Gold catalysis coupled with visible light stimulation: Syntheses of functionalized indoles

Article abstract of DOI:10.1021/ol501071k

A judicious combination of Au-catalysis and synergistic visible-light stimulation formulates an exceptionally simple and mild reaction system capable of directly coupling anilines and alkynes to form multifunctionalized indoles.

Full text of DOI:10.1021/ol501071k

Letter
pubs.acs.org/OrgLett
Gold Catalysis Coupled with Visible Light Stimulation: Syntheses of
Functionalized Indoles
Shunyou Cai, Kai Yang, and David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen, China 518055
S
* Supporting Information
ABSTRACT: A judicious combination of Au-catalysis and
synergistic visible-light stimulation formulates an exceptionally
simple and mild reaction system capable of directly coupling
anilines and alkynes to form multifunctionalized indoles.
metal complexes, such as Rh4f and Ni4g catalysts, were
ndoles are highly versatile heterocyclic structural motifs
Ipresent in many biologically meaningful natural products as demonstrated to be competent in similar contexts. Alter-
well as pharmaceuticals and agrochemicals.1 Their significant
natively, intramolecular cyclizations of imines or enamines
prepared by condensations of anilines and ketones were also
explored in the presence of transition-metal catalysts or strong
oxidants (Scheme 1b). Glorius and co-workers described a
practical indole synthesis through Pd-catalyzed oxidative
cyclizations of N-aryl enamines derived from anilines and β-
dicarbonyl compounds.4b Within this scenario, similar successes
were achieved by other research groups using various transition
metals or oxidants. Despite these significant advances, there
remains a strong need for discovering new and straightforward
protocols that are capable of delivering indole motifs, ideally
densely functionalized, with simpler substrate structures,
minimal preactivations, less use of catalysts or oxidants, or
milder reaction conditions.
We were intrigued by the possibility of merging potentially
synergistic interactions of Au-catalysis5 and visible-light-enabled
photoredox catalysis6−8 to explore a conceptually novel
technology for indole synthesis. Such a design scenario, as
summarized in Scheme 1c, leverages on cascade events of Au-
catalyzed hydroamination and visible-light-enabled photoredox
cross-dehydrogenative coupling that are capable of unifying
readily available anilines and internal alkynes. We were
delighted to disclose herein that, through careful optimizations
of reaction conditions nurturing these strategic events, an
unusually simple and versatile method was eventually
established for rapidly accessing a variety of highly function-
alized indoles at room temperature.
utilities thus have stimulated considerable synthetic efforts
aimed at exploring efficient, mild, and direct methodologies
toward their preparations, and such activities have been
regularly updated and reviewed.2 Although the classical Fischer
indole synthesis3 remains instrumental in constructing various
indole skeletons, the method suffers from drawbacks such as
harsh reaction conditions, moderate functional-group tolerance,
and difficulty in hydrazine preparation. As a response to these
challenges, a variety of milder approaches to indole syntheses
involving strategic C−H functionalizations have been con-
tinuously documented in recent literature.4
In 1998, Larock and co-workers reported an inspirational
indole synthesis via Pd-catalyzed annulation of internal alkynes
with ortho-halogenated anilines (Scheme 1a).4a The work has
subsequently stimulated several other studies aimed at directly
utilizing substrates free of preactivations under transition-metal
catalysis. For example, Jiao and co-workers developed a unique
method for constructing indoles from readily available anilines
and alkynes by C−H functionalizations.4c Other transition-
Scheme 1. Various Indole Syntheses Involving C−H
Functionalizations
Initial reaction condition screenings quickly revealed that
realization of the envisioned reactivity depends critically on the
synergy of several factors, including the Au catalyst, additive,
solvent, and Lewis acid. With N-methyl-4-nitroaniline 1a and
ethyl 3-phenylpropiolate 2a as the model substrates, no desired
product was detectable when the reaction was performed in
1,2-dichloroethane (DCE) at room temperature in the presence
of a catalytic amount of catalyst PPh3AuCl (5 mol %) under a
Received: March 5, 2014
Published: April 29, 2014
© 2014 American Chemical Society
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Letter
balloon-oxygen atmosphere and with visible-light irradiation
from a 45 W household fluorescent compact bulb for 36 h at
room temperature (entry 1, Table 1). Fortunately, a subsequent
formation of the indole 3a at all, thereby confirming both of
them to be essential factors for reproducible production of 3a
(entries 18−19). It is interesting to note here that, somewhat
contrary to the original design hypothesis, the uncovered
reactivity requires the participation of visible light but without
any photocatalyst. Collectively, these screening results estab-
lished the optimal reagent system to be the following: 5 mol %
of Gagosz catalyst PPh3AuNTf2, 100 wt % of activated
powdered 4 Å molecular sieves, and 0.50 equiv of Mg(ClO4)2
in DCE under a balloon oxygen atmosphere at room
temperature.
Table 1. Identification of the Optimal Reaction Conditions
With the optimized reaction conditions identified, a range of
anilines having various electron-withdrawing substituents were
next attempted to couple with ethyl 3-phenylpropiolate 2a, and
the results are compiled in Scheme 2. In most cases, the
Scheme 2. Reactivity Screenings on Substituted Aniline
Substrates 1
a
b
IPrAuCl/AgOTf was used. (John-Phos)AuCl/AgOTf was used.
c
d
Reaction was performed in the absence of light. 100 wt % of additive
e
was employed. Yield of isolated product. IPr = 1,3-bis(2,6-
diisopropyl-phenyl)imidazol-2-ylidene, John-Phos = (2-biphenyl)di-
tert-butylphosphine.
key observation was made that the desired indole 3a was
produced in 28% isolated yield by using the Gagosz catalyst
PPh3AuNTf2 in place of PPh3AuCl (entry 2). In this case,
accompanying 3a was the formation of ethyl 3-oxo-3-phenyl-
propanoate as the major byproduct (43% isolated yield), arising
apparently from direct hydration of 2a or a putative enamine
intermediate. Remarkably, the yield of 3a was improved to 53%
when a moisture scavenger MgSO4 was added into the reaction
(entry 3). By contrast, when powdered 4 Å molecular sieves
were employed as the moisture scavenger, the reaction was
virtually completely inhibited (entry 4). These results
collectively implied that MgSO4 might have additionally
functioned as a Lewis acidic activator. Indeed, when the
Lewis acid LiClO4 was used in conjunction with 4 Å molecular
sieves, a respectable 77% yield of 3a was recorded, albeit with a
longer reaction time (72 h, entry 5). Thus, a range of acids,
such as LiBF4, TsOH·H2O, Sc(OTf)3, and Mg(ClO4)2, were
subsequently screened at various loadings and reaction times
(entries 5−10), from which the utilization of a substoichio-
metric amount of Mg(ClO4)2 (0.50 equiv) clearly stood out to
be optimal (83%, entry 9). It merits a note that other attempts
by employing other Au-catalysts, such as IPrAuCl/AgOTf,
(John-Phos)AuCl/AgOTf, and AuCl3, led to either a lower
product yield or decomposition (entries 11−13). Furthermore,
the solvent effect was found to be very significant in this
transformation. When the solvent was MeOH, THF, ACN, or
DMF, the reactivity was almost completely inhibited under
otherwise identical reaction conditions (entries 14−17).
Finally, control experiments conducted in the absence of either
the PPh3AuNTf2 catalyst or visible-light exposure resulted in no
reactions proceeded smoothly to afford the corresponding
indole product 3 in various isolated yields (61−88%). Some of
the widely encountered election-withdrawing groups, such as
the nitro (3a), sulfonyl (3b), carbonyl (3d-3h), and cyano (3c)
group, were shown to be well accommodated in the reactions in
terms of product yield (73−88%). A closer inspection revealed
that the most strongly electron-withdrawing nitro group in 3a
appeared to have retarded the reaction to some extent, as a
significantly longer reaction time (52 h) was required to achieve
a comparable yield (83%), hinting at the possibility that the
increased difficulty of electron abstraction from the correspond-
ing nitrogen lone pair might have negatively influenced the
photoredox process. The reactions were also successful with
ethyl- or benzyl-substituted anilines (i.e., R2 = Et, Bn), and the
indoles 3i and 3j were thus uneventfully produced in 74% and
67% yields, respectively. Notably, reaction decomposition was
observed with the free aniline (i.e., R2 = H in 3m). When an
unsymmetrically substituted aniline 3k was used, the reaction
led to two inseparable regioisomers in a 1:4 ratio and 61% yield
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Letter
over 60 h. Similarly, meta-substituted aniline 1l was found to
afford two separable regioisomers in a 1:1 ratio and 87% yield
within 38 h. Furthermore, it merits attention that the electronic
characteristics of the aniline aromatic ring substituents (R1) had
evidently a rather sensitive influence on the reaction, where
complicated mixtures resulted with substrates bearing R1 that is
electron-releasing in nature (R1 = Cl, F, or MeO in 3n).
To further examine the substrate scope of the methodology,
direct condensations of several diversely substituted alkynes 2
and the commercial available methyl 4-(methylamino)benzoate
1d were next investigated. As summarized in Scheme 3, the
the action of Pd/C-mediated hydrogenation, and the ester
functionality in 4j was efficiently removed through acid-
promoted decarboxylation.9 These new indole derivatives
could serve as important intermediates for pharmaceutical as
well as natural products syntheses.
The insignificance of a photocatalyst in such observed
reactivity is intriguing and merits further investigations. Some
control experiments were therefore subsequently performed to
shed light on the reaction pathways (Scheme 5). The direct
Scheme 5. Control Experiments on Reaction Parameters
Scheme 3. Reactivity Screenings on Alkyne Substrates 2
coupling of two representative substrates 1a and 2a in the
presence of Mg(ClO4)2, PPh3AuNTf2, and 4 Å molecular sieves
yielded initially enamine 7 as a 3:1 mixture of E/Z isomers in
95% yield within 12 h, which, in conjunction with an earlier
finding (entry 18 in Table 1), points to the operation of a Au-
catalyzed hydroamination event. When 7 was exposed to
visible-light stimulation under a ballooned O2 atmosphere and
in the presence of a photosensitizer,10 Ru(bpy)3Cl2 or Eosin Y,
indole 3a was furnished in 81% yield over 40 h. Performing the
reaction in the absence of O2 or visible light led to either a
dramatic reduction in the yield of 3a (32%) or complete
reactivity inhibition, suggesting that their participations are
essential for reproducible operation of the reactivity. In marked
contrast, the yield of 3a was not at all compromised (86%)
when the said photosensitizer was removed from the reaction.
A plausible mechanistic rationale enabled by these
observations is briefly depicted in Scheme 6. Dual Au/Mg
Lewis acidic activations on 2 would trigger hydroamination
addition11 of 1 to give an enamine species 7, whose highly
polarizable electron densities distributed along the extended
conjugative system would undergo photoexcitation (intermedi-
corresponding indoles 4a−4l were generally delivered in
moderate-to-good isolated yields (up to 87%). These results
demonstrated that both of the aryl ring sizes (4a and 4e) and
the electron-withdrawing as well as -donating nature of the
substituents on the R3 (4b−4h) on the alkynes 2 seemed to
have posed little influence on the reactivities. Moreover, the
substrate carrying a heterocyclic group (2i) or a sterically
bulkier ester (2j) was comparably efficient in both instances
(72% of 4i and 81% of 4j, respectively). Notable reactivity
decreases were reorded in the cases of 4k and 4l when ketones
were employed as the substrates, and the formations of 4k−4l
required more reaction time for completion (57% of 4k after 72
h and 25% of 4l after 74 h, respectively).
Structurally densely functionalized indoles prepared by this
new protocol are amendable for further synthetic editing.
Disclosed in Scheme 4 are two illustrative examples. The nitro
group in 3a could be readily reduced to amine in 90% yield by
Scheme 6. A Plausible Mechanistic Proposal
Scheme 4. Illustrative Synthetic Transformations
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1338. (g) Song, W.; Ackermann, L. Chem. Commun. 2013, 49, 6638.
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transfer with molecular oxygen,12 thereby leading to the
formation of radical cation species B/C. Radical cyclization13
would then take place in the shown deprotonation−
aromatization sequence of D−E−F to yield the final indole
product 3 with the elimination of hydrogen peroxide, thus
concluding a formal visible-light-mediated dehydrogenative
coupling cascade.
In summary, motivated by the initial design concept of
exploring possibly synergistic Au-catalysis as well as visible-light
photoredox catalysis, we have described herein some unusually
simple and mild reactivities allowing for direct preparations of a
diverse range of indole substances bearing multiple useful
functionalities. This new protocol accommodates various
anilines and alkyne substrates and mechanistically operates
through a fascinating cascade of Au-catalyzed hydroamination,
visible-light-promoted electron transfer, and dehydrogenative
coupling. The reactivity, not requiring the assistance of any
photosensitizer, adds further to its practicality. Given the widely
appreciated significance of indole-type substances in pharma-
ceutical and chemical contexts, it is well anticipated these
discoveries would find applications and stimulate further studies
in due course.
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ASSOCIATED CONTENT
* Supporting Information
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Experimental procedures and spectral data for all new
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AUTHOR INFORMATION
Corresponding Author
■
Skrydstrup, T. Org. Lett. 2009, 11, 4208.
(12) Maity, S.; Zheng, N. Angew. Chem., Int. Ed. 2012, 51, 9562.
(13) He, Z.; Liu, W.; Li, Z. Chem.Asian J. 2011, 6, 1340.
*E-mail: dzw@pkusz.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (Grants 20972008 and 21290180 to
D.Z.W.), the national “973 Project” of the State Ministry of
Science and Technology (Grant 2013CB911500 to D.Z.W.),
the Shenzhen Bureau of Science and Technology, and the
Shenzhen “Shuang Bai Project” for financial support.
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