Visible-Light Photoredox Catalyzed Three-Component Cyclization of 2H-Azirines, Alkynyl Bromides, and Molecular Oxygen to Oxazole Skeleton

Article abstract of DOI:10.1021/acs.orglett.6b01696

A novel three-component cyclization of 2H-azirines, alkynyl bromides, and molecular oxygen under visible-light photoredox catalysis at room temperature has been developed, which provides a direct approach to a wide range of substituted oxazoles in moderate to good yields.

Full text of DOI:10.1021/acs.orglett.6b01696

Letter
pubs.acs.org/OrgLett
Visible-Light Photoredox Catalyzed Three-Component Cyclization of
2H‑Azirines, Alkynyl Bromides, and Molecular Oxygen to Oxazole
Skeleton
Lili Chen,† Hongji Li,*,† Pinhua Li,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: A novel three-component cyclization of 2H-
azirines, alkynyl bromides, and molecular oxygen under visible-
light photoredox catalysis at room temperature has been
developed, which provides a direct approach to a wide range of
substituted oxazoles in moderate to good yields.
he unique 2H-azirines with highly strained three-
membered N-heterocyclic motifs are known as reactive
the last decades, development of mild and green chemical
transformations of azirines is highly desirable.
T
intermediates in organic synthesis.1 Although 2H-azirines
featured a CN bond embedded in a highly strained three-
membered cycle, they are stable enough to be isolated and stored
for a long while. As a consequence, a variety of organic
transformations concerning 2H-azirines have been reported.2
Generally, the ring-opening of 2H-azirines underwent three
possible bond cleavage models to release intermolecular strain.
For instance, the direct C−C bond cleavage in 2H-azirines to
generate nitrile ylides under light irradiation (Scheme 1a);3 the
Most recently, visible-light-induced photoredox catalysis has
offered a valuable strategy for organic transformations,9,10 and a
number of elegant works have been reported by MacMillan,9a,b
Yoon,9c Sanford,9d Glorious,9e Stephenson,9f Nicewicz,10a−e
Xiao,10f,g and others.10h−l This rapidly expanding field has
enabled the invention of a series of bond formations, which are
impossible to be constructed previously via the classic methods.
It is well-known that molecular oxygen is always considered an
atom-economical, environmentally benign, and abundant
source.11 In general, oxygen acts as a sink for electrons coming
from catalysts, and which also can be incorporated into the
products. More often, exploring the novel synthesis of oxygen-
containing compounds via molecular oxygen incorporation is
much more practical and valuable. To our knowledge, few
reports exist referring to aerobic chemical process in the presence
of photoredox catalyst,10k,l but less on molecular oxygen
incorporation. Based on these understandings and our recent
works on photochemistry,12 we herein first report an O2-
participated three-component cyclization of 3-aryl-2H-azirines
with 1-aryl-2-bromoacetylenes in the presence of acridinium salt
as a photoredox catalyst under visible light irradiation at room
temperature (Scheme 1d). The photoredox-catalyzed C−N
bond cleavage of azirines and incorporation of oxygen atom into
oxazoles from O2 proceed smoothly under mild and energy-
efficient conditions.
Scheme 1. Representative Bond Cleavage of 2H-Azirines
On the basis of recognizing photoredox catalysis, we set out to
test the model reaction of 3-phenyl-2H-azirine (1a) with 1-
phenyl-2-bromoacetylene (2a) using organic dye as photoredox
catalyst under visible light irradiation in air at room temperature,
as shown in Table 1. Initially, we found that green LED was
capable of enabling the cycloaddition of 1a with 2a in CH3CN
under 9-phenyl-10-methylacridinium perchlorate catalysis (PC-
C−N bond cleavage in 2H-azirines by transition-metal catalysis
to form vinyl nitrenoid intermediates (Scheme 1b);4−6 and the
simultaneous cleavage of both C−C and C−N bonds generates
carbenoid species and nitriles (Scheme 1c).7 Recently, 2H-
azirines have been used for the synthesis of N-containing
compounds.8 In particular, 2H-azirines bearing an aryl group at
the C-3 position are attractive because of their unique activity.
Although many advances have been made on azirine chemistry in
Received: June 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01696
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Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Alkynyl Bromides
b
entry
light source
green LED
additive
yield (%)
1
7
2
white LED
n.r.
62
64
25
46
24
n.r.
43
3
blue LED (1.5 W)
blue LED (3 W)
blue LED (6 W)
blue LED (1.5 W)
blue LED (1.5 W)
blue LED (1.5 W)
blue LED (1.5 W)
blue LED (1.5 W)
blue LED (1.5 W)
4
5
6
PhSSPh
TBHP
Et3N
7
8
9
PivOH
a
Reaction conditions: 1a (0.40 mmol), 2 (0.20 mmol), PC-I (5.0 mol
c
cd
,
10
11
12
77 , 76
%), CH3CN/DCE (V/V = 1:1, 1.0 mL), room temperature, air, 1.5 W
e
b
n.r.
blue LED for 24 h. Isolated yield.
n.r.
a
Reaction conditions: 1a (0.40 mmol), 2a (0.20 mmol), PC-I (5.0 mol
%), CH3CN (1.0 mL) under air atmosphere with light irradiation for
products (3h−m) in 57−67% yields. An obvious steric effect was
observed when 1-(ortho-methyl-substituted phenyl)-2-bromoa-
cetylene reacted with 1a. No products including desired 3n were
obtained, and the starting materials were recovered and
unchanged. It should be noted that 3-(bromoethynyl)thiophene
and 2-(bromoethynyl)naphthalene as substrates reacted with 1a
to give 3o and 3p in 61 and 64% yields, respectively.
b
c
d
24 h. Isolated yield. CH3CN/DCE (V/V = 1:1, 1.0 mL), O2
atmosphere (balloon). In absence of PC-I. n.r. = no reaction.
e
I), albeit with the formation of product 3a in 7% yield (entry 1).
Single crystal X-ray diffraction further confirmed the structure of
oxazole backbone (Supporting Information for detail). Sub-
sequently, screening of light source indicated that white LED did
not promote the model reaction (entry 2). To our delight,
employing blue LED (1.5 W) irradiation for 24 h on the reaction
generated 3a in 62% yield (entry 3). The power of blue LED was
examined, and 3 and 6 W blue LED provided the desired product
3a in 64 and 25% yields, respectively (entries 4 and 5). Addition
of additives, such as PhSSPh, tert-butyl hydroperoxide (TBHP),
NEt3, and PivOH, resulted in lower yields of 3a (entries 6−9).
Furthermore, improved yield of 3a was achieved by using mixed
solvent of CH3CN/DCE in equal volume (entry 10), and
comparable result was obtained when carried out in O2 (entry
10). As expected, no reaction occurred in the absence of PC-I or
light irradiation (entries 11 and 12). Inferior results were
obtained when the other solvents, such as DCE, DMF, MeOH,
and THF, were investigated under the similar conditions (SI,
Table S1, entries 1−4). Further, the screening of some organic
dyes as photocatalysts demonstrated that PC-I was an optimal
photocatalyst among the examined acridinium salts, and the
results are also summarized in Table S1 (entries 5−11).
Subsequently, the generality of 2H-azirine was also inves-
tigated and is summarized in Scheme 3. It is noteworthy that
a
Scheme 3. Scope of 2H-Azirines
Based on the optimal reaction conditions, we turned our
attention to investigate the scope of the substrates. First, the
scope of alkynyl bromides in the reaction was examined, as
described in Scheme 2. The visible-light-induced cyclization of 3-
phenyl-2H-azirine (1a) with an array of 1-aryl-2-bromoacety-
lenes smoothly underwent optimal conditions to generate the
corresponding substituted oxazoles as desired products.
Obviously, the aryl substituents of 2 bearing both electron-
withdrawing and electron-donating groups on the para-position
of the benzene rings exhibited good tolerance. For example, para-
methyl, para-ethyl, para-(iso)propyl, para-butyl, para-(tert)butyl,
and para-methoxyl substituted phenyl-2-bromoacetylenes re-
acted with 1a to afford the corresponding products (3b−g) in
69−80% yields. The reactions also proceeded well when the
reactions of 1a with 1-aryl-2-bromoacetylenes with F, Cl, Br, and
CF3 at para- or meta-position of the phenyl rings were performed
under the standard reaction conditions, providing the desired
a
Reaction conditions: 1 (0.40 mmol), 2a (0.20 mmol), PC-I (5.0 mol
%), CH3CN/DCE (V/V = 1:1, 1.0 mL), room temperature, air, 1.5 W
blue LED for 24 h. Isolated yield. 36 h
b
c
excellent group tolerance was observed when a number of
substituted 2H-azirines were examined in the cycloaddition
reactions. 3-Aryl-2H-azirines attached electron-donating groups
(Me, Et, i-Pr and t-Bu) at para-position of the phenyl rings
reacted with 2a to provide the corresponding products (4a−d) in
good yields. Meanwhile, the reactions of 2H-azirines with a
(para-fluoro)phenyl, (para-chloro)phenyl, and (para-bromo)-
phenyl at 3-position with 2a afforded the desired products (4e−
g) in 63−68% yields. Moreover, 3-aryl-2H-azirines bearing a CF3
or C6H5 group on the para-position of benzene ring gave the
anticipated products 4h and 4i in 59 and 61% yields, respectively.
B
DOI: 10.1021/acs.orglett.6b01696
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The cycloaddition of 2a with 3-(meta-substituted phenyl)-2H-
azirines proceeded smoothly under optimal conditions to give
products (4j−l) in accepted yields. However, an obvious steric
effect was observed for the formation of 4m−p by using 3-(ortho-
substituted phenyl)-2H-azirines as one of the substrates. The
reactions of 3-(3,5-Cl2-phenyl)-2H-azirine, 3-(naphthalen-1-yl)-
2H-azirine, and 3-(naphthalen-2-yl)-2H-azirine, as well as 3-(2-
Cl-phenyl)-2H-azirine and 3-(2-F-phenyl)-2H-azirine with 2a
generated the target products (4m, and 4o−r) in satisfactory
yields after 36 h. In addition, the cycloaddition of several aryl-
substituted 2H-azirines with 1-(4-methylphenyl)-2-bromoacety-
lene under the optimized reaction conditions were examined,
and the according products (4s−x) were obtained in 57−75%
yields.
Scheme 5. Proposed Reaction Mechanism
To gain insight into the reaction mechanism of oxygen
participated cycloaddition, several control experiments were
conducted. First, addition of TEMPO (1.0 equiv) into the
reaction of 1a with 2a suppressed the cycloaddition completely
(Scheme S2, SI), indicating that a radical process may be
involved in the reaction. Subsequently, when 1a reacted with
(iodoethynyl)benzene, (phenylethynyl)copper, and ethynylben-
zene under standard reaction conditions, no product 3a was
obtained, demonstrating that only C−Br bond can be effectively
cleaved under blue LED irradiation (Scheme S2). Moreover,
addition of 18O-labeled water into the model reaction did not
give 18O-3d (Scheme 4). However, when the reaction was
radical. Next, the obtained Br radical as an oxidant gained one
electron from formed (PC-I)− to reset catalyst PC-I, which
proves feasible on the basis of half-peak redox potential of Br•/
Br− (E1/2red = +0.897 V)15 and (PC-I)−/PC-I (E1/2ox = −0.822
V). The fragmentation of D afforded E, followed by
intermolecular cyclization to generate F. Finally, the obtained
F underwent β-H elimination assisted by Br− to form desired 3a
and HBr.
In conclusion, we have developed a novel methodology to
build oxazole skeleton using acridinium salt (PC-I, 5.0 mol %) as
an organic photocatalyst at room temperature under visible light
irradiation. The radical cycloaddition proceeded smoothly to
generate oxazoles in moderate to good yields under mild reaction
conditions, and which provides an alternative approach to
functionalized oxazoles. The initial experiments have been
carried out to gain insight into the possible reaction pathway,
and additional efforts to gain a better understanding of this
transformation are currently underway.
Scheme 4. Selected Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01696.
Full experimental details and characterization data for all
products (PDF)
performed in 18O2 atmosphere for 24 h, 18O-3d was isolated in
75% yield, which was further confirmed by HRMS (Figure S1,
SI). These results clearly illustrated that oxygen atom in oxazole
3d comes from O2 in air, not from H2O (Scheme 4). In addition,
deuterium-labeling study using [D]7-1a unambiguously showed
that the cleavage of C−H bond in the reaction is not a rate-
determining step (Scheme 4). It is important to note that EPR
spectra did not provide any information for the formation of
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hongjili1982@163.com.
*E-mail: leiwang88@hotmail.com.
Notes
The authors declare no competing financial interest.
1
superoxide radical anion (O2−•) or singlet O2 during the
ACKNOWLEDGMENTS
This work is financially supported by the National Science
Foundation of China (No. 21572078, 21372095, 21402060).
■
reaction. Inversely, a vinyl peroxyl radical C (Scheme 5) is
considered as the key intermediate in the aerobic transformation
(Figure S4, SI).
On the basis of the above control experiments and mechanistic
studies, a possible pathway for this cyclization is outlined in
Scheme 5. Initially, a single-electron oxidation of 2H-azirine 1a
(Eox = +0.764 V) by the excited state of organic catalyst (PC-I)*
(Eox = +2.311 V) generated a radical cation A13 and (PC-I)−.10f
Then an addition of A to alkynyl bromide 2a provided
intermediate B. The formed B reacted with O2 to afford peroxyl
radical C, followed by a 4-endo alkene cyclization at very fast
rate14 to generate intermediate D along with the formation of Br
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