Co(III)-Catalyzed, Internal and Terminal Alkyne-Compatible Synthesis of Indoles

Article abstract of DOI:10.1021/acs.orglett.6b01805

A Co(III)-catalyzed, internal and terminal alkyne-compatible indole synthesis protocol is reported herein. The N-amino (hydrazine) group imparts distinct, diverse reactivity patterns for directed C-H functionalization/cyclization reactions. Notable synthetic features include regioselectivity for a meta-substituted arylhydrazine, regioselectivity for a chain-branched terminal alkyne, formal incorporation of an acetylenic unit through C2-desilylation on a C2-silylated indole derivative, formal inversion of regioselectivity through consecutive C3-derivatization and C2-desilylation processes, and formal bond migration for a linear-chain terminal alkyne.

Full text of DOI:10.1021/acs.orglett.6b01805

Letter
pubs.acs.org/OrgLett
Co(III)-Catalyzed, Internal and Terminal Alkyne-Compatible Synthesis
of Indoles
Shuguang Zhou, Jinhu Wang, Lili Wang, Kehao Chen, Chao Song, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: A Co(III)-catalyzed, internal and terminal alkyne-
compatible indole synthesis protocol is reported herein. The N-amino
(hydrazine) group imparts distinct, diverse reactivity patterns for
directed C−H functionalization/cyclization reactions. Notable
synthetic features include regioselectivity for a meta-substituted
arylhydrazine, regioselectivity for a chain-branched terminal alkyne,
formal incorporation of an acetylenic unit through C2-desilylation on
a C2-silylated indole derivative, formal inversion of regioselectivity
through consecutive C3-derivatization and C2-desilylation processes,
and formal bond migration for a linear-chain terminal alkyne.
Scheme 1. Co(III)-Catalyzed, Internal and Terminal Alkyne-
Compatible Synthesis of Indoles: The N-Amino Directing
Group Imparts Distinct, Diverse Reactivity Patterns for C−
H Functionalization/Cyclization Reactions, Which
Translates into Unique Substitution Patterns and Expanded
Structural Space for the Indole Skeleton
ransition-metal-catalyzed C−H functionalization has
T
received widespread attention for its emerging applica-
tions in diverse synthetic contexts.1 Method development in
this nascent field has been dedicated, to a great extent, to the
construction of heterocyclic scaffolds.2 An important and
persistent theme in this respect is the search for distinct
reactivity patterns that allow translation into unique sub-
stitution patterns and therefore access to expanded structural
space. Herein we report a Co(III)-catalyzed, internal and
terminal alkyne-compatible synthetic protocol for the con-
struction of the indole skeleton (Scheme 1). In particular, an N-
amino (hydrazine) group,3 free from an end protecting group,
has been used in combination with a Co(III) catalytic system
for redox-neutral directed C−H functionalization/cyclization
reactions, allowing the generation of a broad range of
substitution patterns for the cyclic framework. This represents
an important contribution to the indole synthetic schemes since
none of the recently disclosed Co(III) catalytic protocols
demonstrated compatibility with terminal alkynes.4 Indeed,
terminal alkynes are notoriously difficult to accommodate into
C−H functionalization reactions, largely because of the
existence of competing alternative reaction pathways (e.g.,
Glaser−Hay-type homocoupling5). Only recently have there
been several reports describing the synthesis of heterocycles via
a C−H activation pathway using terminal alkynes as the
coupling partner.6 However, these methods suffer from one or
more of the following drawbacks: required use of a high
reaction temperature, retention of an undesired bulky group in
the final product, and generation of costly waste products from
external oxidants. For the indole skeleton, only an isolated case
was described,7 and no general applicability was demonstrated.
We have recently uncovered an N-amino directing group for
C−H functionalization and applied that group in a Rh(III)
catalytic system for the synthesis of indoles.3 In spite of the
heightened reactivity imparted by the N-amino group, the
method developed therein is not versatile enough to be
terminal alkyne-compatible. Cobalt is an earth-abundant, low-
Received: June 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01805
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Organic Letters
Letter
ab c
, ,
cost, nontoxic species and has recently demonstrated, in several
transformations, unique reactivity that is elusive for other
transition metals.8 For example, the lower electronegativity of
cobalt relative to its heavier congener can in principle translate
into a higher nucleophilicity for the covalently bound C atom;
the higher nucleophilicity can in turn offer faster C−
heteroatom bond formation kinetics, thus overriding alternative
competing reaction pathways. The results communicated
herein provide further proof that an expanded substrate scope
can indeed be achieved through the use of this first-row
transition metal.
Scheme 2. Substrate Scope of Internal Alkynes
For the synthetic system developed herein, the reaction
involving an internal alkyne affords a single regioisomer for a
meta-substituted arylhydrazine (C−H coupling site para instead
of ortho to the meta group). Significantly, in the transformations
involving terminal alkynes, two distinct reaction pathways have
been observed, depending on whether or not chain branching
exists on the neighboring atom of the CC bond. In the
presence of chain branching, bond position remains the same.
In the absence of chain branching, a formal bond migration
occurs, which proceeds through initial isomerization of the
terminal alkyne to an allene and subsequent kinetically favored,
selective incorporation of the allene moiety into the indole
framework. The regioselectivity is superior for both types of
terminal alkynes, allowing the generation of a single type of
regioisomer. The chain-branched, bulky silyl group at C2 of the
as-synthesized indole can be easily removed, thus enabling the
synthetic equivalent of incorporating an acetylenic unit.
Furthermore, the occupation of C2 by the bulky silyl unit
allows selective functionalization at C3, and its subsequent
removal affords a single type of indole derivative with formal
inverse regioselectivity.
We commenced our investigations by examining the reaction
between an arylhydrazine and an internal alkyne. This reaction
is expected to be synthetically less challenging, and the
optimized reaction conditions obtained for internal alkynes
could serve as a guide for the selection of conditions for
terminal alkynes. With [Cp*CoI2]2 (2 mol %)/AgSbF6 (8 mol
%) as the catalyst precursor, 1a and 2a could indeed, with the
assistance of KOAc (2 equiv), react at 60 °C in a variety of
solvents to form the target indole derivative 3a (see the
Supporting Information). A promising 33% yield was achieved
in DCE, which provided a starting point for further
optimization of the conditions. Thus, a change in additive
from KOAc to other species allowed an increase of yield, and in
the presence of Zn(OTf)2 the yield was boosted to 85%. An
examination of the amount of Zn(OTf)2 revealed that the yield
remained essentially constant for 1.2 equiv and above. A slight
adjustment of the reaction temperature to 50 °C gave us the
optimized reaction conditions and 88% yield. A control
experiment performed in the presence of either AgSbF6 or
Zn(OTf)2 ruled out catalytic reactivity associated with these
additives.
a
Conditions: arylhydrazine substrate (0.4 mmol), alkyne (1.5 equiv),
b
c
DCE (2.0 mL). Isolated yields are shown. The compound in
parentheses is the alkyne substrate for 3z.
in a slightly higher yield for an electronically deficient substrate.
The reaction proceeded well for substrates bearing a cyclic
substituent (closure at the N atom and ortho C atom, 1h and
1i). In the case of meta substitution, the Co(III) system
reported herein exhibited superior regioselectivity compared
with the Rh(III) system,3,9 allowing the generation of a single
type of isomer not only for 1j (methyl) but also for 1k (fluoro)
and 1l (chloro). Although the exact mechanism for the
regioselectivity has yet to be elucidated, the applicability of both
electronically rich and deficient substrates, in combination with
the fact that C−C coupling occurs at the remote site, suggests
that most likely the steric effect plays a dictating role here.
Examination of a variety of para-substituted substrates revealed
broad compatibility of both electronically rich and deficient
substrates. The internal alkyne scope was next investigated
using phenyl/alkyl-disubstituted asymmetric alkynes (1s,
methyl; 1t, ethyl; 1u, propyl) as the test substrates. All of the
reactions proceeded well, allowing single types of regioisomers
to be obtained in yields comparable to that from phenyl/
phenyl-disubstituted alkyne. The CC bond is the site of
coupling in the presence of a potentially competing CC
bond (1v), although the product was furnished in a slightly
diminished yield. Alkyl/alkyl-disubstituted symmetric alkynes
(1w, ethyl; 1x, propyl; 1y, butyl) are also competent substrates
for the transformation. A phenyl/silyl-disubstituted alkyne (1z)
could act as a synthetically equivalent surrogate substrate for
the terminal alkyne phenylacetylene.
With the optimized reaction condition in hand, we next
examined the substrate scope for both arylhydrazines and
internal alkynes (Scheme 2). The reaction yield is inversely
correlated with the bulkiness of the alkyl group (1a, methyl; 1b,
ethyl; 1c, isopropyl) on the N atom, reflecting the operation of
a steric effect. As expected, the reaction proceeded even more
sluggishly for a phenyl-substituted substrate (1d). Insertion of a
methylene bridging group between the N atom and the phenyl
ring allowed partial recovery of the reactivity (1e). The ortho
substitution on the phenyl ring (1f, methyl; 1g, fluoro) resulted
Importantly, the reaction can be scaled up to the multigram
scale with a very low catalyst loading (0.2 mol %) (eq S1),
highlighting the superior reactivity imparted by the N-amino
group.
Switching the substrates from internal alkynes to terminal
alkynes will inevitably generate the issue of competing side
B
DOI: 10.1021/acs.orglett.6b01805
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Letter
reactions, as terminal alkynes are more prone to alternative
reaction pathways. This implies that in order to gain access to
indoles in a synthetically productive manner, the indole
synthesis reaction pathway should be favored kinetically. We
have discovered previously that the counterion (Cl−) in the
Rh(III) system can partially inhibit its catalytic activity.9 In
accordance with this, although [Cp*CoI2]2, [Cp*Co(CO)I2]2,
and [Cp*CoCl2]2, with the assistance of AgSbF6, allowed the
generation of the target product 5a (whose structure was
confirmed with single-crystal X-ray diffraction analysis) via a
model reaction between 1a and triisopropylsilyl (TIPS)-
substituted terminal alkyne (4a), they invariably gave a low
yield (<30%). Replacement of the catalyst precursor with a
cationic Co(III) species, [Cp*Co(MeCN)3][SbF6]2, resulted in
a significant increase in the yield (56%). Adjustment of the
amount of Zn(OTf)2 to 0.2 equiv increased the yield to 76%.
Further tuning of the temperature to 80 °C provided an 83%
yield (Scheme 3).
the Supporting Information). A one-pot reaction between 1n/
1r and 2a revealed preferred reaction for the substrate bearing
an electron-withdrawing group (product distribution: 3n/3r =
0.55), suggesting that concerted metalation−deprotonation is
responsible for the C−H activation process. Two kinetic
isotope effect (KIE) experiments were performed with the
participation of 1a and 1a-d3 (deuteration at two ortho positions
and one para position of the N-amino group). A high KIE value
was observed for the coupling with both internal alkyne (2a,
kH/kD = 2.6) and terminal alkyne (4a, kH/kD = 3.2), suggesting
the participation of C−H bond cleavage in the turnover-
limiting step, as also observed in other Co(III)-based catalytic
systems,4 for both of the transformations.
The bond migration for the reaction involving a linear-chain
terminal alkyne is proposed to proceed through an initial
alkyne-to-allene isomerization (promoted by the Co(III)
catalyst10), subsequent carbocobaltation of the allene (on a
five-membered cobaltacycle formed via C−H cobaltation)3,4a,9
on the internal CC bond (via an alkenylcobalt intermediate
instead of a π-allylcobalt intermediate11), followed by the final
cyclization process (Scheme 4). Supporting lines of evidence
a b c
, ,
Scheme 3. Substrate Scope of Terminal Alkynes
Scheme 4. Bond Migration Mechanism for a Reaction
Involving a Linear-Chain Terminal Alkyne
for this mechanistic proposal include the following: (1) The
reaction involving an internal 2-alkyne gave a mixture of
regioisomers (eq S2), ruling out the initial isomerization from
1-alkyne to 2-alkyne. (2) Replacement of the terminal alkyne
with the same amount of the corresponding allene provided a
single identical regioisomer, albeit in a significantly reduced
yield (eq S3), consistent with participation of the allene in the
carbocobaltation and cyclization processes; along with this
finding is also the identification of many side products on the
TLC plate. The reaction can be rationalized (Scheme 4) by (1)
constant release of minute amounts of allene from the terminal
alkyne (for thermodynamic stability reasons12) and (2)
dominance of allene in the carbocobaltation and cyclization
processes because of its higher reactivity (the presence of only a
minute amount ensures its preferred reactivity along a single
pathway). Indeed, arrival at a thermodynamic equilibrium
between the alkyne and allene typically requires strongly basic
conditions,12 and no such equilibrium was identified on a large
scale for the reaction system reported herein (eq S4).
As a further demonstration of the synthetic utility of this N-
amino-directed C−H functionalization protocol, several organic
transformations on the TIPS-substituted indole derivative 5a
were performed (Scheme 5). TIPS at C2 can be readily
removed by tetrabutylammonium fluoride, affording an indole
derivative that incorporates a formal acetylenic unit.13
Acyloxylation can proceed at C3 with retention of the TIPS
group.14 A sulfenyl group can also be installed at C3 without
affecting the TIPS group.15 Desilylation can then be executed
a
Conditions: 1a (0.4 mmol), alkyne (1.5 equiv), DCE (2.0 mL).
Isolated yields are shown. Compounds in the parentheses are the
b
c
alkyne substrates.
With these reaction conditions in hand, we next examined
the substrate scope of terminal alkynes. A decrease of the
bulkiness in the silyl group resulted in a seemingly surprising
lower yield (4b, trimethylsilyl (TMS); 4c, triethylsilyl (TES)).
The yield in fact correlates well with the availability of the
alkyne substrate in the reaction mixture. The availability is
dictated by the boiling point/volatility. The reaction also
proceeded smoothly for a tert-butyl-substituted terminal alkyne
(4d). Further expansion of the substrate scope to an alkyl-
group-substituted terminal alkyne (4e, pentyne) provided an
intriguing bond-migrated product. Systematic testing with a
variety of alkynes (4f−n) showed the same reactivity pattern as
long as there was no chain branching at the neighboring atom
of the CC bond. Again, the reaction yield also generally
correlated with the availability of the substrate.
Several experiments were then conducted to examine the C−
H activation process. A competition reaction was performed to
evaluate the electronic preference for the transformation (see
C
DOI: 10.1021/acs.orglett.6b01805
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Letter
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Scheme 5. Synthetic Transformations Performed on a C2-
Silylated Indole Derivative
on both the acyloxylated and sulfenylated indole derivatives.
For a Michael addition reaction performed herein, desilylation
occurs simultaneously with the conjugate addition process.16
These three types of desilylated products offer an intriguing
formal inversion of regioselectivity for a nominal terminal
alkyne bearing an acyloxy group, a sulfenyl group, and a ketone-
containing group, respectively.
In summary, a Co(III)-catalyzed, internal and terminal
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developed for the synthesis of indoles. The protocol takes
advantage of the high reactivity imparted by the N-amino
directing group and the unique catalytic activity associated with
the Co(III) system. Alkynes can be regioselectively incorpo-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01805.
(7) Zheng, L.; Hua, R. Chem. - Eur. J. 2014, 20, 2352.
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■
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(c) Wang, H.; Moselage, M.; Gonzal
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Experimental procedures and characterization of the
products (PDF)
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ACS Catal. 2016, 6, 793. (g) Lu, Q.; Vas
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quez-Cespedes, S.; Gensch,
1
Copies of the H and 13C NMR spectra of selected
products (PDF)
Crystallographic data for 5a (CIF)
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AUTHOR INFORMATION
Corresponding Author
■
18284.
*jinz@nju.edu.cn
Notes
(12) Hashmi, A. S. K. In Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Chapter 1.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415 and 21274058) and
the National Basic Research Program of China
(2015CB856303).
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