Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N-Sulfonyl-1,2,3-triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and Pyrrole-Fused Polycyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.7b00180

An efficient synthesis of tetrahydrocarboline-type products and polycyclic spiroindolines has been achieved. The transformation proceeds via rhodium(II)-catalyzed intramolecular annulations of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles. The reaction could be tuned toward either the formal [3 + 2] cycloaddition or the C-H functionalization reaction depending on the electronic and structural features of the substrates, leading to the production of a variety of structurally related heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.7b00180

Letter
pubs.acs.org/OrgLett
Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N‑Sulfonyl-
1,2,3-triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and
Pyrrole-Fused Polycyclic Compounds
Liangbing Fu and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: An efficient synthesis of tetrahydrocarboline-
type products and polycyclic spiroindolines has been achieved.
The transformation proceeds via rhodium(II)-catalyzed intra-
molecular annulations of indolyl- and pyrrolyl-tethered N-
sulfonyl-1,2,3-triazoles. The reaction could be tuned toward
either the formal [3 + 2] cycloaddition or the C−H
functionalization reaction depending on the electronic and
structural features of the substrates, leading to the production of a variety of structurally related heterocyclic compounds.
itrogen-containing heterocycles are commonly embedded
within polycyclic frameworks, among which polycyclic
of 3-substituted indoles with 4-aryl-N-sulfonyl-1,2,3-triazoles
N
(Scheme 1, A).4b Here we describe the intramolecular version of
spiroindolines,1 azepino[4,5-b]indoles,2 and β-carbolines3 are of
significant importance because of their wide presence in complex
natural products and biologically active compounds (Figure 1).
Scheme 1. Rhodium-Catalyzed Annulation of Indoles
Figure 1. Spiroindoline- and β-carboline-containing natural products.
As a result, a variety of methods have been developed to
synthesize these classes of compounds.4−6 However, direct,
simple, and effective approaches for their synthesis still remain
relatively challenging, and the development of general and
divergent methods for their synthesis would be desirable.
The chemistry of rhodium-stabilized donor/acceptor carbenes
has long been a central theme of research in our group.
Traditionally, diazo compounds have been most commonly used
as the carbene precursors.7 Gevorgyan and Fokin showed that N-
sulfonyl-1,2,3-triazoles are capable of undergoing ring-to-chain
isomerization to expose the diazo moiety.8 As a result, these
reagents can act as masked diazo compounds and serve as an
alternative source of carbene precursors.9 Since these initial
reports, several groups have demonstrated the utilitiy of triazoles
as carbene precursors for the development of useful trans-
formations,10 including transannulation reactions for the direct
synthesis of heterocycles.11
this reaction with indoles and pyrroles (Scheme 1, B). During
preparation of this manuscript, a related study was reported by
Shi and co-workers in which polycyclic pyrroloindolines and
azepino[4,5-b]indoles could be formed in intramolecular
reactions of indolyltriazoles (Scheme 1, C).12 Our study goes
beyond the Shi study and shows that the transformation has
broader scope and flexibility: in addition to azepino[4,5-
b]indoles, tetrahydrocarbolines and a range of polycyclic
spiroindolines with different ring sizes and tether groups could
Previously, we developed an enantioselective synthesis of
pyrroloindolines via intermolecular formal [3 + 2] cycloaddition
Received: January 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00180
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Letter
also be generated. Furthermore, pyrrolyltriazoles were demon-
strated to be viable substrates.
Scheme 2. Substrate Scope for the Intramolecular Formal C−
H Functionalization with N-Sulfonyl-1,2,3-triazoles
The optimum conditions for the proposed reaction were
determined using a tethered-indolyl triazole 1a as the model
substrate. The Rh2(OOct)4-catalyzed reaction of 1a in 1,2-
dichloroethane (DCE) at 80 °C gave a Z/E mixture of the
annulated products, which were subsequently reduced with
NaBH3CN in a one-pot fashion to give the sulfonamide 2a in
81% yield (Figure 2, entry 1).10e A series of achiral dirhodium
a
b
The products were not reduced with NaBH3CN. Combined yield of
two isomers.
Figure 2. Optimization of reaction conditions for tetrahydrocarboline
formation.
products in excellent yield (2f,g). The flexibility of the
transformation was further demonstrated by using substrates
with the tethers at C(2), and the product containing β-
tetrahydrocarboline and β-azepine derivatives could be efficiently
synthesized (2h,i).
catalysts and solvents were examined, and the combination of
Rh2(OOct)4 and DCE was found to be the optimal combination
(entry 1). Specifically, other achiral catalysts such as Rh2(TPA)4,
Rh2(Piv)4, Rh2(OAc)4, and Rh2(esp)2 (Figure 3) proved to be
When an N-methyl-homologated substrate 3a was used, the
formal C−H functionalization product was not obtained (Figure
4). Instead, only spiro compound 4a derived from formal
Figure 3. Dirhodium carboxylate catalysts used in this study.
less effective compared to Rh2(OOct)4 (entries 2−5). A solvent
screen (entries 6−8) revealed that nonpolar solvents such as
toluene and c-hexane were less effective for the system. Another
chlorinated solvent chloroform was also a reasonably effective
solvent in the reaction, though not as efficient as DCE.
The substrate scope for this transformation was then examined
under the optimized reaction conditions, and a variety of
carboline-type products could be synthesized (Scheme 2). The
reaction of methoxy derivative 1b generated the tetrahydro-
carboline 2b. Similar to Shi’s observation,12 the homologated and
NH-unprotected substrates 1c−e gave the formal C−H
functionalization products azepino[4,5-b]indoles (2c−e). Inter-
estingly, substrate 1d with an electron-withdrawing bromo
substituent gave exclusively tetrahydrocarboline 2d, whereas
substrate 1e with an electron-donating methyl group at the 5-
position gave a mixture of the spiroindoline and tetrahydrocarbo-
line products (2e and 2e′). Our studies further show that the
transformation could be extended to substrates beyond the
indolyl structure explored by Shi.12 The reactions of pyrrole-
tethered triazoles gave the desired formal C−H functionalization
tetrahydropyrrolopyridine and tetrahydropyrrolo[2,3-d]azepine
Figure 4. Optimization of reaction conditions for spiroindoline
formation.
intramolecular [3 + 2] cycloaddition was observed in 62% yield.
This behavior was also observed by Shi and co-workers.12 The
efficiency of the reaction was found to be dependent on the
nature of dirhodium catalyst and the solvent. Interestingly, ethyl
acetate was found to be the optimal solvent for the trans-
formation (entries 2−5). After systematic exploration of the
dirhodium catalysts for the reaction, Rh2(OOct)4 was found to
be optimal among all of the achiral catalysts (entries 6−8) but
B
DOI: 10.1021/acs.orglett.7b00180
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Letter
inferior to the chiral catalyst Rh2(S-PTTL)4.13 The best
conditions described by Shi were Rh2(S-PTTL)4 as the catalyst
and c-hex/DCM as a solvent mixture.12 Our results showed that
ethyl acetate was a superior solvent for the reaction (87% vs 66%
yield). The diastereoselectivity was routinely high (>19:1), but
the chiral catalysts all gave relatively low levels of enantiose-
lectivity (up to 31% ee with Rh2(S-PTTL)4).
membered ring product 4p was obtained in decreased yield. The
substituent on the indole nitrogen has significant influence on
the reactivity: the reaction of N-Boc substituted substrate gave a
complex mixture, and the desired product was not observed.
The reaction with an ester-tethered substrate 5 led to an
unexpected result (Scheme 4). Only a trace amount of the
Having established the optimal conditions for the trans-
formation, the scope of this reaction was subsequently explored
and was found to be very general (Scheme 3). Similar to Shi’s
Scheme 4. Test of Substrate with an Ester as the Tether
Scheme 3. Substrate Scope of the Intramolecular [3 + 2]
Annulation
1
desired product was observed on the basis of crude H NMR
analysis. Instead, product 7 proposed to be derived from
rearrangement of the zwitterionic intermediate 6 generated by
nucleophilic attack of the oxygen lone pair of the ester toward the
electrophilic rhodium carbene was formed in nearly quantitative
yield.
Plausible mechanistic pathways are outlined in Scheme 5. Shi
and co-workers proposed that when the indole substrates were
Scheme 5. Proposed Mechanistic Pathways
a
Formation of byproduct derived from 1,2-hydride shift was observed.
Performed at 120 °C.
b
observations,12 variation of sulfonyl groups on either the
tethering nitrogen atom or the triazole moiety and substitutions
on the indole ring were well tolerated (3a−l). The optimized
conditions used in our system (Rh2(S-PTTL)4/EtOAc) gave
similar but generally improved yields compared to Shi’s system
(70−93% (average 82%) vs 53−92% (average 73%) yields).
Specifically, a variety of sulfonyl groups on the triazole ring
including mesyl, isopropylsulfonyl, tosyl, and p-chlorobenzene-
sulfonyl were all tolerated (4a−d). Furthermore, reactions of
substrates with different sulfonyl groups on the tether, X = NTs,
NMes, and NBs, all proceeded smoothly to afford the
corresponding products (4a, 4e, and 4f). Different types of
substitutions on the indole ring were tolerated, and the desired
products were obtained in good to excellent yields regardless of
the electronic nature of the substitutions (4g−l).14 Our
exploration also demonstrated that the transformation could be
extended to more diverse substrates. Tethering groups other
than nitrogen were examined: carbon-tethered substrate gave the
desired product in good yield (4m); the oxygen-tethered
analogue gave lower yield, with the observation of an undesired
1,2-hydride shift byproduct (4n); and a similar 1,2-hydride shift
was observed by Shi and co-workers12 in their intramolecular
annulations. The position of the nitrogen tether could be moved
closer to the indole ring (4o). Substrate 3p with the tether
homologated by one carbon also reacted, even though higher
temperature was required for this transformation, and the 7-
protected by an alkyl group, cyclopropanation of the indole
double bond followed by ring expansion gave the formal
cycloaddition products.12 Alternatively, when the indole NH is
unprotected, a Friedel−Crafts-like reaction occurs in which the
intramolecular hydrogen bonding between the indole NH and
the imine group is critical. However, we found that the protected
indole substrates (2a,e−i) still gave Friedel−Crafts-type
products. Hence, we propose that for the annulation pathway,
according to our previous report,7b initial cyclopropanation of
the C(2)−C(3) double bond of the indole followed by
subsequent ring-opening and recombination is the likely pathway
(Scheme 5, path a). However, considering that N-Boc-indole
which was reported to undergo concerted cyclopropanations
with Rh(II) carbenes to afford isolable cyclopropylindolines did
not work under the reaction conditions15 and the presence of
solvent effect in the reaction, a zwitterionic pathway resulting
from substantial polarization of the C(2)−C(3) double bond is
also plausible (Scheme 5, path b). On the other hand, when the
tether is one carbon shorter, or with NH free indole, a Friedel−
Crafts-type reaction takes place. In this case, reaction occurs at
C(2) via zwitterionic intermediate B (Scheme 5, path c) or
undergoes an alkyl shift from zwitterionic intermediate A to form
C
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Letter
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ASSOCIATED CONTENT
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S
TThe Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00180.
Experimental procedures, characterization data, NMR
spectra, and X-ray crystallographic data (PDF)
X-ray data for 4j (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hmdavie@emory.edu.
ORCID
Huw M. L. Davies: 0000-0001-6254-9398
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (Project No.
2R01GM099142-05). We wish to thank Dr. John Bacsa from
the Emory University X-ray Crystallography Center for the X-ray
crystallographic structure determination.
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D
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