α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: Redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles

Article abstract of DOI:10.1002/anie.201310272

α-Halo and pseudohalo ketones are used for the first time as C(sp³)-based electrophiles in transition-metal-catalyzed C-H activation and as oxidized alkyne equivalents in Rh^III-catalyzed redox-neutral annulations to generate diverse N-heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated. Who needs alkynes? α-Halo and pseudohalo ketones (as C(sp³)-based electrophiles) are utilized as oxidized alkyne equivalents in Rh^III-catalyzed redox-neutral annulations to efficiently generate diverse N-heterocycles. Owing to the mild reaction conditions, a variety of functional groups are tolerated.

Full text of DOI:10.1002/anie.201310272

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Angewandte
Communications
DOI: 10.1002/anie.201310272
À
C H Activation
a-MsO/TsO/Cl Ketones as Oxidized Alkyne Equivalents: Redox-
À
Neutral Rhodium(III)-Catalyzed C H Activation for the Synthesis of
N-Heterocycles**
Da-Gang Yu, Francisco de Azambuja, and Frank Glorius*
Dedicated to Professor Manfred T. Reetz on the occasion of his 70th birthday
Abstract: a-Halo and pseudohalo ketones are used for the first
time as C(sp3)-based electrophiles in transition-metal-catalyzed
III
À
C H activation and as oxidized alkyne equivalents in Rh -
catalyzed redox-neutral annulations to generate diverse N-
heterocycles. This transformation is efficient and scalable. Due
to the mild reaction conditions, a variety of functional groups
could be tolerated.
N
-Heterocycles are ubiquitous in natural products and play
important roles in pharmaceutical and material chemistry.[1]
À
Scheme 1. RhIII-catalyzed synthesis of diverse N-heterocycles. DG=dir-
ecting group, MsO=methanesulfonate, TsO=p-toluenesulfonate.
Recently, transition-metal-catalyzed C H activation has
emerged to be one of the most powerful ways for their
synthesis.[2] RhIII catalysis is especially attractive due to its
high efficiency, mild reaction conditions, and diverse reactions
with a plethora of partners.[3]
Arguably, the annulation with alkynes is one of the most
based electrophiles, as the equivalents of preoxidized alkynes.
frequently applied methods to generate N-heterocycles
Herein, we report our efforts to efficiently use a-MsO/TsO/Cl
III
III
À
À
through Rh -catalyzed directed C H activation (Scheme
ketones in Rh -catalyzed C H activation to synthesize
1A).[4] Often, stoichiometric oxidants, such as CuII and AgI
salts, have to be used to regenerate the active RhIII catalyst.
The advent of oxidizing directing groups has emerged as
a powerful alternative, allowing annulations under redox-
neutral reaction conditions.[5,6] Notably, terminal alkynes,
which were previously not applicable, also underwent the
annulations efficiently and selectively (Scheme 1B).[6] How-
ever, the instability and limited variations of oxidizing
directing groups call for new synthetic tools in this field.
Since p bonds have been thoroughly studied, we decided to
evaluate a-halo or pseudohaloketones, which are C(sp3)-
diverse N-heterocycles under mild and redox-neutral reaction
conditions (Scheme 1C).
Ketones are common substrates in organic synthesis
because of their ready accessibility and stability. Among
them, a-(pseudo)halo ketones are widely applied as electro-
philes in organic reactions,[7] including cross-couplings with
organometallic reagents.[8] Although they have never been
[9]
À
applied in transition-metal-catalyzed C H activation, we
wondered if they would react with the in situ generated
C(sp2)–Rh intermediates. Recently, several groups have
demonstrated that these species undergo Grignard-type
additions to imines,[10] aldehydes,[11] isocyanates,[12] aziri-
dines,[13] and even ketones[14] (Scheme 2A). Moreover, the
alkenyl–Rh intermediates, which are generated by insertion
[*] Dr. D.-G. Yu, F. de Azambuja, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut
À
of alkyne into the C Rh bond, could also nucleophilically
attack the ketone-,[15] imine-,[16] amide-, or ester-based
directing groups[17] (Scheme 2B). All of this evidence sug-
gested that C(sp2)–Rh species show nucleophilic character to
some extent and might attack the a-(pseudo)halo ketones to
produce a-aryl- or alkenyl ketones. With a proper N-
containing directing group, further condensation could gen-
erate the N-heterocycles with the assistance of the RhIII
catalyst (Scheme 2C).
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
[**] We thank Dr. Zhuangzhi Shi, Dr. Honggen Wang, Dr. Dongbing
Zhao, and Corinna Nimphius for invaluable discussions and Jan
Paulmann for preparation of some compounds (all WWU Mꢁnster).
Generous financial support by the Alexander von Humboldt
Foundation (D.-G.Y.), S¼o Paulo Research Foundation (grant 2013/
14209-9, F.deA.), the European Research Council (ERC) under the
European Community’s Seventh Framework Program ((FP7 2007–
2013)/ERC grant agreement no. 25936), and the DFG (Leibniz
award) are gratefully acknowledged.
However, three major challenges have to be overcome:
(1) Selectivity. a-(Pseudo)halo ketones have two electro-
philic sites and the in situ generated rhodacycle also has
two nucleophilic sites. Thus it is challenging to achieve
high regioselectivity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310272.
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Chemie
mesylate 2ad (entry 4) were further tested and generated 3aa
in similarly excellent yields. However, the benzoate 2ae
showed no reactivity (Table 1, entry 5). Notably, the reaction
also occurred under air in good yield (Table 1, entry 6). No
3aa was observed in the absence of RhIII catalyst (Table 1,
entry 7). Other N-substituted amides (with H, Me, Ph, OPiv)
and secondary mesylates were also tested, albeit with no
success.
With the optimized reaction conditions in hand, we first
explored the substrate scope of amides 1 (Scheme 3) with a-
mesyloxyketone 2ad due to its higher atom economy.[20] We
III
À
Scheme 2. Rh -catalyzed C H activation and Grignard-type additions
to different electrophiles.
(2) Inhibition of the catalyst by the leaving groups. In many
cases, silver salts are typically required to remove the
chloride from the rhodium coordination sphere in order
to generate the cationic and highly active RhIII catalyst
and improve efficiency. The generated halides or pseu-
dohalides may lower the reactivity of the catalyst.
(3) Compatibility of the two steps. On the basis of the right
sequence, the reaction conditions, especially the pH, have
to be suitable for both steps.
Scheme 3. Substrate scope: Variation of amides 1. See GP1 in the
Supporting Information. [a] See GP2 in the Supporting Information.
With this in mind, we started to explore the reaction
(Table 1). We chose 1a as the starting material due to its good
directing ability and ease of condensation with carbonyl
group.[18] While 2aa furnished the desired product isoquino-
lone 3aa in low yield, 2ab showed much better reactivity and
gave 3aa in 62% yield (Table 1, entry 2). Notably, this is the
found that the reactions of the amides 1 were sensitive to
À
steric hindrance (3aa and 3ba) and the C H functionalization
took place selectively at the less hindered position (3ca).
Interestingly, the electron density of 1 also played an
important role in this transformation. The amides with
electron-donating groups (EDGs, 1e and 1 f) reacted slower
than those with neutral groups (1a and 1g). However, the
desired isoquinolones 3ea and 3 fa were still obtained in high
yields after a reaction time of 24 h. On the other hand, those
with electron-withdrawing groups (EWGs, 1c, 1d, and 1i–1l)
underwent alkylation faster with full conversion of 1 in 4–
15 h, but the condensation step was very slow. Therefore, acid
was added to speed up the condensation reactions and the
desired isoquinolones were obtained in good yields after few
minutes at room temperature. Due to the mild reaction
conditions, this reaction tolerates many functional groups,
such as MeO, NMe2, CF3, ester, and carbon–halide bonds.
Substrate 1h also showed good reactivity and selectivity and
provided 3ha in high yield.
first example in which halides serve as the leaving group in
III
À
À
Rh -catalyzed C C bond formation through C H activa-
tion.[19] Besides, the C3-monoarylated product 3aa could not
be directly accessed, as disclosed here, in analogous annula-
tions of terminal alkynes.[6] Due to the easy availability and
similar reactivity, the tosylate 2ac (Table 1, entry 3) and
Table 1: Reaction condition optimization.[a]
Entry
X (2a)
Yield [%][b]
1
2
X=Br (2aa)
X=Cl (2ab)
10[c]
62
Furthermore, various mesylates
2 were also tested
(Scheme 4). We found that the steric hindrance of an ortho-
fluoro substituent in substrate 2b did not affect the reaction.
The mesylates with electron-poor substituents (2b, 2 f, 2h,
and 2i) showed higher reactivity than those with electron-rich
substituents (2c and 2e). Similarly, many functional groups
were tolerated in this reaction. Moreover, 2-chloro-1-(4-
fluorophenyl)ethanone (2j) also could afford the desired
product 3aj in moderate yield (Scheme 5).
3
4
5
X=OTs (2ac)
X=OMs (2ad)
X=OBz (2ae)
X=OMs (2ad)
X=OMs (2ad)
86
86
0[c]
80
6[d]
7[e]
0[c]
[a] See GP1 in the Supporting Information. [b] Yield of isolated product.
[c] Yield determined by NMR spectroscopy. [d] Under air. [e] Without RhIII
catalyst.
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and 5ba) and 3-methyl-substituted (5ak) 1,2-benzothiazines
(Scheme 6), which are not easy to synthesize by other
methods. Moreover, due to the high importance of indoles
in natural products and drugs, many methods have been
Scheme 4. Substrate scope: Variation of a-mesyloxyketones 2. See GP1
in the Supporting Information.
Scheme 6. Substrate scope: Reactions of sulfoximines. See GP4 in the
Supporting Information. [a] Yield determined by NMR spectroscopy.
developed to generate indoles from aniline derivatives and
alkynes.[4,5] However, only 2,3-disubstituted indoles could be
Scheme 5. Substrate scope: Reactions of different a-chloro- and a-
tosyloxyketones. See GP1 in the Supporting Information. [a] See GP2
in the Supporting Information. [b] See GP3 in the Supporting Informa-
tion.
III
À
directly formed through Rh -catalyzed C H activation. We
were delighted to find that 2-phenylaminopyrimidine 6
generated 2-methylated indole 7 in good yield using this
strategy [Eq. (3)].
Besides the aryl ketones, we found that a dialkyl ketone
derivative, 2-oxopropyl tosylate (2k), also worked efficiently
(Scheme 5). In addition to 1a, other heteroaryl amides,
including furan 1m, thiophene 1n, and benzothiophene 1o,
also reacted with 2k to generate the bisheterocycles in good
yields. Notably, the condensations were more efficient than
those with aryl ketone derivatives and thus no acid was
necessary. In addition, this transformation is scalable and
practical since a gram-scale reaction was equally efficient
[Eq. (1)]. It is important to note that cyclohexenyl amide 1p
also participated in this reaction to generate highly substi-
Finally, we investigated the mechanism of the reaction
with amides 1. The faster alkylation of amides bearing EWGs
À
indicates that the C H activation might proceed through
a concerted metalation–deprotonation (CMD) mechanism.[21]
À
The reactions of 1aa in CD3OD indicate that the C H
À
tuted 2-pyridone 3pk in a good yield through alkenyl C H
activation [Eq. (2)].
activation is reversible in the absence or presence of 2k
(Scheme 7A and B; see the Supporting Information for
details). Moreover, the electron density of the arene affects
the condensation of the ketone intermediates I (Scheme 7C).
For electron-poor amides, the nucleophilicity of nitrogen is
lower than for those substituted with EDGs. In addition, the
acidity of the a-H of corresponding ketone intermediates I is
expected to be higher and the enols II would be more favored,
which will slow down the condensation. This may also explain
why the reactions with 2k, whose ketone intermediates I are
Besides the isoquinolones and 2-pyridones, we also
applied this method to construct other important N-hetero-
cycles with diverse directing groups. Recently, Bolm and co-
workers disclosed the RhIII-catalyzed oxidative annulation of
sulfoximines with internal alkynes to generate 3,4-disubsti-
tuted 1,2-benzothiazines efficiently.[4p] Under slightly modi-
fied reaction conditions, sulfoximines (4a and 4b) also
showed good reactivity in the construction of 3-aryl- (5aa
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Keywords: C H activation · isoquinolones · ketones ·
N-heterocycles · rhodium catalysis
.
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Scheme 7. Mechanistic studies and discussion.
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À
only catalyzed the C H activation and addition to the a-
(pseudo)halo ketones but also promoted the condensation
(Scheme 7D).[18]
In conclusion, we have demonstrated that the a-halo and
pseudohalo ketones could be utilized as oxidized alkyne
equivalents in RhIII-catalyzed redox-neutral annulation to
efficiently generate diverse N-heterocycles. This seems to be
the first time that a-halo and pseudohalo ketones have served
as C(sp3)-based electrophiles in transition-metal-catalyzed
À
C H activation. Various 3-aryl- and 3-alkyl-substituted iso-
quinolones and a 2-pyridone could be generated in moderate
À
to excellent yields through aryl and alkenyl C H activation,
respectively. Notably, this transformation is efficient and
scalable. Moreover, the generality of this method has been
demonstrated by the efficient and selective synthesis of some
C-monoarylated 1,2-benzothiazines and a C-monomethylated
indole, which are not easy to obtain by other methods. Due to
the mild reaction conditions, a variety of functional groups are
compatible with this transformation, leaving the opportunity
for potential further functionalization.
Received: November 26, 2013
Published online: February 2, 2014
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À
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