Formation of o-Allyl- And Allenyl-Modified Amides via Intermolecular Claisen Rearrangement

Article abstract of DOI:10.1021/acs.orglett.0c04300

We developed a new transition-metal-free intermolecular Claisen rearrangement process to introduce allyl and allenyl groups into the α position of tertiary amides. In this transformation, amides were activated by trifluoromethanesulfonic anhydride to produce the keteniminium ion intermediates that exhibit strong electrophilic activity. This atom-economical process delivers α position-modified amides under mild conditions in moderate to good yields and showcases a broad substrate compatibility.

Full text of DOI:10.1021/acs.orglett.0c04300

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Letter
Formation of o‑Allyl- and Allenyl-Modified Amides via
Intermolecular Claisen Rearrangement
Zhi-Jie Niu, Lian-Hua Li, Xue-Song Li, Hong-Chao Liu, Wei-Yu Shi, and Yong-Min Liang*
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ABSTRACT: We developed a new transition-metal-free intermo-
lecular Claisen rearrangement process to introduce allyl and allenyl
groups into the α position of tertiary amides. In this transformation,
amides were activated by trifluoromethanesulfonic anhydride to
produce the keteniminium ion intermediates that exhibit strong
electrophilic activity. This atom-economical process delivers α
position-modified amides under mild conditions in moderate to good yields and showcases a broad substrate compatibility.
s the general building blocks of peptides and proteins,
amides are very important bioactive skeletons in natural
activated amide in the crucial process of producing high-
bioactivity organic skeletons.12 Mechanistic research has
demonstrated that the keteniminium ion with a high
electrophilic reactivity was generated when the amides were
activated by Tf2O and pyridines (Scheme 1).9c,13
A
products, medicines, and functional materials (Figure 1).1,2
Since being discovered by Claisen in 1912, sigmatropic
rearrangement ranks among the most powerful tools in organic
chemist’s toolbox.14 It was also employed in amide
modification by Maulide,13d,15 Ye,16 and other groups.17 As
the strong electrophilic reagent, keteniminium species could
react with diphenyl sulfoxide or N-aryl hydroxamic acid to
undergo [3,3]-sigmatropic rearrangement and form the α
position aryl-substituted amide.15d Intramolecular [3,3]-sigma-
tropic rearrangement also plays a part in the stage, employing
allyloxyamides as starting materials to generate lactones.15a−c
Among them, the allyl and allenyl modifications of the amide
ortho position by intermolecular rearrangement are considered
challenging. Herein, the progress of the hypothesis mentioned
above, as well as the mechanistic studies of the reaction, is
presented.
We initiated the process by employing amide 1a and
allyloxytrimethylsilane 2a as the model substrates. At the very
beginning, there was no anticipated product and even
byproducts were produced when the reaction was carried out
with Tf2O and 2-iodopyridine in 1,2-dichloroethane (DCE) at
80 °C for 12 h (Table 1, entry 1). With this primary result, we
speculated that before substrate 2a reacted with the
keteniminium ion generated by the Tf2O-activated amide, it
might be rapidly decomposed under the acidic condition. On
Figure 1. Amide derivatives in drugs.
The activation of amide has become an efficient strategy for
realizing the modification of protein macromolecular com-
pounds. Because of this, the activation and modification of
amides remain challenging due to the well-understood
resonance effects and have been high priorities of organic
chemists. A large number of works on amide activation have
been published in the past few decades. At first, elegant works
that employed palladium and a Ni complex as the transition-
metal catalyst to activate the C−N bond of amide were
developed by Garg,3 Hu,4 Szostak,5 and others.6 The single-
electron reductant samarium(II) iodide (SmI2) was also used
to generate the ketyl radicals from amides and to proceed to
the activation and modification of amide.5d,7
Trifluoromethanesulfonic anhydride (Tf2O) had been
initially employed by Ghosez in the 1970s to realize the
electrophilic activation of amide without using noble metals.8
Recently, the groups of Charette,9 Maulide,10 and Huang11
have published numerous related works on amide modification
and transformation atop this foundation. On the basis of a
long-standing interest, our group has also employed the Tf2O-
Received: December 30, 2020
Published: February 3, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04300
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1315−1320
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additional base, and DCE as the solvent, stirring in oil bath at
70 °C for 12 h.
Scheme 1. Previous Works and Our Initial Rearrangement
Design
After determining the optimal conditions, we examined the
scope of amides and the functional group tolerance. A number
of alkyl and branched alkyl amides reacted with 2a and
generated the desired products (4aa−4ka) in moderate to
good yields. Amides substituted with alkenyl, alkynyl, and
tetrahydro-2H-pyranyl could neatly undergo this transforma-
tion (4la, 4ma, and 4oa) and amide 1p could also give the
corresponding product in good yield (4pa). It was worth
noting that the amide bearing an allyloxy group (4na)
previously reported for intramolecular rearrangement was
also tolerated in this reaction.15a To our delight, the
trifluoromethyl-substituted amide also performed well in this
reaction (4qa). Then, we examined the amides substituted
with different aryl groups, and the substrates bearing MeO, F,
Cl, or Br at the para position could be compatible in this
reaction (4ra−4wa). The structure of 4wa was confirmed by
X-ray crystallographic analysis. The α-naphthyl and β-naphthyl
type amides coupled with the partner in excellent yields (4xa,
88%; 4ya, 78%). The heterocyclic thiophene and indole were
also compatible with this conversion, but the yields were not
satisfying (4za and 4Aa).
Then we screened the tertiary amides with different
substituents on the N atom (Table 2B). Amides with chain
a
Table 1. Optimization of Reaction Conditions
a
Table 2. Scope of α-Allyl Amides
b
entry
base
additive temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
2-iodopyridine
2-iodopyridine
2-iodopyridine
2-iodopyridine
2-chloropyridine
2-fluoropyridine
2-bromopyridine
2-methylpyridine
2,4,6-collidine
2-iodopyridine
2-iodopyridine
2-iodopyridine
none
80
80
80
80
80
80
80
80
80
60
70
90
12
12
12
12
12
12
12
12
12
12
12
12
0
50
ND
ND
trace
11
trace
ND
ND
63
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
76
37
a
A mixture of an amide (0.2 mmol) and a base (2.2 equiv) in DCE (1
mL) was treated with Tf2O (1.4 equiv) in 0 °C for 15 min, and then
the mixture of 2a (3.5 equiv) and an additive (3.5 equiv) was added
and stirred at rt. After being stirred at rt for 15 min, the reaction
mixture was hetaed in an oil bath at the reported temperature for a
further 12 h. Abbreviations: Tf2O, trifluoromethanesulfonic anhy-
b
dride; DCE, 1,2-dichloroethane; TMS, trimethylsilyl. Isolated yields.
the basis of our hypothesis, different additives were tested
(Table S1). To our delight, the desired product was achieved
with a low yield when cesium carbonate (Cs2CO3) was added
as the additional base (entries 2−4).
With the preliminary result in hand, we started to investigate
the reaction conditions. Various bases and solvents were
examined, and different temperatures and times also were
screened (entries 5−12, details in the Supporting Informa-
tion). After different conditions had been optimized, the best
result was afforded: 1.4 equiv of Tf2O and 2.2 equiv of 2-
iodopyridine as activating reagents, 4.0 equiv of Cs2CO3 as
a
All of the reactions were carried out on a 0.2 mmol scale under the
b
standard condition. Isolated yields are given. Determined by 1H
NMR.
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and branched alkyl groups on the N atom could proceed
through this reaction smoothly (4Ba−4Ea), and the cyclic
substituted amino groups also performed well in this
transformation (4Fa−4Ha). On the contrary, the results of
the investigation of heteroatom-containing cyclic substituted
amino amides were not satisfactory (4Ia and 4Ka). Some
amides substituted with an aryl group on the N atom also did
not perform in this reaction (4Ja and 4Ma).
The results presented above demonstrate the usefulness of
this reaction. We started to ponder the possibility of extending
this transformation to introduce allenyl groups at the α
position of tertiary amide. To validate this assumption, we
employed 1a and trimethyl(prop-2-yn-1-yloxy)silane (3a) as
reaction partners to install allenyl groups at the othro position
of amides under the standard conditions following the reaction
recipes presented in Table 2; corresponding product 5aa was
formed in good yield (5aa, 74%). Encouraged by this result, we
used a number of amides to react with 3a. As shown in Table
3, alkyl-, branched alkyl-, and cycloalkyl-substituted tertiary
substituents on the aromatic rings were used for coupling
with 3a to generate the desired allenyl group-bearing amides.
The α-naphthyl and β-naphthyl type amides and heterocyclic
aromatic ring-substituted amides could also be smoothly
tolerated in this transformation. The structure of 5xa was
confirmed by X-ray crystallographic analysis.
Different substituents on N atom were also examined (Table
3B, 5Ca−5Ma). To our surprise, amide 1J performed well with
3a and yielded 5Ja in good yield (47%), which gave almost a
trace when it coupled with 2a. Substrates 1L and 1M did not
react as anticipated. Some unreacted substrates are shown in
the Supporting Information.
After examining the capability of this reaction, we conducted
some experiments to clarify more details of this reaction. As
depicted in Scheme 2, the reaction was carried out under the
Scheme 2. Control Experiments
a
Table 3. Scope of α-Allenyl Amides
optimized conditions, and the desired product could be
afforded in the reported yields. However, when the reaction
proceeded with a nucleophile without Cs2CO3, no desired
product was observed and substrate 1a was detected by TLC.
These results powerfully confirmed that Cs2CO3 plays a
significant role in the generation of intermediate B2 and
performs smoothly in the next rearrangement.
In addition to the control experiments, we also conducted a
13C NMR experiment to monitor the reaction process. As
shown in Figure 2, at different times, we tracked signal a, which
Figure 2. 13C NMR studies of the reaction mechanism.
a
All of the reactions were carried out on a 0.2 mmol scale under the
standard condition following the reaction recipes presented in Table
b
1
2. Isolated yields are given. Determined by H NMR.
was indicated to be the carbonyl carbon of amide 4x (Scheme
3). After the Tf2O was added and the mixture was stirred at 0
°C for 15 min, signal b appeared and it was indicated as the b-
carbon of intermediate A. After the mixture of the nucleophile
had been added to this reaction mixture at 0 °C, the system
was warmed to ambient temperature for a further 15 min.
Signal c was observed and was supposed to be the c-carbon of
intermediate B1; signal a was also detected at the same time.
amides coupled with 3a and the corresponding compounds
were generated in good yields (5aa−5ka). Amides bearing
alkenyl, alkynyl, allyloxy, tetrahydro-2H-pyranyl, CF3, and 2-
bicyclo[2.2.1]heptan-2-yl groups were also employed to yield
the desired products (5la−5qa). After this, aryl chain-
substituted tertiary amides bearing MeO and halogen
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Scheme 3. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Author
Yong-Min Liang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0001-8280-8211; Email: liangym@
lzu.edu.cn
Authors
Zhi-Jie Niu − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Lian-Hua Li − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Xue-Song Li − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Hong-Chao Liu − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Wei-Yu Shi − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
These results told us that when the mixture was added, some
of the intermediates were converted back into starting
materials. After the mixture had been heated at 70 °C for 8
h, we monitored the reaction and found signal d, the carbonyl
carbon of product 4xa (more details in the Supporting
Information).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04300
Notes
The authors declare no competing financial interest.
Inspired by the control experiments mentioned above and
the literature,13d we proposed a plausible mechanism (Scheme
3). The amide is first activated by Tf2O to generate
intermediate A, and A can be easily converted to B1 or B2
under the 2-iodopyridine and Cs2CO3 conditions. It is worth
noting that Cs2CO3 is supposed to regulate the acidic
environment, and it also favors intermediate A being converted
into the pivotal intermediate, keteniminium ion B2. Then 2a
reacts with keteniminium ion B2 and produces intermediate C.
Finally, intermediate C performs a traceless [3,3]-sigmatropic
rearrangement and gives the target molecule.
In summary, we developed an efficient process for installing
allyl and allenyl groups at the α position of amides. The
keteniminium ion was suggested as a crucial intermediate in
the transformation, and an intermolecular [3,3]-sigmatropic
rearrangement was performed. A large number of substrates
were tolerated in this work. The mechanistic studies
demonstrated the Cs2CO3 is an important additional base
for the promotion of the generation of the keteniminium ion.
More detailed mechanisms and further applications are being
examined in our laboratory.
ACKNOWLEDGMENTS
■
The authors acknowledge support grants from the National
Natural Science Foundation of China (NSF 21772075 and
21532001).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04300.
Experimental procedures, compound characterization,
and NMR spectra (PDF)
Accession Codes
CCDC 2049406−2049407 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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