Regioselective acceptorless dehydrogenative coupling of N-heterocycles toward functionalized quinolines, phenanthrolines, and indoles

Article abstract of DOI:10.1002/anie.201500346

A new strategy has been developed for the oxidant- and base-free dehydrogenative coupling of N-heterocycles at mild conditions. Under the action of an iridium catalyst, N-heterocycles undergo multiple sp³ C-H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel-Crafts addition, resulting in a double functionalization of the N-heterocycles. Regioselectively functionalized quinolines, phenanthrolines, and indoles are obtained by dehydrogenation of N-heterocycles in the presence of electrophiles. This reaction produces H₂ as the only byproduct under mild conditions.

Full text of DOI:10.1002/anie.201500346

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DOI: 10.1002/anie.201500346
À
C H Functionalization
Regioselective Acceptorless Dehydrogenative Coupling of N-
Heterocycles toward Functionalized Quinolines, Phenanthrolines, and
Indoles**
Dinesh Talwar, Angela Gonzalez-de-Castro, Ho Yin Li, and Jianliang Xiao*
In memory of Wu Chi
Abstract: A new strategy has been developed for the oxidant-
and base-free dehydrogenative coupling of N-heterocycles at
mild conditions. Under the action of an iridium catalyst, N-
reported cases, in which an alcohol is first dehydrogenated,
generating an electrophilic carbonyl species that can react
with a common nucleophile.[3,4] Dehydrogenative C C bond
À
heterocycles undergo multiple sp3 C H activation steps,
formation that results in formal alcohol substitution is
a type II ADC reaction. Thus, an alcohol is dehydrogenated
to an electrophilic carbonyl, or a nucleophilic enolate, which
subsequently reacts with a carbon nucleophile, or an electro-
phile, generating an unsaturated bond to be reduced in situ by
the H2 borrowed from the initial dehydrogenation.[5] Alcohol
dehydrogenation that triggers hydrometalation of a p-unsa-
turated substrate is a type III ADC reaction, in which
À
generating a nucleophilic enamine that reacts in situ with
various electrophiles to give highly functionalized products.
The dehydrogenative coupling can be cascaded with Friedel–
Crafts addition, resulting in a double functionalization of the
N-heterocycles.
C
ircumventing the use of stoichiometric oxidants, accept-
orless dehydrogenation reactions have recently become
a rapidly growing area of research.[1] These reactions produce
H2 as the only byproduct, which is a valuable feedstock itself
and energy carrier.[2] Not only can such reactions be applied to
the synthesis of unsaturated compounds, they also allow for
easy bond formation. Indeed, the last few years have
witnessed the application of this novel acceptorless dehydro-
genative coupling (ADC) strategy to the synthesis of many
value-added compounds in a manner that is more straightfor-
ward and economic and greener than the conventional
methods.[1,3,4] There are mainly three types of ADC reactions
that have appeared (Scheme 1). Type I features the most
a nucleophile–electrophile pair is formed, which reacts to
[6]
À
afford alcohol C H functionalization (Scheme 1).
Acceptorless dehydrogenation of N-heterocycles is rare,
however, and ADC of N-heterocycles is even rarer. To the
best of our knowledge, there is only one report, in which an N-
phenyl tetrahydroisoquinoline was alkylated with carbon
nucleophiles at the 1-position,[7] whilst the activation of an
À
amine to generate an enamine to allow for subsequent C C
coupling remains unknown in the context of ADC.[8]
Although a number of excellent examples have been dem-
onstrated in the cross dehydrogenative coupling of N-hetero-
cycles with nucleophiles, these reactions generally necessitate
the use of stoichiometric oxidants, rather than releasing the
hydrogen as H2.[9]
N-Heterocycles are abundant in natural products, fine
chemicals, and pharmaceuticals, and have also been viewed as
organic hydrides for potential hydrogen storage systems.[10,11]
Their dehydrogenation is generally effected with non-chemo-
selective heterogeneous catalysts.[12] The groups of Fujita and
Yamaguchi,[13] Jones,[14] and ours[15] have recently reported
homogeneous acceptorless dehydrogenation of N-heterocy-
cles with well-defined metal complexes.[16] During our inves-
tigation, we were intrigued by the mechanism of the
Scheme 1. General modes of ADC reactions reported in the literature.
[*] D. Talwar, A. Gonzalez-de-Castro, Dr. H. Y. Li, Prof. J. L. Xiao
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
Homepage: http://pcwww.liv.ac.uk/~xiao
[**] We thank EPSRC and the University of Liverpool for a DTA
studentship (D.T.) and EPSRC/TSB for a postdoctoral fellowship
(H.Y.L.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500346.
Scheme 2. ADC, Friedel–Crafts/ADC, and ADC/reduction reactions
accomplished in this study.
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Table 1: Regioselective dehydrogenative sp C H functionalization of 2-
dehydrogenation of 2-methyl-1,2,3,4-tetrahydroquinoline
with a cyclometalated iridium complex.[15] When performed
methyl tetrahydroquinolines.[a,b]
À
in a deuterated solvent, the reaction led to extensive H D
exchange at the a- and b-positions, suggesting that the
dehydrogenation leads to the generation of an imine, which
isomerizes to an enamine at these positions (Scheme 2). We
envisioned that this nucleophilic intermediate might be
intercepted by a carbon-based electrophile, thus affording
À
C C bond formation at the a-methyl. This would lead to
a new method for the functionalization of 2-methyl azaarenes,
complementing those necessitating the use of 2-methyl
azaarenes.[17] Herein, we show that not only does this ADC
strategy enable the coupling of the sp3 carbon with a range of
electrophiles, but it can also be cascaded with Friedel–Crafts
addition at sp2 carbons and with reduction to generate novel
saturated N-heterocycles (Scheme 2).
We initiated our study by testing various cyclometalated
iridium complexes (iridacycles) 1 for the ADC of 2-methyl-
1,2,3,4-tetrahydroquinoline (2a) with ethyl 3,3,3-trifluoropyr-
uvate (TFP) as an electrophile (Scheme 3). After extensive
[a] See the SI for experimental details. [b] Yields of isolated product in
parentheses. [c] Yields determined by 1H NMR spectroscopy.
Scheme 3. Iridacycles used in this study.
screening, complex 1d was identified as the precatalyst of
choice, which was further shown to be most efficient in acidic
trifluoroethanol (TFE) in terms of the yield of the desired
ADC product (see the Supporting Information, SI).
Using the optimal conditions established, the ADC of
various tetrahydroquinolines 2a–v with TFP was explored. In
each case, the corresponding products 3a–v were obtained in
Scheme 4. Regioselective dehydrogenative functionalization of tetra-
and octa-hydrophenanthroline.
À
good to excellent isolated yields, with the C C coupling
taking place almost exclusively at the b-position (Table 1).[18]
These quaternary trifluoromethyl hydroxy compounds are
highly valuable in pharmaceuticals due to their biological
activities.[17g,19]
in acidic media.[19,20] Further to our delight, substrates
containing boronic acid pinacol ester and allyl ether groups
were also well tolerated, furnishing the corresponding prod-
ucts in good yields (3u–v). These functional groups can easily
induce other reactions, such as cross-coupling and aromatic
Claisen rearrangement.[21,22]
Remarkably, the coordinating compounds 4a,b could be
selectively mono- or dialkylated, affording 5a,b in good yield
(Scheme 4). The exclusive monofunctionalization of 4a shows
that dehydrogenation at the saturated ring is much easier than
A variety of functionalities was tolerated, demonstrating
the utility of the protocol in practice. Thus, substrates bearing
either electron-donating or -withdrawing groups all gave
excellent yields regardless of their positions (3b–e and 3k–l),
and hydrogenation-labile aromatic halides afforded the
coupling products 3 f–j in more than 70% yield. Whilst
ester and amide moieties are typically employed in ortho-
[17b–g]
À
À
directed C H functionalization, regioselective ADC took
C H activation
or deprotonation at the 9-Me position
place when 2m–p were coupled with TFP, furnishing excellent
yields for the expected 3m–p. Delightfully, thiophene- and
pyridine-containing substrates (2r–s) underwent the ADC
without poisoning the catalyst. However, when the furan
derivative 2t was subjected to the ADC, competitive Friedel–
Crafts alkylation was observed at the furan ring, leading to
a highly functionalized product 3t. It is known that furan can
undergo electrophilic aromatic substitution at the 2-position
(cf. 2-methyl pyridine: pKa 34),[17a] and the latter reactions,
which would lead to alkylation at that methyl substituent, are
difficult to achieve under the mild ADC conditions employed.
These phenanthrolines are valuable and are often employed
as donor ligands for transition metals.[23] However, selective
dialkylation or monoalkylation of 2-methyl phenanthrolines
has been challenging and is typically performed under harsh
conditions.[24]
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Table 2: Regioselective functionalization with other electrophiles.[a,b]
Table 4: One-pot sequential Friedel–Crafts dehydrogenative sp C H
À
3
[a,b]
À
and sp C H functionalization of 2a.
Electrophile (E+)
Product
[a] See the SI for experimental details. [b] Yields of isolated product in
parentheses. [c] Yields determined by 1H NMR spectroscopy.
To further demonstrate the usefulness of the protocol,
ADC using different electrophiles was investigated. As can be
seen from Table 2, the reaction worked, although the product
yield varied with both the electrophiles and nucleophiles. In
particular, low yields were obtained with 1,1,1-trifluoroace-
tone and pentafluorobenzaldehyde (6g–h), presumably as
a result of their lower electrophilicity. 1,1,1-Trifluoroacetone
can interact with protic solvents, leading to addition prod-
ucts.[25]
[a] See the SI for experimental details. [b] Yields of isolated product in
parentheses.
addition at the 5-position of indoles is challenging, as the 3-
position is more reactive.[26b] As maybe expected, the Friedel–
Crafts reaction did not proceed when 2-methyl quinoline,
instead of 7, was used under the reaction conditions.
It is known that tetrahydroquinolines can undergo
Friedel–Crafts reactions at the 6-position.[26] Indeed, 2a was
alkylated with TFP at this position when they were mixed in
TFE in the absence of 1d (SI). Following the Friedel–Crafts
reaction, introduction of 1d should trigger dehydrogenation
at the other ring, resulting in a one-pot synthesis of 6-
alkylated quinolines. This would provide a simple way of
generating these products, which are traditionally synthesized
using stoichiometric organometallic reagents.[27] Satisfactorily,
reacting 2a and 7a–e with TFP for 2 h followed by adding the
catalyst 1d afforded 8a–f in excellent yields, regardless of the
position of the substituents on the N-containing ring
(Table 3).
More interestingly, double functionalization of tetrahy-
droquinolines becomes possible when the Friedel–Crafts
reaction is cascaded with the ADC. Table 4 presents the
unprecedented, one-pot sequential Friedel–Crafts addition
and ADC reactions, which allow the functionalization of both
the 6-position and a-methyl of 2a to give 11a in excellent
yield. Two different electrophiles can also be introduced into
the nucleophile in this one-pot strategy, as demonstrated by
the synthesis of the highly functionalized 12a and 13a. Such
double functionalization will be difficult, if not impossible,
À
with Pd-catalyzed C H activation or traditional deprotona-
tion.[17]
We have previously reported that the iridacycles are
capable of catalyzing both hydrogenation and transfer hydro-
genation reactions.[28] Thus, saturated, functionalized N-
heterocycles could also be obtained by reduction in a one-
pot fashion. Indeed, hydrogenating 3a with H2, in situ
generated from 2a through ADC, afforded 15a in 74%
yield at 308C (Scheme 5). Surprisingly, a novel compound 14a
was isolated in 71% yield when the reductant was switched
from H2 to HCO2H. Most likely, the high reaction temper-
Furthermore, functionalized indoles could also be
obtained in good yields (Table 3, 10a,b). Friedel–Crafts
Table 3: Selective Friedel–Crafts addition followed by dehydrogenation of
tetrahdroquinolines and indolines.[a,b]
[a] See the SI for experimental details. [b] Yields of isolated product in
parentheses. [c] Yields determined by 1H NMR spectroscopy.
Scheme 5. In situ reduction of dehydrogenated product with the same
catalyst.
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acceptorless dehydrogenation of the N-heterocycles and site-
À
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Received: January 14, 2015
Published online: && &&, &&&&
À
À
Keywords: C C coupling · C H functionalization ·
dehydrogenation · iridium complexes · N-heterocycles
.
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À
C H Functionalization
Regioselectively functionalized quino-
lines, phenanthrolines, and indoles are
obtained by dehydrogenation of N-het-
erocycles in the presence of electrophiles.
This reaction produces H2 as the only
byproduct under mild conditions.
D. Talwar, A. Gonzalez-de-Castro, H. Y. Li,
J. L. Xiao*
&&&& — &&&&
Regioselective Acceptorless
Dehydrogenative Coupling of N-
Heterocycles toward Functionalized
Quinolines, Phenanthrolines, and Indoles
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