Br?nsted Acid-Catalyzed Formal [2 + 2 + 1] Annulation for the Modular Synthesis of Tetrahydroindoles and Tetrahydrocyclopenta[ b]pyrroles

Article abstract of DOI:10.1021/acs.orglett.9b01032

An expedient synthesis of tetrahydroindoles and tetrahydrocyclopenta[b]pyrroles, highlighted by Br?nsted acid catalyzed formal [2 + 2 + 1] annulation reaction, is reported. Using three readily accessible reaction components, i.e., an electrophilic species in silyloxyallyl cations and two distinct nucleophiles in silylenol ethers and amines, our chemistry enables the assembly and functionalization of these biologically important N-heterocycles in a highly modular manner.

Full text of DOI:10.1021/acs.orglett.9b01032

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Acid-Catalyzed Formal [2 + 2 + 1] Annulation for the
Modular Synthesis of Tetrahydroindoles and
Tetrahydrocyclopenta[b]pyrroles
Joshua A. Malone, Courtney E. Toussel, Frank R. Fronczek, and Rendy Kartika*
Department of Chemistry, 232 Choppin Hall, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: An expedient synthesis of tetrahydroindoles and
tetrahydrocyclopenta[b]pyrroles, highlighted by Brønsted acid
catalyzed formal [2 + 2 + 1] annulation reaction, is reported.
Using three readily accessible reaction components, i.e., an
electrophilic species in silyloxyallyl cations and two distinct
nucleophiles in silylenol ethers and amines, our chemistry enables
the assembly and functionalization of these biologically important N-heterocycles in a highly modular manner.
Scheme 1. Synthetic Methods to Access Tetrahydroindoles
and Tetrahydrocyclopenta[b]pyrroles
etrahydroindoles and tetrahydrocyclopenta[b]pyrroles
are a class of nitrogen-containing heterocycles of
T
biological importance.1 Exemplified in compounds 1a to 1c,
these molecular structures are pharmacophores in molecules
that serve as an anti-inflammatory agent,1a or inhibitors for
cyclooxygenase 2,1b and Src tyrosine kinase.1c It has also been
reported that tetrahydroindole 1d exhibits selective dopami-
nergic activities.1d Natural products, such as microindolinone
A and (+)-roseophilin,2 also possess these ring motifs as a key
feature to their architectures. Due to their biological contexts,
the development of synthetic reactions that readily assemble
tetrahydroindoles and tetrahydrocyclopenta[b]pyrroles re-
mains an important synthetic endeavor.3 Scheme 1 illustrates
recent advancements. Kurkin reported a solvent-free approach
to tetrahydroindole core 2b, which was achieved via heat-
induced 5-endo-dig cyclization of amino propargylic alcohols
2a.3c,d Unlike tetrahydroindoles, literature precedents on the
construction of tetrahydrocyclopenta[b]pyrroles are scarce.4
One of which was reported by Zhang who demonstrated that
exposure of alkyne diols 3a to catalytic PPh3AuCl and AgOTf
in the presence of amines produced tetrahydrocyclopenta[b]-
pyrrole 3b, which occurred via Meyer−Schuster rearrangement
and Paal−Knorr cyclization cascade.4a
Combined with the use of expensive organometallic catalysts
to induce ring formation, many of the elegant chemistries to
construct tetrahydroindoles and tetrahydrocyclopenta[b]-
pyrroles rely on linear preconstruction of the substrates prior
to cyclization. These strategies are at a disadvantage in terms of
enabling the introduction of a vast array of functionalities to
these rings in an expedient manner, a practice that is essential
in drug discovery.5 Herein we describe our approach toward
broadly substituted tetrahydroindoles and tetrahydro-
cyclopenta[b]pyrroles, which will be enabled by two distinct
nucleophiles in silylenol ethers and primary amines, and an
electrophile in silyloxyallyl cations that will be generated in situ
upon ionization of α-hydroxy silylenol ether 4a. Catalyzed by
Brønsted acid,6,7 these three simple modular components
should readily undergo a formal [2 + 2 + 1] annulation
reaction as represented in framework 4f. Our rationale is as
Received: March 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01032
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Organic Letters
Letter
follows. The regioselective interception of silyloxyallyl cations
4b with silylenol ether should create a new C−C connectivity
in the resulting γ-keto silylenol ether 4c.7 The ensuing
protodesilylation under the Brønsted acidic conditions will
produce 1,4-diketone 4d. In the presence of primary amine, the
Paal-Knorr condensation should occur,8 thus completing our
synthesis of tetrahydroindole and tetrahydrocyclopenta[b]-
pyrrole motifs 4e.
Nonetheless, the efficiency of Paal-Knorr condensation
diminished dramatically without heat (entry 9). Overall, our
optimized conditions are as follows: ensuing the coupling
between α′-hydroxy silylenol ether 5 and 2.0 equiv of silylenol
ether 6 promoted by 0.2 equiv of pyridinium triflate in
acetonitrile at room temperature, 0.3 equiv of tosic acid
monohydrate was introduced to induce protodesilylation. After
the addition of 4.0 equiv of propylamine, the mixture was
warmed to reflux, furnishing tetrahydrocyclopenta[b]pyrrole 7
in 83% yields in just 5 h of total reaction time.
Our proof-of-concept and reaction optimization is summar-
ized in Table 1,9 in which α′-hydroxy silylenol ether 5,
To identify the scope of our method, we began by screening
the applicability of various primary amines (Scheme 2). In
Table 1. Reaction Optimization
Scheme 2. Scope of Amines
a
additive
equiv.
PrNH2
equiv.
total reaction time
(h)
yield
(%)
entry additive
1
2
3
4
5
6
7
8
9
-
-
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
4.0
168
96
4
8
6
5
8
7
192
77
74
62
82
83
83
77
75
PPTS
TfOH
CSA
TsOH
TsOH
TsOH
TsOH
TsOH
0.5
0.5
0.5
0.5
0.3
0.2
0.3
0.3
b
56
a
b
Isolated yield after column chromatography. Reaction was
performed at room temperature.
acetophenone-derived silylenol ether 6, and propylamine were
employed as model substrates. As shown in entry 1, we began
by subjecting compounds 5 and 6 to catalytic pyridinium
triflate in acetonitrile at room temperature to allow formation
of the key monosilylated 1,4-diketone construct in a
regioselective manner.7a Excess propylamine was then added
to the mixture after complete consumption of α′-hydroxy
silylenol ether 5 and the ensuing protodesilylation as easily
monitored by TLC, and the reaction was then warmed to
reflux. Interestingly, this pilot experiment indeed led to the
formation tetrahydrocyclopenta-[b]pyrrole 7, which was
isolated in 77% yield after 7 days of reaction time. We noted
while the coupling of α′-hydroxy silylenol ether 5 with silylenol
ether 6 concluded in just approximately 1 h, the rate-
determining steps in these initial conditions appeared to be
controlled by protodesilylation of the forming γ-keto silylenol
ether.
Following this initial result, we focused our efforts to
improve the protodesilylation sequence with a notion that the
efficiency of this step could be affected by an introduction of
an additive, such as a secondary Brønsted acid catalyst. As
shown in entries 2−5, our hypothesis was tested through the
screening of pyridinium tosylate, triflic acid, camphorsulfonic
acid, and tosic acid monohydrate. These additives were added
in the amount of 0.5 mol equiv after completion of the
preceding reaction between α′-hydroxy silylenol ether 5 and
silylenol ether 6, but before the addition of propylamine.
Indeed, the addition of stronger Brønsted acids substantially
enhanced the rate of protodesilylation. To this end, we
ultimately chose tosic acid. Entries 5−8 indicate that the molar
amount of tosic acid or propylamine could be further reduced
without notably affecting the robustness of the reaction.
a
Isolated yield after column chromatography.
these studies, both 5- and 6-membered α-hydroxy silylenol
ethers 5 and 8 were employed to furnish a diverse library of N-
substituted tetrahydrocyclopenta[b]pyrrole and tetrahydroin-
dole 7 and 9, respectively. Commencing with aniline and its
derivatives, i.e., 4-trifluoromethylaniline, 4-aminoacetophe-
none, and 4-methoxy-aniline, our reaction successfully
produced the corresponding adducts 7a−7d and 9a−9d in
good yields. Interestingly, the use of ammonia as the Paal-
Knorr reactant furnished unprotected N-heterocyclic core 7e
and 9e in 84% and 56% yields, respectively. Cyclopropylamine,
propylamine, allylamine, and benzylamine were tolerated by
our reaction conditions. These aliphatic amines furnished the
corresponding tetrahydrocyclopenta[b]pyrrole 7f−7i and
tetrahydroindole 9f−9i again in excellent yields within several
hours of reaction time. We also subjected neurotransmitter
tryptamine, which produced tethered heterocyclic motifs 7j
and 9j in 84% and 70% yields, respectively. Compounds 7j and
9a existed in the crystalline form, allowing us to assign their
structure by X-ray diffraction.10 Interestingly, these experi-
ments revealed formation of 6-membered tetrahydroindole 9
B
DOI: 10.1021/acs.orglett.9b01032
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Organic Letters
Letter
was generally lower yielding than that of its 5-membered
counterpart 7. This phenomenon is most likely stemmed from
challenges associated with the generation of 6-membered
silyloxyallyl cations from the corresponding α′-hydroxy
silylenol ether 5.11
Our investigation continued with substituent effects at the α-
carbon. In this study, we employed a series of secondary α′-
hydroxy silylenol ethers 10 and 11 in the presence of silylenol
ether 6 and aniline as coupling partners. Schemes 3 and 4
explored linear n-octyl chain as well as branched isobutyl and
cyclohexyl groups. Interestingly, steric effects did not play
significant role, as the resulting 5-membered products 12e−
12g and 6-membered products 13e and 13g were all isolated in
high yields. We also observed that several of the 6-membered
substrates required a higher loading of silylenol ether 6 to
improve the rate of the initial coupling reaction. Due to their
crystalline form, we were able to confirm the structures of 13b
and 13g by X-ray diffraction.10
Our previous studies revealed that unsymmetrical silylox-
yallyl cations could be effectively generated from tertiary α-
hydroxy silylenol ethers.6 To examine the utility of this
alternate substrate motif in this chemistry, we subjected a
series of 5-membered starting materials 14 that were
elaborated with identical aromatic and aliphatic substituents
at the α-carbon to those of substrates 10. Indeed, exposure of
these compounds to our method furnished target products
12b−12g. Nonetheless, a substantial attrition in the product
yields was observed, as these substrates could not be fully
consumed despite the prolonged reaction time. We suspected
that the underlying cause for this phenomenon lay in the steric
barrier imposed by the tertiary alcohols, therefore slowing the
rate of ionization and ultimately prompting competitive
quenching of the catalyst by either silylenol ether 6 or α-
hydroxy silylenol ethers 14 via protodesilylation.
Scheme 3. Substituent Effects
Using both 5-membered and 6-membered substrates 5 and 8
and propylamine as the coupling partners, we then varied
silylenol ethers 15 to demonstrate our ability to expediently
diversify the C2 and C3 positions of tetrahydrocyclopenta[b]-
pyrrole 16 and tetrahydroindole 17 (Table 2). Interestingly,
we identified in some 6-membered systems that protodesily-
lation of the resulting γ-keto silylenol ether constructs
unexpectedly led to concomitant intramolecular cyclization,
prior to addition of propylamine, therefore affording
tetrahydrobenzofuran byproducts. To circumvent this un-
desired furan annulation, we produced an alternate set of
protodesilylation conditions to unmask the 1,4-diketone motif
using CsF at reflux (Conditions B).9 This protocol was
followed by addition of TsOH and propylamine to affect the
Paal-Knorr condensation.
a
b
Isolated yield after column chromatography. The reaction was
performed in 0.2 M concentration using 4.0 equiv of silylenol ether 6.
c
3.0 equiv of silylenol ether 6 was employed.
a
Scheme 4. Alternate Substrates
With the two complementary conditions in hand, we
subjected acetophenone-derived silylenol ethers bearing
electronically opposing trifluoromethyl and methoxy groups
(entries 1 and 2), revealing that the electron-deficient group
appeared to be less robust. Our method allows for
simultaneous incorporation of functional groups at the C2
and C3 positions of the forming heterocycles. For instance, α-
tetralone and cyclohexanone derived silylenolates were found
to be compatible to furnish their respective polycyclic adducts
16c and 16d as well as 17c and 17d in good yields. As shown
in entry 5, we employed a highly substituted silylenol ether that
was prepared from 3-pentanone. This nucleophile selectively
introduced C2-ethyl and C3-methyl substituents in products
16e and 17e with 50% and 54% isolated yields, respectively. A
similar observation was noted when 2-phenylacetophenone
derived silylenol ether nucleophile was applied to our reaction
(entry 6). In this case, the resulting tetrahydrocyclopenta[b]-
pyrrole 16f and tetrahydroindole 17f, both of which were
decorated with two phenyl groups at the pyrrole moiety, were
isolated in good yields. Finally, we attempted to elaborate
exclusively on the C3 position using phenylacetaldehyde
derived nucleophile (entry 7). While the resulting annulation
product 16g was accessible from 5-membered substrate 5 in
a
[a]Isolated yield after column chromatography. [b]3.0 equiv of
silylenol ether 7 was employed.
depict our results, starting with the use of unsubstituted α′-
hydroxy silylenol ethers, which led to products 12a and 13a,
however in poor yields due to decomposition of materials
under the reaction conditions. Nonetheless, our method was
tolerated by both aromatic and aliphatic substituents at the α-
carbon. For instance, arene-bearing substrates, such as phenyl,
toluoyl, and p-chlorophenyl, readily afforded tetrahydro-
cyclopenta[b]pyrrole 12b−12d and tetrahydroindole 13b−
13d in high yields. A slower rate of reaction and diminishing
yield of the products involving chlorine-containing starting
materials was noted. With respect to the aliphatic variants, we
C
DOI: 10.1021/acs.orglett.9b01032
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Accession Codes
Table 2. Scope of Silylenol Ethers
CCDC 1894940−1894943 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rkartika@lsu.edu.
ORCID
Frank R. Fronczek: 0000-0001-5544-2779
Rendy Kartika: 0000-0002-2042-2812
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R01GM127649.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health. Generous financial supports from
Louisiana Board of Regents RCS One-Year Program
(LEQSF(2017-18)-RD-A-05) and Louisiana State University
are gratefully acknowledged. This work is dedicated to Prof.
George G. Stanley on the occasion of his retirement from
Louisiana State University.
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Isolated yield after column chromatography. Substrate 8 was not
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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