N-oxide as a traceless oxidizing directing group: Mild rhodium(III)- catalyzed C - H olefination for the synthesis of ortho-alkenylated tertiary anilines

Article abstract of DOI:10.1002/anie.201307174

Double role: A traceless directing group also acts as an internal oxidant in a novel Rh^III-catalyzed protocol developed for the synthesis of ortho-alkenylated tertiary anilines (see scheme). A five-membered cyclometalated Rh^III complex is proposed as a plausible intermediate and confirmed by X-ray crystallographic analysis. Copyright

Full text of DOI:10.1002/anie.201307174

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Communications
DOI: 10.1002/anie.201307174
À
C H Activation
N-Oxide as a Traceless Oxidizing Directing Group: Mild
À
Rhodium(III)-Catalyzed C H Olefination for the Synthesis of ortho-
Alkenylated Tertiary Anilines**
Xiaolei Huang, Jingsheng Huang, Chenglong Du, Xingyi Zhang, Feijie Song, and Jingsong You*
À
Tertiary anilines are important structural motifs frequently
found in pharmaceuticals, dyes, natural products, biologically
active molecules, and organic functional materials,[1] and their
functionalization has been attracting great interest in the
synthetic organic chemistry community. It is well known that
the electron-donor characteristics and the steric hindrance of
tertiary amino groups commonly lead to the preferential
para-functionalization of anilines through the Friedel–Crafts
directing groups is starting to attract interest in C H
activation,[9] which has the clear advantages of high levels of
selectivity for ortho and monocoupling as well as improved
levels of reactivity. The elegant contributions from the
research groups of Cui and Wu, Fagnou, Glorius, Ackermann,
Hartwig, Li, Jeganmohan, Chiba, and Lu have disclosed that
quinoline N-oxides, hydroxamic acids and their derivatives,
oximines, vinyl azides, and N-phenoxyacetamides can
[10]
À
À
pathway and renders the ortho-selective C H functionaliza-
undergo an external-oxidant-free C H activation reactions.
tion of tertiary anilines difficult. Therefore, the transition-
It is known that easily available tertiary aniline N-oxides are
not only prototypical oxidants,[11] but also coordinate readily
to metal centers.[12] In addition, several reports have shown
that the functionalization at ortho position to the nitrogen
atom of pyridine and other heterocycles can be achieved by
using the N-oxide group as a key platform.[10a,13] Therefore, we
envisioned that these properties could be combined to
develop a strategy based on a traceless oxidizing directing
À
metal-catalyzed chelation-assisted aromatic C H functional-
ization through a cyclometalation should be an ideal strategy
to meet these substantial challenges.[2]
Generally, primary and secondary anilines can be con-
veniently substituted to install various directing groups (e.g.,
the NH- or N-substituted urea and amide, phosphoramidate,
2-pyridylsulfonyl, 2-pyridyl, N-nitroso, and methanesulfon-
À
À
amide groups) for aromatic C H functionalization at the
group to achieve the ortho-selective aromatic C H function-
alization of tertiary anilines, in which the five-membered
cyclometalated intermediate could be formed easily.
proximal site.[3] Very recently, Miura et al. and Jiao et al. have
reported that primary anilines can serve as a directing group
[4,5]
À
À
for ortho C H olefination and azidation, respectively.
In
The metal-catalyzed oxidative olefination of aryl C H
addition, the N,N-dimethylaminomethyl group has been
disclosed as a directing group for both oxidative Heck and
arylation reactions.[6] However, the transition-metal-cata-
bonds has emerged as one of the most important methods for
creating functionally diverse and structurally complex aro-
matic compounds.[14,15] In recent reports, acetanilide and its
derivatives, N-(2-pyridyl)sulfonyl anilines, and N-nitros-
amines have proven to be very effective in directing
transition-metal-catalyzed C H olefination (Scheme 1).
À
lyzed C H activation of tertiary anilines remains less
developed except for few examples on para-selective trans-
formations[7] and the recently reported oxidative ortho C H
[3g,i,16]
À
À
À
alkenylation/N-dealkylative carbonylation of tertiary anilines
Herein, we report on the Rh-catalyzed ortho C H olefination
(tertiary amines probably act as a directing group).[8] There-
of tertiary aniline N-oxides to illustrate our strategy based on
a directing group that is also an internal oxidant for the ortho
functionalization of tertiary anilines (Scheme 1).
À
fore, it is highly valuable to develop C H activation for the
synthesis of ortho-functionalized tertiary anilines.
While the amino group of tertiary anilines is directly used
as the directing group, the four-membered cyclometalated
intermediate will be formed. This type of cyclometalated
species is usually not easily available. Recently, the use of
oxidizing directing groups as both internal oxidants and
[*] X. Huang, J. Huang, C. Du, X. Zhang, Dr. F. Song, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry
and State Key Laboratory of Biotherapy
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (PR China)
E-mail: jsyou@scu.edu.cn
[**] This work was supported by grants from the National Basic
Research Program of China (973 Program, 2011CB808600), and the
National NSF of China (nos. 21025205, 21272160, 21021001, and
J1103315J0104).
Scheme 1. Evolution of the transition-metal-catalyzed ortho-selective
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307174.
C H olefination of diverse anilines. FG=functional group, DG=dir-
ecting group.
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We started our exploration with attempts to perform the
olefination of N,N-dimethylaniline N-oxide (1a) with ethyl
acrylate (2a) to afford the ortho-alkenylated N,N-dimethyla-
niline 3a (for details, see Table S1 in the Supporting
Information). After we had screened several parameters
(e.g., metal source, additive, and solvent), the catalytic system
comprising [{Cp*RhCl2}2] (2.5 mol%) (Cp* = C5Me5),
AgSbF6 (10 mol%), CsOPiv (30 mol%), and PivOH
(2.0 equiv) in MeOH proved to be efficient. Under these
conditions, 3a was obtained in 75% yield along with a trace
amount of N,N-dimethylaniline (less than 5%), which ruled
out the action of tertiary aniline N-oxides as external oxidants
(Table S1, entry 15). Further experiments indicated that an
excess of N-oxide 1a turned out to benefit the coupling
reaction, and 3a was obtained in 89% yield at 908C (Table S1,
entry 16). We were pleased to find that the reaction could give
the coupled product 3a in 80% yield along with the recovery
of 0.8 equiv of N-oxide 1a at room temperature (Table S1,
entries 17 and 18). It is worth noting that no product was
observed when N,N-dimethylaniline was used instead of 1a
(Table S1, entry 19).
oxides possessing either electron-donating or electron-with-
drawing groups on the phenyl ring could undergo the
olefination (3h–3q). 3,4-Disubstituted N,N-dimethylaniline
N-oxides smoothly afforded the products in good yields (3r
and 3s). The completely regioselective coupling occurred at
the sterically less hindered position. Surprisingly, the 2-
naphthylamine-derived N-oxide gave the C3-alkenylated
product in 77% yield, whereas N,N-dimethyl-1-naphthyl-
amine N-oxide produced the C2-alkenylated target in only
9% yield (3t and 3u). N-Methyl-1,2,3,4-tetrahydroquinoline
N-oxide underwent this transformation in 62% yield (3v). It
is notable that N,N-diethylaniline N-oxide had limited
reactivity under the optimized conditions probably due to
the steric hindrance of diethyl group (3e).
Subsequently, we investigated of the scope of olefins and
found that other acrylates had similar reactivity (Scheme 3,
4a–4d). Acrylamide and vinyl phosphonate also served in the
olefination to give products in acceptable yields (Scheme 3,
4e and 4g). The rhodium-catalyzed coupling of acrylonitrile
with 1a required an elevated temperature (908C).
With the optimized conditions in hand, we next examined
the scope of this methodology. As summarized in Scheme 2,
various N-methyl-N-alkylaniline N-oxides smoothly reacted
with acrylate 2a to afford the corresponding mono-alkeny-
lated products in moderate to high yields. For example, N-
benzyl-N-methylaniline N-oxide coupled with 2a to afford 3d
in 64% yield. The reactive site is located in the C2 position of
the aniline rather than the aromatic ring of the benzyl group.
Moreover, cyclic amine N-oxides could be transformed to the
desired products in satisfactory yields (3 f and 3g). Aniline N-
Scheme 3. The scope of the olefins. Unless otherwise noted, the
reactions were performed using 1 (1.0 mmol), 2a (0.5 mmol), and
MeOH (1 mL) at room temperature. Yields refer to the yield of isolated
product based on 2. [a] Reaction temperature: 908C.
Alkenylated tertiary anilines frequently appear in organic
functional materials such as OLEDs and photoluminescent
materials.[1a,b,d,17] In this context, we examined the synthetic
usefulness of our protocol for the rapid elongation of p-
conjugated skeletons of existing tertiary dianilines for the
screening of fluorescent molecules. (E,E)-2,5-Bis[2-(ethoxy-
carbonyl)ethenyl]-1,4-dipiperidinobenzene (6a),a minimal
fluorophore reported by the Shimizu group,[17a] could be
obtained in a very simple manner through the coupling of 1,4-
bis(N-piperidinyl)benzene N,N’-dioxide (5a) with ethyl acry-
late (2a). Nonfluorescent N,N,N,N-tetramethyl-(1,1’-biphen-
yl)-4,4’-diamine and N,N,N,N-tetramethyl-(1,1’-biphenyl)-
3,3’-diamine could be conveniently transformed to the
luminescent dialkenylated tertiary dianilines 6b and 6c,
respectively. These novel p-conjugated molecules with
a “push–pull” p-electron system exhibited significant fluo-
rescence emission in both the solid state and in solution
(Figure 1; for details, see Figures S1–S3 and Tables S2–S4 in
the Supporting Information).
Scheme 2. The scope of the tertiary aniline N-oxides. Unless otherwise
noted, the reactions were performed using 1 (1.0 mmol), 2a
(0.5 mmol), and MeOH (1 mL) at room temperature for 24 h. Yields
refer to the yield of isolated product based on 2a. [a] Reaction
temperature: 908C. [b] Reaction time: 48 h.
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To gain insight into the mechanism of the olefination, the
following experiments were conducted. A hydrogen/deute-
rium exchange experiment showed that cleavage of the ortho
À
C H bond was a reversible process [Eq. (1)]. A primary
kinetic isotopic effect (KIE) of 2.4 was observed for two
parallel competition reactions between 1a and [D5]-1a with
ethyl acrylate (2a) [Eq. (2)],[10l,20,21] which revealed that the
À
C H bond cleavage might be involved in the rate-determin-
ing step.[22] In addition, the competition reactions between
electronically differentiated 1a and 1k, and 1j and 1k with 2a
afforded 3a/3k and 3j/3k in ratios of 4.75 and 6.10,
respectively [Eq. (3)]. The higher reactivity of the electron-
rich arenes suggests that an electrophilic-type rhodation
might be involved in the catalytic cycle.[23]
Fortunately, the five-membered cyclometalated RhIII
complex 10 was obtained and its structure was established
by X-ray crystallographic analysis (Figure 2).[24] The complex
10 could not only react stoichiometrically with ethyl acrylate
(2a), but also catalyze the olefination of 1p to afford the
Figure 1. Top: Structures of 6a–c. Bottom: Normalized emission
spectra of 6b and 6c.
Subsequently, we tried to perform debenzylation of 3d
(Scheme 4). Using 3% Pd/C and 1.2 equiv of NaH2PO2·H2O
in MeOH/H2O,[18a] we obtained the secondary aniline 7 in
desired product 3p in 42% and 63% yield, respectively (for
details, see the Supporting Information, Part IX), which
implies the possible intermediacy of a five-membered com-
plex in the catalytic cycle.
Based on the above observations, a plausible mechanistic
pathway is proposed (Scheme 5). First, the cyclorhodium
intermediate A was formed through the reaction of N-oxide
with the [RhIIICp*] species generated from [{RhCp*Cl2}2] and
AgSbF6, and a subsequent reversible carboxylate-assisted
Scheme 4. Debenzylation of 3d.
74% yield, which could further be transformed into 1-
methylquinolin-2(1H)-one (8) in 73% yield.[18b] Interestingly,
when we increased the amount of NaH2PO2·H2O to 3.0 equiv,
debenzylation and reduction of alkene occurred synchro-
nously to produce 1-methyl-3,4-dihydroquinolin-2(1H)-one
(9) in 86% yield. The system of Raney Ni in MeOH/H2O/
H2SO4 could also realize this transformation in 82% yield.[18c]
It is worth noting that both quinolin-2(1H)-one and 3,4-
dihydroquinolin-2(1H)-one derivatives are structural units
found in many pharmacologically important natural and
synthetic compounds, and also are versatile building blocks
for the synthesis of structurally complex compounds.[3i,19]
Figure 2. ORTEP diagram of complex 10. Thermal ellipsoids are shown
at the 50% probability level.
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[2b,23]
À
electrophilic C H activation process.
The resulting
intermediate A coordinated with an olefin to give the
complex B, which was transformed into C by migratory
insertion of alkene. After b-hydride elimination along with
[8] At the time we submitted our manuscript, Lei et al. reported an
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À
the N O bond cleavage, the desired product was released,
À
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a traceless directing group that is also an internal oxidant to
À
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achieve the ortho C H functionalization of tertiary anilines.
À
This tactic was used for the highly selective ortho C H
olefination of easily available tertiary aniline N-oxides to
prepare 2-alkenylated tertiary anilines. The rhodium-cata-
lyzed external-oxidant-free synthesis presents a series of
advantages, such as very mild conditions (room temperature),
avoidance of bisolefinated anilines, complete ortho selectivity,
and relatively broad functional group tolerance. We believe
that this protocol represents a practical route to alkenylated
tertiary anilines.
Received: August 15, 2013
Published online: November 12, 2013
À
Keywords: anilines · C H activation · olefination ·
.
directing groups
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