Rh(III)-catalyzed chemoselective C-H functionalizations of tertiary aniline: N -oxides with alkynes

Article abstract of DOI:10.1039/c6cc02217k

In this work, we report novel Rh(iii)-catalyzed chemoselective functionalizations of tertiary aniline N-oxides with alkynes, including annulation via the sequential C(sp²)-H and C(sp³)-N activation for the formation of N-alkylindoles and an O-atom transfer (OAT) process for the synthesis of acetophenones.

Full text of DOI:10.1039/c6cc02217k

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Rh(III)-catalyzed chemoselective C–H functionalizations of tertiary
aniline N-oxides with alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaolei Huang, Wenbo Liang, Yang Shi and Jingsong You*
DOI: 10.1039/x0xx00000x
www.rsc.org/
In this work, we report novel Rh(III)-catalyzed chemoselective developed (Scheme 1c).7 We envision that the C(sp3)−N bond
functionalizations of tertiary aniline N-oxides with alkynes, activation could be integrated with the Rh(III)-catalyzed ortho-C–H
including an annulation via the sequential C(sp2)–H and C(sp3)–N activation of tertiary aniline N-oxides to form valuable heterocyclic
activations for the formation of N-alkylindoles and an O-atom compounds using alkynes as the coupling partner.
transfer (OAT) process for the synthesis of acetophenones.
Rh(III)-catalyzed ortho-C-H activation
R1
R2
Tertiary anilines are important building blocks in organic synthesis
R1
R2
N
O
N
R
and widely exist in natural products, pharmaceuticals and material
molecules.1 Thus, the transformations of tertiary anilines are a
lasting hot topic in organic chemistry. Because of electron-donor
characteristics and steric hindrance, ortho-selective aromatic C–H
Rh(III)
R
a)
b)
+
C(sp2)-H/C(sp2)-H activation
R1
R1
N
O
N
CO2
R
N2
Rh(III)
CO2R
functionalization of tertiary anilines remains
a tremendous
+
C(sp2)-H/C(sp3)-H activation
RO2
C
CO2R
challenge. To resolve this problem, our group recently developed a
Rh(III)-catalyzed ortho-C–H activation strategy2,3 using tertiary
aniline N-oxides as both the internal oxidant and the traceless
directing group for the synthesis of 2-alkenylated tertiary anilines
(Scheme 1a).4 Later, with this strategy, Zhou and co-workers
reported a Rh(III)-catalyzed regioselective annulation reaction of 1-
naphthylamine N-oxides with diazo compounds via C(sp2)–
H/C(sp3)–H activation to afford various 1H-benzo[g]indoline
derivatives (Scheme 1b).5 As far as we know, this traceless internal
oxidant/directing strategy is only applied in the coupling reactions
with olefins and diazo compounds so far, and it is thus highly
valuable to develop new transition metal-catalyzed ortho-C–H
activation/functionalizations of tertiary aniline N-oxides to further
demonstrate the synthetic utility of this strategy.
Transition metal-catalyzed or mediated C(sp3)-N activation
R1
R1
R2
[M]
R1
[M]
c)
N
R2
N
CH2R3
[M]
N
R2
oxidant
R3
This work: C-H functionalizations via the substrate-controlled selectivity switch
R1 R2 R2
R1
R3
N
R3
N
O
R1
N
Rh(III)
OAT
R3
Rh(III)
C(sp2)-H/C(sp3)-N activation
O
R
d)
+
R
R4
R
R4
R4
R
nitro and acetyl etc.
R = alkyl, methoxy, halogens, ester etc.
R1 = alkyl, R2 = alkyl
=
or cyclic arylamine -oxides
N
Scheme 1. Evolution of Rh(III)-catalyzed C–H functionalizations of tertiary aniline
N-oxides.
Meanwhile, transition metal-catalyzed activation of the C−N
bond has been attracting great interest since 2010.6 Since tertiary
anilines are a kind of important N-containing compounds, cleaving
the C−N bonds of terꢀary anilines and uꢀlizing the generated
nitrogen and carbon sources in organic synthesis are of great
significance. However, owing to the high C−N bond dissociation
energy, the C−N bond acꢀvaꢀon of terꢀary anilines, especially
C(sp3)−N bonds, is sꢀll a significant challenge and remains less
It is known that N-oxides can undergo an O-atom transfer (OAT)
to alkynes through transition metal catalysis.8 Recently, the groups
of Li,9a Chang,9b,9c Lu,9d Sundararaju,9e and Ackermann9f successfully
combined an OAT process and a Rh(III)- or Co(III)-catalyzed N-oxide
assisted aromatic C–H activation of quinoline N-oxides and
arylnitrones with alkynes to afford substituted acetophenones. A
Rh(III)-catalyzed OAT from tertiary aniline N-oxides to
diazomalonates was reported by Zhou and co-workers in 2015.5
Herein, we would like to disclose Rh(III)-catalyzed chemoselective
C–H functionalizations of tertiary aniline N-oxides with alkynes,
including an annulation via the sequential C(sp2)–H and C(sp3)–N
activations to provide N-alkylindole derivatives10,11 and an OAT
process to deliver acetophenone derivatives (Scheme 1d).
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Our study commenced with the annulation of N,N- in satisfactory yields (3d-3k). 3,4-Disubstituted N,N-dimethylaniline
dimethylaniline N-oxide 1a and diphenylacetylene 2a as the model N-oxide could also undergo the annulation in a 62% yield (3l).
reaction (For details, see Table S1 in ESI). Initially, using 5.0 mol% of Furthermore, N-ethyl-N-methylaniline N-oxide reacted with 2a to
[Cp*RhCl2]2 (Cp* = pentamethylcyclopentadienyl) and 20 mol% of produce N-ethyl and N-methyl substituted indoles 3b and 3a in 47%
AgSbF6 as the catalyst, and 2.0 equiv of PivOH as the additive in and 18% yields, respectively (eq. 1). When N-benzyl-N-
methanol at 60 °C for 24 h, a 60% yield of the desired N- methylaniline N-oxide was treated with 2a, a 72% yield of 3a and a
methylindole derivative 3a along with a 25% yield of the OAT 13% yield of benzaldehyde were obtained without the formation of
product 3a′ as a by-product was obtained (Table S1, entry 1). Other N-benzyl substituted indole (eq. 2). These observations indicate an
solvents such as 1,4-dioxane, DMF, DCE and t-AmOH were less order of reactivity of C(benzyl)−N > C(methyl)−N > C(ethyl)−N,
effective for the formation of 3a (Table S1, entries 2-5). Next, which provides a significant hint for the selective cleavage of the
various acid and base additives were investigated. CyCOOH proved C(alkyl)–N bonds.
to be superior to PivOH, HOAc, CF3COOH, AdCOOH, Cu(OAc)2 and
CsOPiv, and 3a was obtained in a 70% yield (Table S1, entries 1 and
6-11). The yields of 3a were decreased when AgPF6, AgOPiv, and
AgOAc were used instead of AgSbF6 (Table S1, entries 12-14). It is
noteworthy that 3a could be obtained in a 44% yield in the absence
of Ag+ salt (Table S1, entry 15). Increasing the loading of AgSbF6 to
40 mol% from 20 mol% led to a comparable yield of 3a (Table S1,
entries 9 and 16). Furthermore, the reaction of 1a with 1.0 equiv of
2a in the presence of 1.2 equiv of AgSbF6 gave the 3a in a 61% yield.
(Table S1, entry 17). Using N,N-dimethylaniline or N-methylaniline
instead of the N-oxide 1a as the substrate, no desired product was
formed (Table S1, entry 18), which suggests the key role of the N–O
bond for the transformation. Thus, we established the catalytic
system comprising [Cp*RhCl2]2 (5.0 mol%), AgSbF6 (20 mol%) and
CyCOOH (2.0 equiv) in MeOH under an N2 atmosphere at 60 °C for
24 h.
Et
N
O
Ph
Et
[RhCp*Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
N
N
Ph
Ph
+
+
(1)
CyCOOH (2.0 equiv)
MeOH, 60 oC, 24 h
Ph
Ph
Ph
3b, 47% by 1H NMR
3a, 18% by 1H NMR
1m
2a
N
O
Ph
CHO
Bn
[RhCp*Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
N
Ph
+
+
CyCOOH (2.0 equiv)
MeOH, 60 oC, 24 h
(2)
Ph
Ph
3a, 72%
13% by 1H NMR
1n
2a
R1
R1
N
O
R1
[RhCp*Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
CyCOOH (2.0 equiv)
MeOH, 60 oC, 24 h
N
+
Ph
R
Ph
Ph
R
Ph
2a
1
3
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
, 57%
Ph
3c, 60%a
3a, 70%
3e, 52%
3i, 53%
3d, 72%
3b
N
N
N
N
Ph
Ph
Ph
Ph
But
MeO
Br
Ph
Ph
N
Ph
Ph
3f, 65%a
3g, 80%
3h
, 60%
EtO2C
Br
Cl
N
N
F
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3k, 62%a
3l, 62%
3j, 66%
Scheme 3 The scope of alkynes. Reaction conditions: 1a (0.50 mmol, 2.0 equiv), 2
(0.25 mmol), [RhCp*Cl2]2 (5.0 mol%), AgSbF6 (20 mol%) and CyCOOH (2.0 equiv)
in MeOH (1.0 mL) at 60 oC for 24 h under an N2 atmosphere. Isolated yields are
given. a AgSbF6 (40 mol%) and 110 oC were used.
Scheme 2 The scope of tertiary aniline N-oxides. Reaction conditions: 1 (0.50
mmol, 2.0 equiv), 2a (0.25 mmol), [RhCp*Cl2]2 (5.0 mol%), AgSbF6 (20 mol%) and
CyCOOH (2.0 equiv) in MeOH (1.0 mL) at 60 oC for 24 h under an N2 atmosphere.
Isolated yields are given. a AgSbF6 (40 mol%) and 110 oC were used.
Next, we examined the scope of the internal alkynes. A variety of
diarylacetylenes containing the common functional groups such as
Me, MeO, But, X (X = F, Cl), and CF3 could smoothly undergo the
annulation process with N,N-dimethylaniline N-oxide 1a to form the
indole derivatives (Scheme 3, 4a-4h). In addition, the
unsymmetrical prop-1-yn-1-ylbenzene was compatible with the
protocol, affording the desired product with an exclusive
regioselectivity in a moderate yield (Scheme 3, 4i). When the
With the optimal conditions in hand, we next explored the scope
of tertiary aniline N-oxides. As summarized in Scheme 2, various
N,N-dialkyl aniline N-oxides could react with diphenylacetylene to
afford the corresponding N-alkylindoles (3a-3c). Moreover, both the
electron-donating (Me, But, and MeO) and electron-withdrawing
groups (F, Cl, Br, and CO2Et) on the phenyl ring of aniline N-oxides
were compatible with this protocol, delivering the desired products
2 | J. Name., 2012, 00, 1-3
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reaction of N,N-dimethylaniline N-oxide 1a with terminal a 10% yield of 3a was obtained (eq. 4, E). Thus, although the details
phenylacetylene, no desired product was detected (Scheme 3, 4j).
of the indole formation is not entirely clear at the present stage, the
pathway involving the generation of the OAT product and the
subsequent cyclization seems less favored.
Scheme 4 Rh(III)-catalyzed O-atom transfer reactions of tertiary aniline N-oxides
with alkynes. Reaction conditions: 1 (0.50 mmol, 2.0 equiv), 2 (0.25 mmol),
[RhCp*Cl2]2 (5.0 mol%), AgSbF6 (20 mol%) and CyCOOH (2.0 equiv) in MeOH (1.0
mL) at 60 oC for 24 h under an N2 atmosphere. Isolated yields are given.
Interestingly, when the N,N-dimethylaniline N-oxides with the
strong electron-withdrawing nitro and acetyl groups on the phenyl
ring were treated with diphenylacetylene under the standard
conditions, the OAT products rather than N-methylindoles were
formed exclusively (Scheme 4, 5a-5c). In addition, cyclic arylamine
N-oxides could also participate in the OAT reaction. For example,
various 1−arylpiperidine N−oxides containing both the electron-
donating and electron-withdrawing groups coupled with
diphenylacetylene to afford the OAT products in good to excellent
yields (Scheme 4, 5f-5k).
The H/D exchange experiments implied that the ortho-C–H bond
cleavage was a reversible process (eq. 5). A KIE value of 1.9 was
observed in an intermolecular competition reaction between 1a
and 1a-[D5] with 2a (eq. 6 and eq. 7), demonstrating that the C–H
bond cleavage might be related with the rate-determining step.12
Moreover, the five-membered cyclometalated Rh(III) complex 6
could serve as the catalyst in the reaction of 1g with 2a to give the
desired product 3g in a 48% yield (eq. 8). This result indicate the
possible intermediacy of a rhodacycle species in the catalytic cycle.
An O18 labeling experiment was performed, and no O18
incorporation was observed in the product, showing that the N-
oxide group is likely the source of O atom in the formation of
acetophenones (eq. 9).9a
Based on the the above observations, a plausible mechanistic
pathway of the formation of N-alkylindoles is proposed in Scheme 5.
First, the N-oxide-assisted C−H acꢀvation reaction of 1a with the
[Rh(III)Cp*] species affords the cyclometalated Rh(III) species IM1,
which further reacts with alkyne 2a to form the intermediate IM2
via a migratory insertion process. Next, the reaction encounters two
possible pathways. In path a, IM2 undergoes a methyl C(sp3)−Rh
bond formation to give the intermediate IM3. After an
intramolecular rearrangement, IM3 is converted to IM4, which may
also be generated from a Polonovski-type reaction of IM2.5 IM4
undergoes the C=N bond cleavage,7c-7f leading to the intermediate
IM5 with the release of one molecule of formaldehyde.
Furthermore, a reductive elimination results in 3a and [Rh(I)Cp*]
species. Finally, the generated [Rh(I)Cp*] species is reoxidized to
To gain some preliminary insights into the reaction mechanism,
further experiments were carried out. First, 0.14 mmol of N,N-
dimethylaniline was isolated from the reaction of 1a and 2a under
the standard conditions, indicating that N,N-dimethylaniline N-
oxide 1a also serves as an oxidant in the annulation (eq. 3). Next, a
series of control experiments on the conversion of the OAT product
3a′ into N-methylindole 3a were performed. The results showed
that the isolated 3a′ could not be converted into 3a without AgSbF6
(eq. 4, A, B, D). Treatment of 3a′ in the presence of AgSbF6 in MeOH
afforded 3a in a 14% yield (eq. 4, C). Under the standard conditions,
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3
For selected reviews on Rh(III)-catalyzed C−H acꢀvaꢀon, see:
(a) T. Satoh and M. Miura, Chem.—Eur. J., 2010, 16, 11212;
(b) D. A. Colby, A. S. Tsai, R. G. Bergman and J. A. Ellman, Acc.
Chem. Res., 2012, 45, 814; (c) G. Song, F. Wang and X. Li,
Chem. Soc. Rev., 2012, 41, 3651; (d) G. Song and X. Li, Acc.
Chem. Res., 2015, 48, 1007.
For selected examples on Rh(III)-catalyzed redox-neutral C−H
activation, see: (a) N. Guimond, S. I. Gorelsky and K. Fagnou,
J. Am. Chem. Soc., 2011, 133, 6449; (b) Y.-F. Wang, K. K. Toh,;
J.-Y. Lee and S. Chiba, Angew. Chem. Int. Ed., 2011, 50, 5927;
(c) G. Liu, Y. Shen, Z. Zhou and X. Lu, Angew. Chem. Int. Ed.,
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Chem. Int. Ed., 2013, 52, 12426; (e) B. Liu, C. Song, C. Sun, S.
Zhou and J. Zhu, J. Am. Chem. Soc., 2013, 135, 16625; (f) S.
Yu, S. Liu, Y. Lan, B. Wan and X. Li, J. Am. Chem. Soc., 2015,
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the [Rh(III)Cp*] species by 1a to complete the catalytic cycle. In
another route (path b), the reductive elimination of IM2 affords the
intermediate IM6, which is further transformed into IM7 or IM8 via
an oxidative addition.9d After a protonation, the OAT product 3a′ is
generated. In the presence of Ag+, the C(sp3)−N bond cleavage of 3a′
gives IM9.13 Further intramolecular nucleophilic addition and β-
hydride elimination produce the indole 3a.
4
5
6
X. Huang, J. Huang, C. Du, X. Zhang, F. Song and J. You,
Angew. Chem. Int. Ed., 2013, 52, 12970.
B. Zhou, Z. Chen, Y. Yang, W. Ai, H. Tang, Y. Wu, W. Zhu and Y.
Li, Angew. Chem. Int. Ed., 2015, 54, 12121.
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Chem. Rev., 2011, 111, 4073; (b) K. Ouyang, W. Hao, W.-X.
Zhang and Z. Xi, Chem. Rev., 2015, 115, 12045.
7
For selected examples, see: (a) S. Ueno, N. Chatani and F.
Kakiuchi, J. Am. Chem. Soc., 2007, 129, 6098; (b) Y. Kuninobu,
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,
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Baiyin and M. Jia, J. Org. Chem., 2014, 79, 803; (g) Y. Zhao
and V. Snieckus, Org. Lett., 2014, 16, 3200.
8
9
(a) X. Li, C. D. Incarvito, T. Vogel and R. H. Crabtree,
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Chem. Commun., 2009, 5233; (c) J. Xiao and X. Li, Angew.
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Scheme 5 Plausible mechanism for the formation of N-alkylindole.
(a) X. Zhang, Z. Qi and X. Li, Angew. Chem. Int. Ed., 2014, 53
,
In conclusion, we have addressed for the first time a Rh(III)-
catalyzed regioselective annulation of tertiary aniline N-oxides with
alkynes via the sequential C(sp2)–H and C(sp3)–N activation, which
provides a novel method to prepare N-alkylindoles. Using N-oxide
as a traceless directing group, this annulation proceeds well under
the mild reaction conditions and does not need metal oxidants. The
N,N-dimethylaniline N-oxides with the strong electron-withdrawing
nitro and acetyl groups on the phenyl ring and cyclic arylamine N-
oxides encounter a selectivity switch to afford the OAT products
rather than the indole derivatives under the same conditions.
Further investigation to verify the mechanism of this methodology
is in progress.
10794; (b) U. Sharma, Y. Park and S. Chang, J. Org. Chem.,
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,
6
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,
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Academic Press, San Diego, 1996; (b) T. Eicher and S.
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This work was supported by grants from the National NSF of
China (Nos 21432005, 21272160 and 21321061).
Notes and references
1
For selected examples, see: (a) A. Hagfeldt, G. Boschloo, L.
Sun, L. Kloo and H. Pettersson, Chem. Rev., 2010, 110, 6595;
(b) P. Ruiz-Sanchis, S. A. Savina, F. Albericio and M. Álvarez,
Chem. Eur. J., 2011, 17, 1388; For selected books, see: (c) C.-
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the Chemistry of Organic Natural Products, Vol. 96 (Eds.: A. D.
Kinghorn, H. Falk, J. Kobayashi), Springer-Verlag, New York,
2012.
,
4 | J. Name., 2012, 00, 1-3
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