressing the site at which imine
formation first occurred. Reaction with either the 2,3-diketoester
or the cyclohexanone is possible, and we examined each by (1)
first combining 1a with aniline and then adding cyclohexanone
(4a was formed in less than 10% yield) and (2) first combining
cyclohexanone with aniline at 65 °C and then adding 2,3-
diketoester 1a (4a was formed in 58% yield) (Scheme 6). These
c
proline (0.30 mmol), DCM (10 mL), rt, 24 h; then 7 (0.10 mmol), 2a
(0.11 mmol), benzoic acid (0.02 mmol), toluene (0.5 mL), 65 °C, 24
d
h. Isolated yield; dr was determined by 1H NMR spectroscopy.
e
1
Yields were determined by H NMR using CH2I2 as the internal
standard.
results show that condensation of cyclohexanone with aniline
occurs initially after which aldol condensation and subsequent
reactions occurred to form the pyrrole product. Independently,
the aldol condensation product formed between 2,3-diketoester
1a and cyclohexanone formed 4a in 70% yield when treated with
aniline under optimized conditions employed in Table 1 (see (3)
in Scheme 6).
Based on these observations, we propose that enamine
formation from cyclohexanone preceeds aldol condensation
with the dehydrated 2,3-diketoester to form enamine A (Scheme
7). Cyclization by condensation of A with the keto group at the 3-
position forms B. Acid promoted loss of water (B to C) and
dehydration by 1,4-elimination (C to D) result in aromatization
that with proton transfer forms 5-vinyl-pyrrole products (E).
In summary, we have reported a new, efficient, and
straightforward methodology for the synthesis of 5-vinyl-
C
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
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General experimental procedures, the X-ray structure of 4m, and
spectroscopic data for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01855.
AUTHOR INFORMATION
Corresponding Author
■
(8) Truong, P.; Xu, X. F.; Doyle, M. P. Tetrahedron Lett. 2011, 52,
2093−2096.
*E-mail: michael.doyle@utsa.edu.
Notes
(9) Truong, P.; Mandler, M. D.; Doyle, M. P. Tetrahedron Lett. 2015,
56, 3042−3045.
The authors declare no competing financial interest.
(10) Truong, P.; Shanahan, C. S.; Doyle, M. P. Org. Lett. 2012, 14,
3608−3611.
ACKNOWLEDGMENTS
■
(11) Truong, P.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem. 2014, 126,
6586−6590.
Q.S. acknowledges China Scholarship Council (CSC) for its
financial support. We acknowledge the U.S. National Science
Foundation and the University of Texas at San Antonio for
supporting this research.
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DOI: 10.1021/acs.orglett.5b01855
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