Rhodium(iii)-catalyzed C-H activation/[4+3] annulation of N-phenoxyacetamides and α,β-unsaturated aldehydes: An efficient route to 1,2-oxazepines at room temperature

Article abstract of DOI:10.1039/c4cc05485g

An efficient Rh(iii)-catalyzed coupling reaction of N-phenoxyacetamides with α,β-unsaturated aldehydes to give 1,2-oxazepines via C-H activation/[4+3] annulation has been developed. This transformation does not require oxidants and features C-C/C-N bond formation to yield seven-membered oxazepine rings at room temperature. Further derivation of 1,2-oxazepines leads to important chroman derivatives. This journal is

Full text of DOI:10.1039/c4cc05485g

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Rhodium(III)-catalyzed C–H activation/[4+3]
annulation of N-phenoxyacetamides and
a,b-unsaturated aldehydes: an efficient route
to 1,2-oxazepines at room temperature†
Cite this: Chem. Commun., 2014,
50, 12135
Received 18th July 2014,
Accepted 15th August 2014
Pingping Duan,a Xia Lan,a Ying Chen,a Shao-Song Qian,b Jie Jack Li,c Liang Lu,d
DOI: 10.1039/c4cc05485g
Yanbo Lu,a Bo Chen,*a Mei Hong*a and Jing Zhao*ad
www.rsc.org/chemcomm
An efficient Rh(III)-catalyzed coupling reaction of N-phenoxyacetamides
with a,b-unsaturated aldehydes to give 1,2-oxazepines via C–H
activation/[4+3] annulation has been developed. This transformation
does not require oxidants and features C–C/C–N bond formation to
yield seven-membered oxazepine rings at room temperature. Further
derivation of 1,2-oxazepines leads to important chroman derivatives.
Rhodium-catalyzed chelation-assisted C–H activation–annulation
reaction has emerged as a powerful tool for the construction of
diversified complex molecules.1 [Cp*RhIII] is a well-known catalyst
for the C–H bond activation, thanks to its high efficiency, mild
reaction conditions and excellent functional group compatibility.
The direct insertion of unsaturated molecules has been developed
in RhIII-catalyzed direct aryl C–H functionalization.2 While
several examples have been reported on the formation of five-
and six-membered ring scaffolds, studies using the [Cp*RhIII]
complex to form seven-membered rings lag behind and the
Scheme 1 Heterocycle synthesis through oxyacetamide-directed C–H
activation/annulation.
examples are rare.3 Notably, there are three reports highlighting a seven-membered ring scaffolds and the difficulties in their
[4+3] annulation strategy via Cp*RhIII-catalyzed C–H functionaliza- quick assembly using conventional methods, there is a great
tion. Glorius and co-workers pioneered a Rh-catalyzed reaction need to expand their synthetic repertoire.
between amides and unsaturated aldehydes and ketones to
Recently, our group reported a palladium-catalyzed inter-
yield azepinones (Scheme 1a).3a Cui and co-workers reported molecular [4+1] annulation reaction of N-phenoxyacetamides4
two ingenious synthetic designs to obtain azepinones via and aldehydes to form 1,2-benzisoxazoles. This development sug-
Rh-catalyzed coupling of amides with methylenecyclopropanes gested that the aldehyde could serve as an excellent C1 component
and vinylcarbenoids.3b,c Considering the importance of the in C–H functionalization (Scheme 1b). Herein we hypothesized that
a,b-unsaturated aldehydes could serve as C3 components in C–H
a Shenzhen Key Lab of Nano-Micro Material Research, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen,
518055, China. E-mail: jingzhao@pkusz.edu.cn
activation/[4+3] annulation. If realized, this reaction would provide
a convenient entry to oxazepines from simple oxyamides and widely
available a,b-unsaturated aldehydes (Scheme 1c).
b School of Life Sciences, Shandong University of Technology, Zhangzhou Road 12,
1,2-Oxazepine and its derivatives are an important class of
seven-membered heterocycles that have been found in pharma-
ceuticals with potential biological and medicinal activities.5
With our continued interest in C–H activation/annulation, we
report oxyacetamide-directed RhIII-catalyzed C–H activation/
[4+3] annulation reactions between N-phenoxyacetamides and
a,b-unsaturated aldehydes to access 1,2-benzoxazepines. The
atom-economic synthetic protocol features mild reaction con-
ditions and good to excellent yields.
Zibo 255049, China
c Department of Chemistry, University of San Francisco, 2130 Fulton Street,
San Francisco 94117-1080, USA
d State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences,
Institute of Chemistry and BioMedical Sciences, Nanjing University, Nanjing,
210093, China
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all new compounds. CCDC 1003334 (3aa), 1003335
(3oa), 1003336 (4) and 1011647 (6). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc05485g
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Table
1
RhIII-catalyzed annulation of N-phenoxyacetamides
1 with
salts were also tested and we found that Ag2CO3 was the best choice
(entries 4–6). Finally, a variety of solvents were screened and they all
gave slightly lower yields than CH3CN (entries 7–12). Omission of the
[Cp*RhCl2]2 catalyst completely shut down the reaction (entry 13).
Replacing [Cp*RhCl2]2 with Cp*Rh(OAc)2 avoided the need for silver
additives and the results indicated that acids promoted the reaction
and PivOH was superior to AcOH (entries 14–16).
a,b-unsaturated aldehydes 2a
With the optimized conditions in hand, we first explored the
scope of N-phenoxyacetamides. The substituents on nitrogen
were first examined. Replacing the acetyl group with a propionyl
group gave 3ba in 86% yield. The benzyloxycarbonyl group was
also a suitable protecting group for this reaction, although we
obtained the desired product 3ca in 40% yield in addition to the
aliphatic aldehyde derivative 3ca0 in 46% yield. The substituents
on N-phenoxyacetamides were also investigated. The electron-
donating substituents such as methyl (1d, 1e, and 1f), dimethyl
(1g) and methoxyl (1h) and electron-withdrawing groups such as
fluorine (1i), bromine (1j and 1k), chlorine (1l), phenyl (1m), and
ester (1n) all proceeded smoothly to afford the corresponding
products in moderate to high yields. It was worth noting that we
obtained the mixture of regioisomers 3ha and 3ha0 in a 2 : 1 ratio
from substrate 1h bearing a methoxyl substituent in the meta-
position. It occurred with significantly altered regioselectivity as
compared to other meta-substituted N-methoxybenzamides,
such as 1e, 1i and 1j.2a Substrate 1i was annulated only at the
less hindered ortho position with complete regiospecificity even
though the fluorine atom is small. More excitingly, the reaction
also proceeded well for nonaromatic substrates (1o and 1p),
affording the products in 81% and 65% yields, respectively. The
crystal structure of 3oa was shown in the ESI.† We also examined
the scope of unsaturated aldehydes, and found that (E)-pent-2-
enal (2b) and (E)-hex-2-enal (2c) could successfully proceed in
96% and 88% yields, respectively. However, when the alkyl chain
was replaced by an aryl group, such as cinnamaldehyde, the reaction
failed. Attempts to introduce a methyl group at the a-position of
unsaturated aldehydes resulted in no reaction.
To probe the catalytic reaction mechanism, isotope experiments
were carried out (Scheme 2). Exposure of substrate 1a to PivOD/
CD3CN afforded the substrate by 18% H/D scrambling ortho to the
oxyacetamide group (Scheme 2a). We also conducted the reaction
using PivOD as the acid and CD3CN as the solvent, affording the
desired product with 15% deuterium incorporation observed at the
C-9 position (Scheme 2b). These results demonstrated that the C–H
activation step was reversible.6 Parallel experiments using equimolar
amounts of d5-1a and N-phenoxyacetamide 1a were conducted
independently to assess the rates of reaction for ortho-C–H vs.
C–D. It gave a KH/KD ratio of 1.3, indicating that C–H bond
cleavage could not be the rate-determining step (Scheme 2c).7
To further explore the catalytic cycle, we carried out the
synthesis and analysis of the possible intermediate. The substrate
(1a) was treated with the active catalyst [Cp*RhIIIPy] species, prepared
in situ from stoichiometric quantities of [Cp*RhCl2]2, Ag2CO3 and
pyridine (Py) in CH2Cl2 at rt in the presence of NaOAc and Et3N. The
cyclometalated intermediate A0 was obtained with 90% yield.
Then it was treated with acrolein (2a) under our standard
reaction conditions, affording the corresponding product 3aa
a
Conditions: 1 (0.4 mmol), 2 (0.8 mmol), [Cp*RhCl2]2 (3 mol%), Ag2CO3
(10 mol%) in CH3CN (2 mL) at rt under a nitrogen atmosphere for 18 h,
unless otherwise noted. Isolated yields. Using 2 (3.0 equiv.), the
product containing an additional aliphatic aldehyde in the 9-position
was also obtained in 33% yield. Using 2 (3.0 equiv.).
b
c
At the outset of this study, we chose N-phenoxyacetamide
(1a) and acrolein (2a) as the starting materials (ESI,† Table S1).
The reaction took place in the presence of 3 mol% [Cp*RhCl2]2,
10 mol% Ag2CO3 and 2 equiv. AcOH in CH3CN at room temperature,
affording 1,2-benzoxazepine 3aa in 71% yield (Table 1, entry 1). The
structure of 3aa was confirmed by X-ray crystallographic analysis
(Fig. 1). The reaction did not proceed in the absence of Ag2CO3
(entry 2). To our pleasant surprise, the use of pivalic acid (2 equiv.)
dramatically improved the yield to 98% (entry 3). A series of silver
Fig. 1 Crystal structure of 1-(3-hydroxy-4,5-dihydrobenzo[f][1,2]oxazepin-
2(3H)-yl)ethanone (3aa).
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intermediate E was formed via intramolecular nucleophilic attack,4a,9
which was then protonated to produce the desired product 3 and
regenerate the [Cp*RhIII] species.
Interestingly, when an unsaturated ketone such as pent-1-
en-3-one (2d) was used as the coupling partner, we only
obtained the di-alkylated product 4 in 48% yield with no
cyclized products [eqn (1)].10 The structure of 4 was confirmed
by X-ray crystallography (see ESI†). Furthermore, we examined
the influence of both the oxyacetamide and amide directing
groups with compound 1q. Compound 1q is interesting in that
it has two directing groups to compete for sites of C–H activation.
The reaction occurred regiospecifically at the position ortho to the
amide group in Rh-catalyzed C–H activation, affording product 5
in 80% yield [eqn (2)].11
Scheme 2 Deuteration experiments.
(1)
Scheme 3 Synthesis of the cyclometalated intermediate and transformation.
(2)
in 30% yield (Scheme 3). Pyridine was used to stabilize the
cyclometalated intermediate,8 but it suppressed the [4+3] annulation
reaction to some extent as a controlled experiment in the presence of
15 mol% pyridine afforded the desired product in 44% NMR yield,
much lower than the 98% NMR yield of 3aa.
On the basis of these observations and literature precedence, a
plausible mechanism was proposed, as shown in Scheme 4. First, an
active catalyst [Cp*RhIII] was generated from [Cp*RhCl2]2 and Ag2CO3.
Then coordination of substrate 1 to [Cp*RhIII] species went through a
cyclorhodation step, affording intermediate A. Intermediate C was
obtained via alkene insertion. And then it produced the alkylated
species D with the aid of acid. Lastly, the seven-membered ring
We also explored the synthetic transformation of the obtained
1,2-oxazepines. The product 3aa underwent the reduction reaction
with a H2 balloon, affording the unexpected benzo-fused oxygen
heterocycle chroman derivative 6 in 80% yield.12 Chromans are
important building blocks in a number of biologically important
molecules (Scheme 5).13
In summary, we have developed an efficient Rh(III)-catalyzed
intermolecular [4+3] annulation method for the synthesis of
1,2-oxazepines from N-phenoxyacetamides and a,b-unsaturated
aldehydes. This atom-economic protocol features mild reaction
conditions, good to excellent yields, and no need for oxidants.
Deuteration experiments suggested that the C–H activation step
is reversible and not rate-determining. The cyclometalated
intermediate was synthesized and analysed. A mechanism
involving C–H activation, alkene insertion, and intramolecular
nucleophilic attack from a Rh amide was proposed. Reduction
of the coupled 1,2-oxazepine product generated biologically
important chroman derivatives. Investigations on developing
new annulation methods based on the O-NHAc moiety are
underway and will be reported in due course.
We thank Professor John F. Hartwig for his valuable insights
and discussion. This work was financially supported by grants
Scheme 5 Synthetic transformation of the seven-membered ring
Scheme 4 Plausible mechanism.
product.
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˜
˜
(d) A. Seoane, N. Casanova, N. Quinones, J. L. Mascarenas and
from the National High Technology Research and Development
Program of China (2014AA020512). J.Z. thanks the Doctoral
Fund of Ministry of Education of China, the National Natural
Science Foundation of China (grant no 21332005) and the
Guangdong Government (S20120011226) for support.
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