N-Heterocyclic Carbene-Catalyzed Cyclization of Aldehydes with α-Diazo Iodonium Triflate: Facile Access to 2,5-Disubstituted 1,3,4-Oxadiazoles

Article abstract of DOI:10.1021/acs.orglett.1c01128

Herein, we report a novel organocatalytic process for synthesis of complex 1,3,4-oxadiazoles from readily accessible aldehydes. By exploiting the nucleophilicity of the putative Breslow intermediate and the inherent electrophilicity of α-diazo iodonium triflate, we have found that N-heterocyclic carbene catalyst promotes efficient cyclization of various aldehydes and α-diazo iodonium triflates. The reaction proceeds under mild conditions with a wide range of functional group tolerance. The heterocyclic products can be readily further functionalized, rendering the protocol highly valuable.

Full text of DOI:10.1021/acs.orglett.1c01128

pubs.acs.org/OrgLett
Letter
N‑Heterocyclic Carbene-Catalyzed Cyclization of Aldehydes with
α‑Diazo Iodonium Triflate: Facile Access to 2,5-Disubstituted 1,3,4-
Oxadiazoles
Hang Huang, Xianghua Zou, Si Cao, Zhihong Peng,* Yingying Peng, and Xi Wang*
Cite This: Org. Lett. 2021, 23, 4185−4190
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ABSTRACT: Herein, we report a novel organocatalytic process for synthesis of complex 1,3,4-oxadiazoles from readily accessible
aldehydes. By exploiting the nucleophilicity of the putative Breslow intermediate and the inherent electrophilicity of α-diazo
iodonium triflate, we have found that N-heterocyclic carbene catalyst promotes efficient cyclization of various aldehydes and α-diazo
iodonium triflates. The reaction proceeds under mild conditions with a wide range of functional group tolerance. The heterocyclic
products can be readily further functionalized, rendering the protocol highly valuable.
electrophilicity of α-diazo iodonium salts,9 herein, we report a
novel metal-free cyclization approach to prepare 1,3,4-
oxadiazoles from readily available aldehydes under mild
conditions (Scheme 2c).
ecause of their unique properties, 1,3,4-oxadiazole
1
Bderivatives
hold a distinctive place in medicinal
chemistry2 and functional materials,3 which account for the
significance of exploitation of practical synthetic approaches to
access oxadiazole-containing molecules.4,5
We began our investigations by subjecting 4-iodobenzalde-
hyde (1a) as a representative substrate in combination with α-
diazo iodonium triflate (2a) and selection of commonly
encountered precursors of NHC catalyst (Table 1, entries 1−
4). We found that NHC A, reported by the Rovis group,11 was
the only effective catalyst to promote this reaction, giving 3a in
58% NMR yield (entry 1). A study of diazo sources quickly
revealed the reaction specificity of α-diazo iodonium triflate. α-
Diazo benziodoxole 2b (entry 5), α-diazo sulfonium salt 2c
(entry 6),12 and α-diazo ammonium salt 2d (entry 7)13 were
The previous established methods for the construction of
1,3,4-oxadiazole cores involve the use of carbonyl derivatives,
such as acyl hydrazide,4a−e acyl chloride,4f hydrazone,4b,g,h 2-
oxo-2-arylacetaldehyde,4d and acetophenone.4c Very recently,
the synthesis of 2,5-diaryl 1,3,4-oxadiazoles though N-acylation
of aryl tetrazoles with readily available aldehydes in the
presence of oxidant DTBP (tBuOOtBu) has been reported by
He and co-workers (Scheme 2a).4i The choice of benzoyl
formic acid and α-diazo iodonium salt5,6 as the cyclization
partners to synthesize 2,5-disubstituted 1,3,4-oxadiazoles via a
photocatalyzed decarboxylative radical cyclization derives from
the study of Li and Liu (Scheme 2b).4j On the other hand, N-
heterocyclic carbenes (NHCs) are versatile organocatalysts7
that can reverse the polarity (umpolung) of aldehydes to form
carbon−carbon bonds8−10 via the formal acyl anion equiv-
alents.
i
demonstrated to be ineffective. To our surprise, PrOH had a
visible positive effect on the yield (entry 8). We observed a
modest yield improvement by slightly increasing the amount of
2a to 1.05 equiv (entry 9), whereas an excess amount of 2a was
used, resulting in lower yields (entries 10−13). By replacing
t
iPrOH with BuOH, the NMR yield was subtly increased to
Although remarkable progress has been made, the problem
still exists. Most previous established methods suffer from
limitations of using strong oxidants or transition metal, high
reaction temperature, as well as limited substrate scope. One-
step formation of 1,3,4-oxadiazoles from aldehydes in terms of
metal-free organocatalysis is underdeveloped. Taken together
with the nucleophilicity of acyl anion equivalents and the
Received: April 1, 2021
Published: May 14, 2021
https://doi.org/10.1021/acs.orglett.1c01128
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4185−4190
4185

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Scheme 1. Representative 1,3,4-Oxadiazole Derivatives
Applied in Medicinal Chemistry and Material Chemistry
Table 1. Reaction Optimization
a
b
entry
2 (equiv)
NHC
base
additive
yield
58%
1
2
3
4
5
6
7
8
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2b (1.0)
2c (1.0)
2d (1.0)
2a (1.0)
2a (1.05)
2a (1.1)
2a (1.2)
2a (1.3)
2a (1.6)
2a (1.05)
2a (1.05)
2a (1.05)
2a (1.05)
2a (1.05)
A
B
C
D
A
A
A
A
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
DIPEA
none
none
none
none
none
none
none
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
ND
ND
ND
ND
ND
ND
62%
72%
68%
63%
60%
29%
9
A
10
11
12
13
14
15
16
17
18
A
A
A
A
c
A
74% (70%)
ND
A
A
Et3N
ND
A
Cs2CO3
TMEDA
ND
none
ND
Scheme 2. Recent Progress on the Synthesis of 1,3,4-
Oxadiazoles
a
Reaction conditions: 1a (0.20 mmol, 1.0 equiv), 2, NHC (0.020
mmol, 10 mol %), base (0.30 mmol, 1.5 equiv), additive (0.60 mmol,
b
3.0 equiv), DCE (4 mL), 0 °C, 10 h. The yield was determined by
1H NMR analysis using methylene dibromide as an internal standard.
c
“ND” stands for “not detected”. Isolated yield.
74% and 3a was isolated in 70% yield (entry 14). The use of
Hu
̈
nig’s base (entry 15), Et3N (entry 16), and Cs2CO3 (entry
heterocycle substrates with the knowledge that these moieties
are potentially valuable pharmacophores. We found that six-
atom heterocyclic aldehydes bearing pyridine, pyridazine,
quinoline, and quinoxaline were smoothly converted into
corresponding heterocycle substituted oxadiazoles (3s−3z).
Besides, the successful application of this approach in the
synthesis of various oxadiazoles substituted with five-atom
heterocycles, such as thiazole, imidazole, pyrazole, furan,
benzofuran, and benzothiazole, further highlighted the good
compatibility of the reaction (3aa−3af).
The scope of the reaction with respect to the α-diazo
iodonium triflate was summarized in Table 3 and further
exhibited universality of the approach to the synthesis of 1,3,4-
oxadiazoles. The ester moiety on hypervalent iodonium salt 2
can be modified: alternative alkyl substituents such as benzyl, t-
butyl, allyl, and (−)-menthyl groups were tolerated (3ee−
3eh), albeit in somewhat diminished yields of 3ee and 3eg.
The ester group can also be replaced by a ketone with a small
impact on the yield of 3ei. We were delighted to observe the
formation of the corresponding 3ej by using phosphonate
substituted α-diazo iodonium triflates 2ej.
17) failed to generate the desired oxadiazole 3a. Ultimately, the
control experiment showed that the conversion requires NHC
catalyst (entry 18).
Our studies on the scope of the reaction began with the
variation of the aryl and heteroaryl aldehydes, as summarized
in Table 2. The electronic perturbation on the aryl moiety
affects the efficiency of the reaction: generally, the aromatic
aldehydes bearing an electron-withdrawing group provided the
corresponding oxadiazoles 3a−3g in moderate to good yield,
whereas only 22% yield of 3h was observed through the
conversion of p-anisaldehyde. The aldehydes bearing a
methoxy and acetoxy group at the meta-position on arene
reacted cleanly to afford 3i and 3j. The tolerance of aromatic
ortho substituents, especially large steric bulk, was an
additional benefit of this novel process (3k, 3l). Multi-
substituted benzaldehydes were suitable substrates (3m−3o).
Also of note, polycyclic aromatic aldehydes were successfully
engaged in the reaction, giving synthetic useful yield of 3p and
3q. For 3-arylpropiolaldehyde, the reaction gave only a low
yield of the product 3r. Next, we turned our attention to
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pubs.acs.org/OrgLett
Letter
a b
,
a b
,
Table 2. Substrate Scope of Aldehydes
Table 3. Substrate Scope of α-Diazo Iodonium Triflates
a
Reaction conditions: 1e (0.20 mmol, 1.00 equiv), 2 (0.21 mmol,
1.05 equiv), NHC A (0.020 mmol, 10 mol %), TMEDA (0.30 mmol,
1.50 equiv), tBuOH (0.60 mmol, 3.0 equiv), DCE (4 mL), 0 °C, 10 h.
b
Isolated yield.
Scheme 3. Derivatization of 1,3,4-Oxadiazole Products
a
Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2a (0.21 mmol, 1.05
equiv), NHC A (0.020 mmol, 10 mol %), TMEDA (0.30 mmol, 1.5
t
equiv), BuOH (0.60 mmol, 3.0 equiv), DCE (4 mL), 0 °C, 10 h.
b
c
Scheme 4. Mechanistic Studies
Isolated yield. After 10 h, renewed 2a (0.21 mmol, 1.05 equiv),
NHC A (0.020 mmol, 10 mol %), and TMEDA (0.30 mmol, 1.5
equiv) addition and continued stirring at 0 °C for another 10 h.
The feasibility of the protocol has been demonstrated by a
set of efficient derivatization reactions of product 3a, including
Sonogashira cross-coupling, amidation, and reductive decar-
boxylation,14 affording products 4, 5, and 6 in good to
excellent yield, respectively (Scheme 3).
We noticed that further increasing the amount of 2a led to
inhibition of the conversion (Table 1, entries 10−13), whereas,
in some cases, the addition of renewed catalyst, 2a combined
with TMEDA, resulted in full conversion of starting materials
as well as improved yield (Table 2, 3b, 3c, 3g, 3h, 3i), which
revealed that 2a was not the actually active species promoting
the formation of oxadiazoles. By mixing 2a with TMEDA (1.5
equiv) in DCE at 0 °C, we prepared TMEDA supported α-
diazo ammonium triflate 7 in 66% yield (Scheme 4a),15 which
underwent cyclization to afford 2c in 65% yield under the
standard conditions (Scheme 4b). These results demonstrated
that α-diazo ammonium triflate 7 was the active species in the
reaction.
A postulated pathway is illustrated in Scheme 5. Initially, a
nucleophilic addition of free NHC A to the aldehyde 1 to give
adduct, which is in equilibration between its Breslow
intermediate B16 and its tautomer tetrahedral intermediate
B′,17 undergoes N-selective nucleophilic attack at in situ
generated α-diazo ammonium triflate 7,18 affording the
zwitterion adduct C. Subsequently, the ammonium D is
formed by release of catalyst A to close the catalytic cycle.
Finally, in the presence of base, deprotonation of D, followed
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Letter
Engineering, Advanced Catalytic Engineering Research
Scheme 5. Proposed Mechanism
Center of the Ministry of Education, Hunan University,
Changsha 410082, P. R. China
Yingying Peng − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Advanced Catalytic Engineering Research
Center of the Ministry of Education, Hunan University,
Changsha 410082, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01128
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Grant No. 21801073) and the China
Hunan Provincinal Science&Technology Department (Grant
No. 2018RS3044) are greatly appreciated.
by cyclization of E via intramolecular nucleophilic attack,
produces the desired 1,3,4-oxadiazoles 3 (Scheme 5).
In summary, we have reported a novel strategy for the
cyclization of readily accessible aldehydes with α-diazo
iodonium triflate. The approach enables straightforward access
to various 1,3,4-oxadiazole derivatives under mild conditions.
Ongoing efforts will focus on synthetic applications, developing
a better understanding of the mechanism, and exploration of
the reactivities of α-diazo iodonium triflates newfound α-diazo
ammonium triflates.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01128.
Synthetic procedures, IR, NMR, and HRMS of the
inclusion complexes (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhihong Peng − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Advanced Catalytic Engineering Research Center
of the Ministry of Education, Hunan University, Changsha
410082, P. R. China; Email: pzh7251@hnu.edu.cn
Xi Wang − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Advanced Catalytic Engineering Research Center
of the Ministry of Education, Hunan University, Changsha
410082, P. R. China; orcid.org/0000-0003-1064-9973;
Email: cccewangxi@hnu.edu.cn
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Authors
Hang Huang − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Advanced Catalytic Engineering Research
Center of the Ministry of Education, Hunan University,
Changsha 410082, P. R. China
Xianghua Zou − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Advanced Catalytic Engineering Research
Center of the Ministry of Education, Hunan University,
Changsha 410082, P. R. China
Si Cao − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
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Org. Lett. 2021, 23, 4185−4190

Organic Letters
pubs.acs.org/OrgLett
Letter
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper originally was published ASAP on May 14, 2021.
Part of Table 1 was missing and a new corrected version of the
paper was posted on May 17, 2021.
4190
https://doi.org/10.1021/acs.orglett.1c01128
Org. Lett. 2021, 23, 4185−4190