Visible-light-induced formal [3+2] cycloaddition for pyrrole synthesis under metal-free conditions

Article abstract of DOI:10.1002/anie.201400602

A photocatalytic formal [3+2] cycloaddition of 2H-azirines with alkynes has been achieved under irradiation by visible light in the presence of organic dye photocatalysts. This transformation provides efficient access to highly functionalized pyrroles in good yields and has been applied to the synthesis of drug analogues. A primary trial of photocascade catalysis merging energy transfer and redox neutral reactions was shown to be successful. Photo(chemistry) op: A photocatalytic formal [3+2] cycloaddition of 2H-azirines with alkynes has been established under the irradiation of visible light in the presence of an organic dye. This transformation provides efficient access to highly functionalized pyrroles in good yields and has been applied to the formal synthesis of an inhibitor for HMG-CoA reductase.

Full text of DOI:10.1002/anie.201400602

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Chemie
DOI: 10.1002/anie.201400602
Heterocycle Synthesis
Visible-Light-Induced Formal [3+2] Cycloaddition for Pyrrole
Synthesis under Metal-Free Conditions**
Jun Xuan, Xu-Dong Xia, Ting-Ting Zeng, Zhu-Jia Feng, Jia-Rong Chen, Liang-Qiu Lu,* and
Wen-Jing Xiao*
Abstract: A photocatalytic formal [3+2] cycloaddition of 2H-
azirines with alkynes has been achieved under irradiation by
visible light in the presence of organic dye photocatalysts. This
transformation provides efficient access to highly functional-
ized pyrroles in good yields and has been applied to the
synthesis of drug analogues. A primary trial of photocascade
catalysis merging energy transfer and redox neutral reactions
was shown to be successful.
P
hotoredox catalysis driven by visible light has recently
emerged as a flourishing research area owing to its inherent
features of green chemistry and sustainability.[1] In this
context, visible-light-induced photocatalytic cycloadditions
have been successfully achieved for the synthesis of structur-
ally diverse carbo- and heterocyclic molecules.[2] Surprisingly,
however, [3+2] cycloaddition reactions proceeding through
a photocatalytic amine oxidation process has received less
attention. In 2011, our group[3] and the group of Rueping[4]
independently disclosed a photocatalytic oxidation/[3+2]
cycloaddition/oxidative aromatization sequence in which
a metal photosensitizer catalyzed the generation of azome-
thine ylides from tertiary amine moieties (Scheme 1a). In
addition, Zheng and co-workers elegantly developed a [3+2]
cycloaddition of cyclopropylamines with olefins in the
presence of a ruthenium complex and visible light, thus
furnishing various cyclopentane derivatives in good yields
(Scheme 1b).[5] Despite the advances, further exploration of
Scheme 1. Visible-light-induced photocatalytic [3+2] cycloadditions.
bpy=2,2’-bipyridine, bpz=2,2’-bipyrazine, EWG=electron-withdraw-
ing group, DCE=1,2-dichloroethane, NBS=N-bromosuccinimide.
photocatalytic cycloaddition reactions employing non-terti-
ary amine precursors and avoiding the use of precious metal
catalysts is a highly desirable, yet challenging goal.
Polysubstituted pyrroles constitute an important family of
five-membered N-containing heterocycles with diverse bio-
logical properties and synthetic applications.[6] Not surprins-
ingly, great efforts have been devoted to the development of
practical, atom- and step-economic approaches to the pyrrole
architecture.[7] In particular, the exploition of novel reagents
and strategies has led to pyrrole syntheses using mild
conditions and exhibting good functional-group tolerance.
Recently, 2H-azirines (1) were established as highly valuable
synthetic intermediates for constructing different azacyclic
compounds, usually by using transition-metal catalysts or UV
light irradiation.[8] From the viewpoint of green chemistry, it is
significant to update the synthetic transformation of 2H-
azirines under operationally simple and environmentally
friendly conditions. As part of our ongoing research interests
in developing new methods for the synthesis of carbo- and
heterocycles by visible-light photoredox catalysis,[9] we report
herein a novel visible-light-induced [3+2] cycloaddition
reaction of the 2H-azirines 1 with activated alkynes 2
(Scheme 1c). The method provides an efficient route to
various polysubstituted pyrroles under very mild reaction
conditions (visible-light irradiation, metal-free, and room
temperature).
[*] J. Xuan, X.-D. Xia, T.-T. Zeng, Z.-J. Feng, Prof. Dr. J.-R. Chen,
Dr. L.-Q. Lu, Prof. Dr. W.-J. Xiao
CCNU–uOttawa Joint Research Centre, Key Laboratory of Pesticide
& Chemical Biology, Ministry of Education, College of Chemistry
Central China Normal University (CCNU)
152 Luoyu Road, Wuhan, Hubei 430079 (China)
and
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
E-mail: luliangqiu@mail.ccnu.edu.cn
wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/
Prof. Dr. W.-J. Xiao
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, CAS (China)
[**] We are grateful to the National Science Foundation of China (NO.
21232003, 21202053, and 21272087) and the National Basic
Research Program of China (2011CB808603) for support of this
research. We thank Prof. Li-Zhu Wu and Qin-Yuan Meng in Technical
Institute of Physics and Chemistry (CAS) for the quantum yield
measurements.
Initially, the formal [3+2] cycloaddition reaction was
investigated under irradiation from a 3 W white LED light by
using 2,3-diphenyl-2H-azirine (1a) and dimethyl but-2-yne-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400602.
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Table 2: Optimization of the reaction conditions.[a,b]
dioate (2a) as model substrates. In terms of the relatively high
oxidative potential of 1a (+ 1.65 V),[8d] 9-mesityl-10-methyl-
acridinium perchlorate (4)[10] was strategically chosen as the
photoredox catalyst because of its high oxidizing power in the
excited state (+ 2.06 V)[11] and strong absorption band in the
visible region.[12] As shown in Table 1, either none or only
Table 1: Optimization of reaction conditions.[a]
Entry
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
DMF
DMSO
MeOH
CH3CN
DCE
CH2Cl2
THF
CHCl3
DCE
DCE
DCE
DCE
DCE
48
48
48
48
48
48
48
48
16
24
24
48
48
0
0
16
57
61
49
25
40
98
0
9[c,d]
10[e]
11[f]
12[g]
13[h]
0
0
0
[a] Unless otherwise noted, reaction conditions are as follows: 1a
(0.3 mmol), 2a (1.5 mmol), photocatalyst (5 mol%), solvent (3 mL),
3 W white LED, at room temperature. [b] Yield of the isolated product.
[c] 7 W blue LED (450–460 nm) was used. [d] The quantum yield was
0.066. [e] [Ru(bpy)3Cl2]·6H2O was used. [f] [Ir(ppy)2(dtbbpy)]PF6 was
used. [g] In the absence of photoredox catalyst. [h] In the absence of light
source. DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide,
THF=tetrahydrofuran.
[a] Unless otherwise noted, the reaction conditions are as follows:
1 (0.3 mmol), 2 (1.5 mmol), photocatalyst (5 mol%), DCE (3 mL), 7 W
blue LED (450–460 nm), at room temperature. [b] Yield of the isolated
product. [c] CH3CN (3 mL) was used as reaction media. [d] Regioselec-
tivity was 6.5:1.
16% yield of desired cycloaddition product 3a was obtained
when the reaction was performed in polar solvents such as
DMF, DMSO, and MeOH (Table 1, entries 1–3). Further
investigation revealed that the yield of 3a could be improved
to 57% when using CH3CN as the reaction media (Table 1,
entry 4). To our delight, DCE gave slightly better results than
CH3CN (Table 1, entry 5). Note that the reaction proceeded
less efficiently in other solvents, including CH2Cl2, THF, and
CHCl3 (Table 1, entries 6–8). Importantly, the light source
had a significant effect on the reaction efficiency. When a blue
LED was used, the yield of isolated 3a was dramatically
improved and the reaction time was shortened to 16 hours
(Table 1, entry 9). Note that this [3+2] cycloaddition process
did not occur when transition-metal complexes, such as
[Ru(bpy)3Cl2].6H2O or [Ir(ppy)2(dtbbpy)]PF6 were used as
photocatalysts (Table 1, entries 10 and 11). Control experi-
ments revealed that no reaction occurred in the absence of
either the light source or the photoredox catalyst (Table 1,
entries 12 and 13).
thus giving the corresponding polysubstituted pyrroles 3b–
e in excellent yields. Moreover, this reaction is also quite
tolerant with respect to other functional groups, such as
naphthyl, furyl, vinyl, and different kinds of alkyl groups (3 f–
k). More importantly, significant structural variation in the
electron-deficient alkyne component can be realized. Both
diethyl but-2-ynedioate (2l) and methyl 4-oxo-4-phenylbut-2-
ynoate (2m) reacted well with 1a to afford the corresponding
tetrasubstituted pyrroles 3l (86%) and 3m (76%), respec-
tively. In addition, the activated alkynes can be successfully
extended to terminal alkynes. It was found that methyl and
ethyl propiolate, but-3-yn-2-one, and propiolonitrile were all
suitable substrates, thus providing the corresponding 3-ester,
3-keto, and 3-cyano substituted pyrroles (3n–q) in good
yields. To our delight, the reaction showed good regioselec-
tivity when two nonsymmetric components were involved.
For instance, the reaction of the 2H-azirine 2k with methyl
propiolate gave the corresponding pyrrole 3r and its regio-
isomer with 6.5:1 regioselectivity, albeit with moderate yield.
Under the optimal reaction conditions, the substrate
scope of this photocatalytic [3+2] cycloaddition process was
examined. As highlighted in Table 2, various substituents on
the phenyl ring of 1 did not influence the catalytic efficiency.
Both electron-donating (Me, OMe, PhO) and the electron-
withdrawing (Cl) groups could be successfully introduced,
2
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[3+2] cycloaddition process required continuous irradiation
with visible light indicated that the radical chain process
might not be the predominant pathway.[14]
Very recently, the group of Yoon[15] disclosed that an azide
group on an sp2-carbon atom can be sensitized by transition-
metal photocatalysts through an energy-transfer mecha-
nism.[16] And the resultant nitrene intermediate generated
from azide, by release of a molecule of nitrogen gas, can easily
2
À
insert into the sp C H bonds to form a 2H-azirine product.
Based on these observations, a photocascade catalysis merg-
ing energy transfer and redox pathways was successfully
carried out (Scheme 4). To our delight, the photocatalytic
Scheme 2. Formal synthesis of the HMG-CoA reductase inhibitor 7.
To further demonstrate the synthetic utility of this photo-
catalytic formal [3+2] cycloaddition, a formal synthesis of the
HMG-CoA reductase inhibitor
7
was performed
(Scheme 2).[13] In the presence of the organic dye photo-
catalyst 4, the 2H-azirine 1s reacted with 2a to give the
cycloaddition product 3s in moderate yield under irradiation
by a blue LED for 40 hours. Subsequently, the SN2 substitu-
tion reaction of 3s with 2-(2-bromoethyl)-1,3-dioxolane gave
the fully substituted pyrrole 6 in 54% yield upon isolation,
a compound which is the key synthetic intermediate to the
target molecule 7.[13] This operationally simple process reveals
that biologically important drug candidates can be rapidly
accessed by using this unprecedented visible-light-induced
formal [3+2] cycloaddition reaction as the key step.
Scheme 4. The first example of a metal-free photocatalytic cascade
transformation involving two different mechanisms.
A plausible reaction mechanism is proposed to illustrate
the redox neutral reaction process (Scheme 3). The single-
electron oxidation of the 2H-azirine in the presence of the
cascade reaction of the azide 8a and alkyne 2a occurred
efficiently and the desired polysubstituted pyrrole 3a was
accessed in high yield under our standard photocatalytic
condition. To our knowledge, this is the first example of
cascade reactions which involve two visible-light-induced
processes with different mechanisms.
In conclusion, we have developed a practical pyrrole
synthesis by means of a visible-light-induced photocata-
lytic formal [3+2] reaction of 2H-azirines with electron-
deficient alkynes. This metal-free photocatalytic process
has been successfully employed in the formal synthesis of
a HMG-CoA reductase inhibitor. Notably, the first
example of a visible light-induced photocascade catalysis
has been realized by combining energy transfer and
photoredox reactions. Additional investigations on this
chemistry are ongoing in our laboratory.
Scheme 3. Plausible reaction mechanism.
excited state of photocatalyst has proven to be feasible
according to the oxidation potential of the reactants[8d,10] and
luminescence quenching experiment results.[14] The radical
cation A undergoes a ring-opening process to generate the 2-
azaallenyl radical cation B and its electronic isomer B’.[8a–d]
Then, radical addition of B’ to activated alkynes delivers the
intermediate C, which subsequently undergoes an oxidation/
intramolecular cyclization/aromatization sequence to give the
final polysubstituted pyrroles. Moreover, the fact that this
Experimental Section
Representative procedure: 1a (0.3 mmol), 2a (1.5 mmol), 9-mesityl-
10-methylacridinium perchlorate (0.015 mmol), and anhydrous DCE
(3.0 mL) were added to a 10 mL Schlenk flask equipped with
a
magnetic stir bar. The resulting mixture was degassed by
a “freeze-pump-thaw” procedure (3 times). Then the solution was
stirred at a distance of ca. 5 cm from a 7 W blue LED (450–460 nm) at
room temperature. Upon the completion of reaction as monitored by
TLC, the solvent was removed by vacuum. The crude reaction
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Received: January 20, 2014
Revised: March 18, 2014
Published online: && &&, &&&&
Keywords: cycloaddition · dyes · heterocycles · photochemistry ·
.
synthetic methods
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Heterocycle Synthesis
J. Xuan, X.-D. Xia, T.-T. Zeng, Z.-J. Feng,
J.-R. Chen, L.-Q. Lu,*
W.-J. Xiao*
&&&& — &&&&
Visible-Light-Induced Formal [3+2]
Cycloaddition for Pyrrole Synthesis under
Metal-Free Conditions
Photo(chemistry) op: A photocatalytic
formal [3+2] cycloaddition of 2H-azirines
with alkynes has been established under
the irradiation of visible light in the
presence of an organic dye. This trans-
formation provides efficient access to
highly functionalized pyrroles in good
yields and has been applied to the formal
synthesis of an inhibitor for HMG-CoA
reductase.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!