[3 + 2] Cycloaddition/Oxidative Aromatization Sequence via Photoredox Catalysis: One-Pot Synthesis of Oxazoles from 2H-Azirines and Aldehydes

Article abstract of DOI:10.1021/acs.orglett.5b01994

A novel [3 + 2] cycloaddition/oxidative aromatization sequence via visible light-induced photoredox catalysis is disclosed. It provides a general synthetic route to 2,4,5-trisubstituted oxazoles from easily accessible 2H-azirines and aldehydes under mild reaction conditions. The potential of this strategy was further demonstrated by the rapid synthesis of a cyclooxygenase-2 inhibitor as well as the success of employing electron-deficient alkenes and imines as the reaction partners.

Full text of DOI:10.1021/acs.orglett.5b01994

Letter
pubs.acs.org/OrgLett
[3 + 2] Cycloaddition/Oxidative Aromatization Sequence via
Photoredox Catalysis: One-Pot Synthesis of Oxazoles from
2H‑Azirines and Aldehydes
Ting-Ting Zeng, Jun Xuan, Wei Ding, Kuan Wang, Liang-Qiu Lu,* and Wen-Jing Xiao*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, China
S
* Supporting Information
ABSTRACT: A novel [3 + 2] cycloaddition/oxidative
aromatization sequence via visible light-induced photoredox
catalysis is disclosed. It provides a general synthetic route to
2,4,5-trisubstituted oxazoles from easily accessible 2H-azirines
and aldehydes under mild reaction conditions. The potential of
this strategy was further demonstrated by the rapid synthesis
of a cyclooxygenase-2 inhibitor as well as the success of employing electron-deficient alkenes and imines as the reaction partners.
2H-Azirines, though a strained three-membered ring, are
bench-stable and readily available reagents first reported by
Neber and Burgard in 1932.1 Due to their inherent reactivity,
2H-azirines have been extensively used as versatile precursors
to prepare diverse aza-heterocycles through ring opening
reactions.2 Early reports indicated that cleavage of the C2−N
bond can be achieved by treatment with heat3 or metal salts4 or
through reaction with metal carbenes,5 delivering nitrene or
1,3-azadiene intermediates for a wide range of cycloaddition
reactions. Alternatively, cleavage of the C2−C3 bond is also a
viable path to form imino diradicals, nitrile ylides, or 2-
azaallenyl radical cations under thermal conditions6 or
irradiation with high-energy UV light.7 Usually, breaking the
C2−C3 bond is more challenging than the C2−N bond
because of its slightly higher bond energy than the latter.8,2c
Recently, our group realized this goal using visible light
photocatalysis9 via a single-electron-transfer process.10,11 The
key to success is the application of a commercially available
organic dye photocatalyst.12 In this work, we expand the
success of this strategy to construct other useful N-heterocycles.
Oxazole derivatives are frequently found in natural
products,13 pharmaceuticals,14 and as functional materials15
and usually display numerous significant bioactivities and
unique properties. Encouraged by these findings, numerous
strategies have been deveploped to forge this heterocyclic unit,
mainly involving oxidation of oxazoline,16 metal/halogen-
promoted intramolecular cyclization,17 or transition-metal-
catalyzed bimolecular annulation.18 However, known ap-
proaches to accessing polysubstituted oxazoles often require
poorly accessible starting materials and still face problems such
as the need for high temperatures, tedious operations, and/or
require transition metal catalysts.
reaction via amine oxidation for the synthesis of pyrrolo[2,1-
a]isoquinolines,20a imidazoles,20b and polysubstituted pyr-
roles10 (Scheme 1, eq 1). As a part of our continuing work,
Scheme 1. Visible Light Photoredox-catalyzed Cycloaddi-
tion Reactions of 2H-Azirines
herein we disclosed the preparation of 2,4,5-trisubstituted
oxazoles from 2H-azirines21 and commercially avaliable
aldehydes via a photoredox-catalyzed [3 + 2] cycloaddition/
oxidative aromatization sequence (Scheme 1, eq 2).
Initially, we tested the formal [3 + 2] cycloaddition of 2H-
azirine 1a and benzaldehye 2a to obtain 2,5-dihydrooxazole 3aa
using 9-mesityl-10-methylacridinium perchlorate (PC-I) as the
photocatalyst and 1,2-dicloroethane (DCE) as the solvent
under the irradiation of a 7 W blue LED. Gratifyingly, the
desired [3 + 2] reaction proceeded smoothly, giving 2,5-
dihydrooxazole in 37% yield (Table 1, entry 1).22 By adding
desiccant, the yield was improved (Table 1, entries 2−3),
especially when 4 Å molecular sieves (MS) were used (Table 1,
entry 2: 61% yield). Evaluation of the effect of solvent showed
that halogenated solvent and acetonitrile were better than more
polar solvents such as MeOH and DMF (Table 1, entries 2 and
4−7), with DCE still being the best solvent. Other reaction
parameters such as concentration and substrate ratio were
examined, although they did not lead to further improvement
Visible-light-induced photoredox catalysis has been identified
as a green and sustainable synthetic method for the assembly of
diverse heterocycles under mild reaction conditions.19 In this
regard, we have investigated the photocatalyzed [3 + 2]
Received: July 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Condition Optimization for 2,5-Dihydrooxazole
Scheme 2. Substrate Scope of 2H-Azirines
b
entry
PC
solvent
additive
yield (%)
1
PC-I
PC-I
PC-I
PC-I
PC-I
PC-I
PC-I
PC-I
PC-I
PC-I
PC-II
PC-III
PC-I
−
DCE
DCE
DCE
DCM
MeCN
MeOH
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
−
37
61
45
47
45
13
0
c
c
c
c
c
c
2
4 Å MS
3
MgSO4
4
4 Å MS
5
4 Å MS
6
4 Å MS
7
4 Å MS
cd
,
8
4 Å MS/K2CO3
4 Å MS/Li2CO3
4 Å MS/Na2CO3
4 Å MS/Li2CO3
4 Å MS/Li2CO3
4 Å MS/Li2CO3
4 Å MS/Li2CO3
70
77
69
0
cd
,
9
cd
,
10
11
12
13
14
cd
,
cd
,
22
0
cde
, ,
a
Reaction conditions: 1 (0.3 mmol), 2a (1.5 mmol), PC-I (5 mol %),
DCE (3 mL) at rt under the irradiation of a 7 W blue LED for 24−61
h. DDQ was added after the complete consumption of substrate 1 and
cd
,
0
a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), photocatalyst (5
b
mol %), solvent (3 mL) at rt for 24 h under the irradiation of a 7 W
stirred at rt for 14−34 h. Isolated yield.
blue LED. PC-I: 9-mesityl-10-methylacridinium perchlorate. PC-II:
b
Ru(bpy)3Cl2·6H2O. PC-III: Ir[dF(CF3)ppy]2(dtbbpy)PF6. Isolated
the benzene ring underwent this reaction with good efficiency
(4ga: 75% yield; 4ha: 58% yield). 2H-Azirines with alkyl or
heteroaromatic substituents were also examined; however, only
a trace amount of products were observed.
c
d
yield. 200 mg of desiccant were added. 2 equiv of base were added.
e
Without visible light.
in efficiency.23 Since aldehydes are prone to be oxidized to
carboxylic acids, we postulated that a weak acidic environment
was detrimental to this transformation.24 Thus, a number of
bases were introduced, and increased yields were indeed
observed under these conditions (Table 1, entries 8−10).
Among them, Li2CO3 greatly improved the reaction efficiency,
delivering the cycloadduct in 77% yield (Table 1, entry 9). In
addition, other transition metal photocatalysts, such as the
ruthenium complex PC-II or iridium complex PC-III, were
tested for the photocatalyzed cycloaddition reactions; however,
very low yields resulted (Table 1, entries 11−12). Removing
the light source or eliminating the photocatalyst from the
optimal reaction conditions led to no product, indicating it is a
photocatalytic process (Table 1, entries 13−14). To realize the
one-pot synthesis of oxazole, an oxidizing agent, 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ), was added to the
reaction system after total consumption of 1a. After being
stirred at room temperature for 14 h, to our delight, the desired
oxazole 4aa was isolated in 78% yield (Scheme 2, 4aa). Other
oxidants such as molecular oxygen and N-bromosuccinimide
were tried as well, but no desired oxazole product was produced
with these reagents.
Having established the optimal conditions, we started to
probe the scope of 2,3-disubstituted 2H-azirines that partipated
in this cycloaddition (Scheme 2). When electron-donating (Me,
OMe, OPh) and electron-withdrawing (Cl) groups were
introduced to the C3-phenyl ring adjacent to the CN
bond, the reaction worked well, generating the corresponding
oxazoles in moderate to good yields (4ba−4ea, 50%−77%).
Moreover, the structure of 4ea was unambiguously determined
by X-ray diffraction analysis.25 Sterically hindered substrates can
also be tolerated by this transformation. For example, when
naphthyl-substituted 2H-azirine 1f was applied, the desired
oxazole 4fa was afforded in 67% yield. Modification of the
subtitution of the C2-phenyl ring also proved to be viable. 2H-
Azirines with R2 possessing Cl at the meta- or para-positions of
Next, the scope of aldehyde components was examined in
this [3 + 2] cycloaddition/oxidative aromatization sequence. As
highlighted in Scheme 3, benzaldehydes bearing para-F/Cl/Br/
a b
,
Scheme 3. Substrate Scope of Aldehydes
a
Reaction conditions: 1a (0.3 mmol), 2 (1.5 mmol), PC-I (5 mol %),
DCE (3 mL) at rt under the irradiation of a 7 W blue LED for 24−97
h. DDQ was added after complete consumption of substrate 1a and
b
c
stirred at rt 14−25 h. Isolated yield. The second step was run at 50
°C. 10 equiv of aldehyde and 0.6 equiv of DDQ were used.
d
NO2 substituents proved to be compatible with this reaction
system, giving the desired oxazoles in moderate to good yields
(4ab−4ae, 53%−80% yield). When meta-anisaldehyde was
applied to the reaction conditions, the corresponding product
4af was delivered in 79% yield, albeit after an extended reaction
time. To our delight, heteroaryl aldehydes reacted well with
2H-azirine 1a. For instance, when pyridyl and thienyl aldehydes
were used, the corresponding heterocycle-substituted oxazoles
were afforded in 75% (4ag) and 80% yields (4ah), respectively.
B
DOI: 10.1021/acs.orglett.5b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We expect that this transformation will be very useful in
constructing such oxazoles in a regioselective manner.26 In
addition to the aforementioned aldehydes, the reaction went
smoothly with phenylglyoxal hydrate (4ai: 54% yield) and ethyl
glyoxylate (4aj: 74% yield) as substrates. Notably, the ester
group can be removed to obtain a 2,4-disubstituted oxazole or
further transformed to the oxazole analogue of urocanic acid,
which shows immunosuppressive activity.26,27 In addition, after
increasing the amount of aldehyde, propanal can also undergo
this transformation, affording the desired product 4ak in an
acceptable yield (36%). Lastly, 5-alkynyl substituted oxazole 4al
can be readily prepared in moderate yield (56%) by using
alkynyl aldehyde 2l. Compared with existing methods that use
transition-metal-catalyzed cross-coupling reactions or multistep
synthesis from arylacrylic acids,28 this strategy features a simple
procedure and mild conditions.
Scheme 5. Plausible Reaction Mechanism
To further explore the potential of this method, the
cyclooxygenase-2 inhibitor29 4im was synthesized in a good
yield (Scheme 4, eq 1: 66% yield) in a single pot. Apart from
available 2H-azirines and aldehydes. It features a broad
substrate scope and mild reaction conditions (i.e., 7 W LED
irradiation and organic dye catalyst). Significantly, this strategy
enabled the synthesis of a cyclooxygenase-2 inhibitor in one
simple operation and can be further applied to the synthesis of
biologically important pyrroles and 2,5-dihydroimidazoles.
Scheme 4. Synthetic Potentials of this Protocol
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01994.
Experimental procedures, characterization data, and
NMR spectra (PDF)
Crystallographic data for cis-8 (CIF)
Crystallographic data for 4ea (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
aldehydes, the electron-deficient alkene acrylonitrile 5 can be
utilized in this reaction, affording pyrrole 6 in moderate yield
(Scheme 4, eq 2:52% yield). It is worthy to note that imine 7
can also participate in the visible-light-photocatalyzed [3 + 2]
cycloaddition reaction, affording the 2,5-dihydroimidazole
product 8 in a good yield and moderate diastereoselectivity
(Scheme 4, eq 3:82% yield, 3.5:1 dr),30 although it did not
undergo the oxidative aromatization step under standard
conditions.
*E-mail: luliangqiu@mail.ccnu.edu.cn.
*E-mail: wxiao@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the NSFC (Nos.
21272087, 21472058, 21202053, and 21232003) for support of
this research.
On the basis of our previous work10 and literature reports,7 a
plausible mechanism for this transformation was proposed as
shown in Scheme 5. 2H-Azirine 1a can be converted to 2-
azaallenyl radical cation B after single-electron oxidation by the
excited photocatalyst and homolytic cleavage of the C−C bond.
Then, nucleophilic attack of benzaldehyde 2a on B would result
in the formation of cation radical C, which could undergo
subsequent intramolecular radical addition to afford the new
cation radical D. After that, this transient species would be
readily reduced by a low-valent photocatalyst, delivering the
cycloadduct 3aa and regenerating the photocatalyst PC-I.
Finally, the oxidative aromatization of 2,5-dihydrooxazole 3aa
furnished the desired oxazole product 4aa.
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DOI: 10.1021/acs.orglett.5b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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