PIDA-Mediated Rearrangement for the Synthesis of Enantiopure Triazolopyridinones

Article abstract of DOI:10.1021/acs.orglett.0c02278

A tandem oxidative cyclization/1,2-carbon migration of hydrazides for the synthesis of otherwise inaccessible hindered or enantiopure triazolopyridinones has been developed. This protocol exhibits broad substrate scope and can be easily scaled up by continuous flow synthesis under mild conditions. Most importantly, this method demonstrates a rearrangement with retention of configuration and can be readily applied for the late-stage modification of carboxylic-acid-containing pharmaceuticals, amino acids, and natural products to access enantiopure triazolopyridinones.

Full text of DOI:10.1021/acs.orglett.0c02278

pubs.acs.org/OrgLett
Letter
PIDA-Mediated Rearrangement for the Synthesis of Enantiopure
Triazolopyridinones
Zenghui Ye, Hong Zhang, Na Chen, Yanqi Wu, and Fengzhi Zhang*
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sı Supporting Information
ABSTRACT: A tandem oxidative cyclization/1,2-carbon migra-
tion of hydrazides for the synthesis of otherwise inaccessible
hindered or enantiopure triazolopyridinones has been developed.
This protocol exhibits broad substrate scope and can be easily
scaled up by continuous flow synthesis under mild conditions.
Most importantly, this method demonstrates a rearrangement with
retention of configuration and can be readily applied for the late-stage modification of carboxylic-acid-containing pharmaceuticals,
amino acids, and natural products to access enantiopure triazolopyridinones.
earrangement reactions have been recognized as powerful
Scheme 1. Representative Triazolopyridinones and Their
Synthetic Strategies
R
chemical transformations for the construction of carbon−
carbon (C−C) or carbon−heteroatom (C−X) bonds, and they
were frequently employed for generating structural complexity
1
in bioactive (un)natural product synthesis. According to the
nature of the migrating group, they can be classified into
nucleophilic, electrophilic, radical, and sigmatropic rearrange-
ments, and the migrating group can be shifted from C to C (such
2
3
4
as Wagner−Meerwein, pinacol, and Favorskii rearrange-
5
6
7
ments), C to X (such as Beckmann, Hofmann, Curtius, and
Schmidt rearrangements), or X to C (such as Stevens,
8
9
10
11
Sommelet−Hauser, and Wittig rearrangements). Among
them, the 1,2-migration processes from C to X are particularly
useful to introduce a heteroatom into the carbon framework or
construct the heterocycles from carbocycles. However, these
rearrangements generally require a leaving group attached on
the heteroatom and proceed via the loss of either nitrogen
(
Schmidt and Curtius reactions), halogen (Hofmann reaction),
12
or carboxylic acid (Baeyer−Villiger oxidation) under relatively
harsh acidic or basic conditions, which might limit their
substrate scope and wide applications. Furthermore, few of
13
them can be conducted with retention of stereochemistry.
Nevertheless, more novel enantioselective rearrangement
reactions which can be conducted under mild conditions are
highly demanded for efficient access of those otherwise
inaccessible molecules to further explore their chemical space
and synthetic applications.
17
alcohol (Scheme 1b). This method normally requires toxic
carbonylating agents such as triphosgene and harsh reaction
conditions. Also, it was limited by the availability of alkyl halides
or alcohols, and the tertiary substituted triazolopyridinone
The triazolopyridinone skeleton is widely found in materials,
pharmaceuticals, and agrochemicals due to their special
1
4
properties. A wide range of biological activities have been
15
Received: July 9, 2020
reported with this skeleton, such as antidepressive and
16
antidiabetic activities (Scheme 1a). The conventional syn-
thesis of triazolopyridinone derivatives generally requires a two-
step procedure: the formation of the triazolopyridinone skeleton
from 2-hydrazinopyridine and carbonyl source followed by a
nucleophilic substitution reaction with alkyl halide or alkyl
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02278
A
Org. Lett. XXXX, XXX, XXX−XXX

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pubs.acs.org/OrgLett
Letter
derivatives which have never been reported before cannot be
prepared by this method. Furthermore, there is only one chiral
triazolopyridinone derivative reported with 89% enantiometric
excess (ee). Therefore, a novel synthetic method is highly
demanded for the efficient synthesis of enantiopure and
sterically hindered triazolopyridinones, which remain an
underexplored area of chemical space.
entry 11). Interestingly, the secondary (CHMePh) and tertiary
( Bu) substituted hydrazides reacted more efficiently at 40 °C
within 30 min and gave the corresponding products in 99 and
83% yields, respectively (Table 1, entries 12 and 13).
With the optimized conditions in hand, the scope of this
reaction was evaluated, as shown in Scheme 2. Various
t
1
8
Scheme 2. Substrate Scope ,
a b
In 2007, the Adib group reported a synthetic method of
imidazopyridiones via aryl migration to an adjacent α,β-
19
unsaturated carbonyl group (Scheme 1c). The inexpensive
and ubiquitous alkyl carboxylic acid is one of the most common
20
chemical building blocks on Earth. Generally, it is employed
for the preparation of ester or amide, and it was well-explored for
decarboxylative coupling reactions by providing a reactive alkyl
2
1
intermediate. We envisaged that the hydrazides, readily made
from diverse alkyl carboxylic acids and pyridinyl hydrazines,
could be easily oxidized to the azo compounds due to their low
22
oxidation potential. The tandem nucleophilic addition of the
pyridine to the carbonyl moiety followed by a 1,2-carbon
migration would construct the triazolopyridinone skeletons
(Scheme 1d). If the migrating group has a stereocenter, this
oxidative cyclization/1,2-carbon migration process might take
place with retention of stereochemistry to afford the enantiopure
triazolopyridinones.
To verify our hypothesis, the initial efforts were focused on the
condition optimization with pyridinyl hydrazide 1 as a model
substrate. With primary (CH Ph) substituted hydrazide as the
2
substrate, we first put special emphasis on screening the effects
of various oxidants with methanol as the solvent at 40 °C (Table
1
, entries 1−9). It was found that only a trace amount of
Table 1. Condition Optimization
a
b
entry
R
oxidant
K S O
AgOAc
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
CH Ph
40
40
40
40
40
40
40
40
40
rt
trace
trace
22
25
25
44
44
48
65
41
89
99
83
2
2
2
8
CH Ph
a
2
Reaction conditions: hydrazide (0.2 mmol), PhI(OAc) (0.22 mmol,
2
b
c
CH Ph
NaClO2
2
1.1 equiv), MeOH (2 mL), air, 40 °C, 5−30 min. Isolated yields. 70
°C.
CH Ph
NaClO
2
CH Ph
m-CPBA
DDQ
DMP
PIFA
PIDA
PIDA
PIDA
PIDA
PIDA
2
CH Ph
hydrazides were prepared readily from the corresponding
pyridinyl hydrazines and alkyl carboxylic acids. First, the
primary benzyl-substituted hydrazides were tested (2aa−2ay),
and pleasingly, this reaction exhibits broad functional group
tolerance and substrate scope. Generally, the substrates with
electron-rich benzyl substituents (2ai−2al, 2at−2av) gave
corresponding products in yields much higher than those with
electron-deficient ones (2am and 2an). The quinolinyl (2ag and
2ah), naphthyl (2aw), thienyl (2ax), or allylic (2ay) substituted
substrates are also effective. It is worth mentioning that most of
the substrates reacted well at 40 °C except for substrates with
2
CH Ph
2
CH Ph
2
CH Ph
2
1
1
1
1
0
1
2
3
CH Ph
2
CH Ph
70
40
40
2
CHMePh
tBu
a
Reaction conditions: 1a (0.2 mmol), oxidant (0.22 mmol, 1.1 equiv),
b
solvent (2 mL), air, 5−30 min. Isolated yield of product. DMP =
Dess−Martin periodinane. PIFA = PhI(OCOCF ) .
3
2
CF substituents (2ae and 2an). Next, the secondary substituted
3
triazolopyridinone 2 was formed with either K S O or AgOAc
hydrazides with substituents at the α position, including ether,
ester, amide, and cyclic systems, were tested, and all gave the
corresponding products (2ba−2bd, 2bf−2bh) in 80−99%
yields except 2be and 2bi. Finally, the tertiary substituted
hydrazides, such as simple alkyl substituted (2ca−2cf),
deuterated (2cg), and cyclic systems (2ch−2ck), were tested
and afforded the corresponding novel hindered triazolopyr-
idinone derivatives effectively, which cannot be prepared by the
2
2
8
as the oxidant (Table 1, entries 1 and 2). By switching to the
other oxidants, the desired product 2 was isolated in 22−48%
yields (Table 1, entries 3−8). The yield could be improved to
6
5% with PIDA as the oxidant (Table 1, entry 9). The yield
decreased significantly when the reaction was conducted at rt
Table 1, entry 10). To our delight, the yield was improved to
9% when the temperature was increased to 70 °C (Table 1,
(
8
B
https://dx.doi.org/10.1021/acs.orglett.0c02278
Org. Lett. XXXX, XXX, XXX−XXX

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pubs.acs.org/OrgLett
Letter
conventional nucleophilic substitution from the corresponding
triazolopyridinone and alkyl halides or alcohols. However, when
the migrating group was a primary aliphatic group, the
corresponding diazo compound was detected during the
reaction and decomposed after heating, and the secondary
aliphatic migrating group would afford a trace amount of the
desired product.
Scheme 4. Synthesis of Enantiopure Triazolopyridinone
Derivatives and Gram-Scale Continuous Flow Synthesis
To further demonstrate the utility of this novel rearrange-
ment, we applied it for the late-stage modification of
commercially available and acid-containing anti-inflammatory
drugs (such as diclofenac 3a, flurbiprofen 3b, loxoprofen 3c, and
ketoprofen 3d), anti-hyperlipidemic agent (such as clofibrate 3e
and gemfibrozil 3h), amino acids (3f and 3g), and natural
products (dehydroabietic acid 3i and enoxolone 3j), and the
corresponding triazolopyridinone derivatives were prepared in
good to excellent yields (Scheme 3), which demonstrated an
efficient and fast way to access their analogues for structure−
activity relationship studies in medicinal chemistry.
Scheme 3. Late-Stage Modification of Pharmaceuticals,
,
a b
Amino Acids, and Natural Products
In conclusion, we have presented a novel and facile
rearrangement involving a tandem oxidative cyclization/1,2-
carbon migration. By employing this method, the previous
inaccessible enantiopure triazolopyridinone derivatives can be
prepared efficiently with diverse and cheap alkyl carboxylic acids
as starting materials.
ASSOCIATED CONTENT
sı Supporting Information
■
a
Reaction conditions: hydrazide (0.2 mmol), PhI(OAc) (0.22 mmol,
.1 equiv), MeOH (2 mL), air, 40 °C, 5−30 min. Isolated yields.
2
*
b
1
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02278.
To verify whether the configuration could be retained in this
tandem oxidative cyclization/1,2-carbon migration if the
migrating terminus has a stereocenter, various optically pure
hydrazides were synthesized from chiral acids including best-
selling drugs (ibuprofen (S)-3k, naproxen (S)-3l) and amino
acids ((R)-3f, (R)-3g) (Scheme 4a). Under the standard
conditions, the corresponding novel triazolopyridinone prod-
ucts were obtained in excellent yields and ee. The X-ray
crystallographic analysis of (S)-3l was conducted, and it was
confirmed that the products were obtained with retention of
configuration. To demonstrate the scalability of this reaction, we
further conducted the gram-scale reaction by employing
continuous flow chemistry (Scheme 4b). Various (enantiopure)
triazolopyridinones can be prepared efficiently on a larger scale,
which shows the potential applications in industry. It
demonstrated that this novel rearrangement provides an
efficient strategy for the synthesis of those valuable (enantio-
pure) triazolopyridinone derivatives, which are difficult to
prepare by previous methods.
Experimental procedures and spectroscopic character-
ization data (PDF)
Accession Codes
CCDC 1951212 contains the supplementary crystallographic
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.
AUTHOR INFORMATION
Corresponding Author
■
Fengzhi Zhang − College of Pharmaceutical Science and
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China; orcid.org/0000-0001-
9542-6634; Email: zhangfengzhi@zjut.edu.cn
C
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Organic Letters
Authors
pubs.acs.org/OrgLett
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Hong Zhang − College of Pharmaceutical Science, Zhejiang
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Na Chen − College of Pharmaceutical Science, Zhejiang University
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