Construction of Cyclobutanes by Multicomponent Cascade Reactions in Homogeneous Solution through Visible-Light Catalysis

Article abstract of DOI:10.1002/chem.201804946

[2+2] Photocycloaddition of two olefins is a general method to assemble the core scaffold, cyclobutane, found in numerous bioactive molecules. A new approach to synthesize cyclobutanes through multicomponent cascade reactions by merging aldol reaction and Witting reaction with visible-light-induced [2+2] cycloaddition is reported. An array of cyclobutanes with high selectivity has been achieved from commercially available aldehydes, ketones (or phosphorus ylide), and olefins with visible-light irradiation of a catalytic amount of (fac-tris(2-phenylpyridinato-C₂,N)iridium) ([Ir(ppy)₃]) at room temperature. Control experiments and spectroscopic studies revealed that the triplet–triplet energy transfer from the excited [Ir(ppy)₃]* to enones, generated in situ from aldehyde and ketone or aldehyde and phosphorus ylide, is responsible for these simple and efficient muticomponent transformations.

Full text of DOI:10.1002/chem.201804946

A Journal of
Accepted Article
Title: To Construct Cyclobutanes by Multicomponent Cascade
Reactions in Homogeneous Solution via Visible Light Catalysis
Authors: Li-Zhu Wu, Tao Lei, Chao Zhou, Xiang-Zhu Wei, Bing Yang,
Bin Chen, and Chen-Ho Tung
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Chemistry - A European Journal
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To Construct Cyclobutanes by Multicomponent Cascade
Reactions in Homogeneous Solution via Visible Light Catalysis
Tao Lei,[a, b] Chao Zhou,[a, b] Xiang-Zhu Wei,[a, b] Bing Yang,[a, b] Bin Chen,[a, b] Chen-Ho Tung,[a, b] and Li-
Zhu Wu*[a, b]
Abstract: Photo[2+2]cycloaddition of two olefins is general to
assemble the core scaffold, cyclobutane, found in numerous
bioactive molecules. We report here a new approach to synthesize
cyclobutanes via multicomponent cascade reactions by merging
aldol reaction and Witting reaction with visible light induced [2+2]
cycloaddition, respectively. An array of cyclobutanes with high
selectivity have been achieved from commercially available
aldehydes, ketones (or phosphorus ylide) and olefins with visible
The ability to use visible light rather than the ultraviolet light can
selectively photo-excite transition metal photocatalysts so as to
avoid undesired background reaction of photochemically
sensitive organic substrates and functional groups. In the last
five years, the intermolecular [2+2] photocycloaddition of some
olefins have been highlighted. [9,10]
In the present work, we report a new approach,[11] that is
multicomponent cascade reactions, using commercially
available aldehyde, ketone (or phosphorus ylide) and olefin, to
assemble into a cyclobutane under extremely mild condition
(Scheme 1c). Control experiments and spectroscopic studies
revealed aldehyde reacting with either ketone via aldol
reaction[12] or phosphorus ylide via Witting reaction[13] to
generate acyclic enone in situ at room temperature. The
generated enone species is capable of interacting intimately with
light irradiation of a catalytic amount of Ir(ppy)
Control experiments and spectroscopic studies revealed that the
triplet-triplet energy transfer from the excited Ir(ppy) * to enones,
3
at room temperature.
3
generated in situ from aldehyde and ketone or aldehyde and
phosphorus ylide, are responsible for these simple and efficient
muticomponent transformations
3 2
the excited Ir(ppy) * (fac-tris(2-phenylpyridinato-C ,N) iridium)
photocatalyst via triplet-triplet energy transfer. Subsequently, the
enone in triplet excited state reacts with another olefin in the
ground state to form cyclobutane without requiring any extra
Introduction
Cyclobutane is one kind of significant structures that is found in
numerous natural products and synthetic drugs.[1] Such
importance has stimulated considerable interests in developing
its synthetic strategies. To date, Lewis acid metal like Au, Ag, Cu,
Ti, and Ru, or organic molecules like oxazaborolidine and
second amine can activate some olefins with specific auxiliary
group to realize [2+2] cycloaddition of two olefins, albeit with a
narrow substrate scopes (Scheme 1a).[2] Photo [2+2]
cycloaddition reaction of two olefins is general and promising to
construct cyclobutanes (Scheme 1b).[3] Ultraviolet light can
directly excite a given olefin from ground state to corresponding
excited state and subsequently add to another olefin to construct
3
additives. With visible light irradiation of Ir(ppy) , a system of
aldehydes (aryl and alkynyl ones), ketones (aryl and aliphatic
ones), olefins (aryl ones and dienes) via aldol condensation/[2+2]
reaction sequence, and aldehydes (aryl and alkynyl ones),
phosphorus ylides (aryl and aliphatic carbonyl, esters
substitutions), olefins (aryl ones and dienes) via Witting
reaction/[2+2] reaction sequence can be smoothly converted to
corresponding cyclobutanes with high selectivity. In contrast to
[9,10]
[
2+2]cycloaddition of two olefins in documents,
this method
presented starts from commercial reactants, and offers an
alternative way to intermolecular [2+2] cycloaddition of two
acyclic olefins under visible light irradiation.
[
4]
the high-energy cyclobutane. A number of systems in solution ,
solid[5] and molten[6] state, and supramolecular host-guest
complexes[ have been developed. However, the requirement of
equipment, background reactions, and tolerance of functional
groups limit photo [2+2] cycloaddition for further potential
application. Recently, the booming of visible light catalysis has
shifted the attention from ultraviolet light to visible light region. [8]
7]
†
†
[
a]
Dr. T. Lei , C. Zhou , X.-Z. Wei, Dr. B. Yang, Dr. B. Chen, Prof. Dr.
C.-H. Tung, Prof. Dr. L.-Z. Wu
†
These authors contributed equally to this work
Key Laboratory of Photochemical Conversion and optoelectronic
Materials, Technical Institute of Physics and Chemistry, The
Chinese Academy of Sciences
Beijing, 100190, PR China
E-mail: lzwu@mail.ipc.ac.cn
†
†
[
b]
Dr. T. Lei , C. Zhou , X.-Z. Wei, Dr. B. Yang, Dr. B. Chen, Prof. Dr.
C.-H. Tung, Prof. Dr. L.-Z. Wu
School of Future Technology, University of Chinese Academy of
Sciences
Beijing, 100049, PR China
Scheme 1. The synthetic routes to cyclobutanes.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Chemistry - A European Journal
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Results and Discussion
promoted to 87% (Table 1, entry 12). Screening solvents of DCE,
CH
could be detected in CH
39% yield in DCE and THF, respectively (Table 1, entries 1, 5-8).
Increasing the concentration of substrates or base or
3
CN, THF, DMF and DMSO revealed that trace products
Construction of cyclobutane via multicomponent reactions.
In our initial study, benzaldehyde A, acetophenone B, and 1,1-
3
CN, DMF, DMSO but a 76% yield and
diphenylethylene
C
were used as the substrates and
A
ClCH CH Cl (DCE) as solvent to perform the reaction at room
temperature (Table 1). To our delight, anti-phenyl(2,3,3-
triphenylcyclo butyl)-methanone 1 was obtained as a single
2
2
prolonging the reaction time contributed little to the yields of
cyclobutanes (Table 1, entries 10, 13, 14). As a result, the
optimal ratio of benzaldehyde A, acetophenone B, 1,1-
diphenylethylene C, NaOH was determined to be 2:1:3:2 and the
amount of olefins C decreased from previous 5-10 eq to 3 eq
without losing the reaction activity. [10g, 10l]
With the optimized conditions in hand, we screened the
substrate scope of this multicomponent reaction, and found
kinds of commercially available aldehydes, ketones and olefins
were suitable for this reaction (Scheme 2). Analysis of these
results leads to the following conclusions: (a) Aryl group
substituted aldehydes, ketones and olefins were suitable for the
conversion regardless of the electronic property and steric effect
product in the presence of Ir(ppy)
irradiation (Table 1). Perusal of the reaction condition suggested
that Ir(ppy) was essential and 1 mol % was enough for the best
conversion. Among various bases investigated (NaOH, Cs CO
3
and NaOH under visible light
3
2
3
,
LiOH, KOH, Table 1, entries 1-4), NaOH was found to be the
best. When 2 equiv NaOH was added, the yield could be
Table 1. The optimization of conditions[a]
.
(
1-8, 10-15, 21-22). (b) Alkyl benzaldehyde, methoxy substituted
acetophenone and chlorine or methoxy substituted 1,1-
Entry[a]
Ir(ppy)
Base
Solvent
DCE
Yield[b] (%)
3
1
2
3
4
5
6
7
8
9
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
1 mol %
1 mol %
1 mol %
1 mol %
1 mol %
1 mol %
--
NaOH
76
<5
<5
42
<5
39
<5
<5
76
76
72
87
90
87
0
Cs2CO3
LiOH
DCE
DCE
KOH
DCE
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
--
3
CH CN
THF
DMF
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
1
1
1
1
1
1
1
1
0[c]
1[d]
2[e]
3[f]
4[e,g]
5[e]
6[e]
7[e,h]
1 mol %
1 mol %
0
NaOH
0
[
a] Reaction condition: A (0.4 mmol), B (0.2 mmol), C (0.6 mmol), base (0.2
mmol), Ir(ppy)
Determined
3
, solvent (2 mL), Ar, blue light, at room temperature, 11 h. [b]
1
by
H
NMR
analysis
with
(4-chlorophenyl)(4-
methoxyphenyl)meth-anone as internal standard. [c] A (0.6 mmol). [d] C (0.4
mmol). [e] NaOH (0.4 mmol). [f] NaOH (0.6 mmol). [g] 24 h. [h] No light.
Scheme 2. The scope of substrates (aldehydes, ketones and olefins).
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Chemistry - A European Journal
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diphenylethylene gave almost quantitative yield of corresponding
products (3-4, 11, 13, 21-22). (c) The heteroaromatic substrate
like furan-2-carbaldehyde also showed good reactivity (8). (d) In
spite of unsatisfied reactivity of alkyl aldehyde (9), aliphatic
ketones 3-methylbutan-2-one, pentan-2-one, even nonan-2-one
with long aliphatic chain could be converted to their respective
cyclobutanes with good yields (16-18). (e) For cyclopropyl and
cyclohexyl reactants, the rings remained in their cyclobutanes
formyl and acyl groups were all compatible in this one-pot
reaction (34-37). d) With refer to olefin partners, different 1,1-
diphenylethylene and monosubstituted styrene derivatives
underwent the reaction smoothly to generate the anticipated
products with excellent yields (80-99%) regardless of the
electronic property (38-44).
Mechanistic studies on the multicomponent reactions. The
efficient multicomponent reaction to construct cyclobutanes
stimulated us to confirm the reaction pathway. By using
benzaldehyde A, acetophenone B, and 1,1-diphenylethylene C
as template substrates, detailed mechanism studies were
(
19-20). (f) In addition to aryl olefins, simple styrene and 1,3-
diene could also proceed smoothly to afford the cooresponding
cyclobutanes (23-24).
The multicomponent reaction was further extended to
aldehydes, phosphorus ylides and olefins system to establish
the generality. Via simple optimization, this reaction was found
explored. As shown in Figure 1, only Ir(ppy)
irradiated light (λ = 450 nm) among all components. Excitation of
Ir(ppy)
at 450 nm led to strong 3MLCT emission with a
maximum at 510 nm in DCE solution. With the addition of 1,1-
diphenylethylene C into the solution, the 3MLCT emission of
3
responded to the
3
[
14]
to work well in DMSO with 1 mol % Ir(ppy)
3
as photocatalyst.
Investigation of the reactivity of aldehydes, phosphorus ylides
and olefins led to the following conclusions (Scheme 3): a)
Benzaldehydes with different electronic properties afforded the
corresponding cyclobutanes in good yields (25-30), except the
ortho substitution in phenyl group (31), indicating an obviously
steric effect. b) Alkynyl aldehydes connected with aromatic cycle
and aliphatic chain also showed good reactivity to produce
alkynyl cyclobutanes with 83% and 91% yield and 2:1 d.r.
respectively (32-33). c) As for phosphorus ylide, alkoxycarbonyl,
Ir(ppy)
3
was markedly quenched, whereas the other two
substrates, benzaldehyde A and acetophenone B, did not show
the same quenching behavior at all. These observations
indicated that olefin of 1,1-diphenylethylene C could interact with
the excited Ir(ppy)
3
* photocatalyst rather than the other two
benzaldehyde A and acetophenone B species.
Figure 1. (a) Absorption spectra of Ir(ppy)
1
3
, benzaldehyde A, acetophenone B,
,1-diphenylethylene C and chalcone D. (b) Emission quenching of Ir(ppy) by
] = 0.025mM. [A] = 5.0 mM, [B] = 2.5 mM, [C] = 7.5 mM,
3
A, B, C and D. [Ir(ppy)
3
[D] = 2.5 mM. For (b) excitation wavelength is 450 nm..
However, no reaction took place when benzaldehyde A or
acetophenone B was omitted from the template reaction. Given
that benzaldehyde A or acetophenone B had no influence on the
emission of the solution containing Ir(ppy)
diphenylethylene C, we believed that the interaction of the
activated 1,1-diphenylethylene C by Ir(ppy) * photocatalyst with
3
and 1,1-
3
the other two substrates benzaldehyde A or acetophenone B
was rather weak. In the absence of light, however, the mixture of
benzaldehyde A, acetophenone B, NaOH and 1,1-
diphenylethylene C afforded enone D with 86% yield at room
temperature. Direct reaction of enone
D
and 1,1-
diphenylethylene C gave only 70% yield of [2+2] product. It
seemed to say that the activated 1,1-diphenylethylene C by
Ir(ppy)3* reacted with enone D to produce a cyclobutane in
higher yield. In the following experiments, however, we could not
obtain the homo-dimer of 1,1-diphenylethylene C, whereas
homodimerized enone D generated from aldehyde A and ketone
B was achieved under the same condition (the scope of
homodimerization see Part 4 in Supporting Information).
Scheme 3. The scope of substrates (aldehydes, phosphorus ylides and
olefins).
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Ir(ppy)
3
* photocatalyst by enone D is the result of energy
transfer. The fact that the above three iridium photocatalysts,
6
Ir(ppy) , Ir(ppy) (dtbbpy)(PF ) and Ir[dF(CF )ppy] (dtbbpy)(PF )
3
2
6
3
2
have the slightly higher triplet energy (57.8, 49.2, 60.8 kcal/mol)
than that of enone D (50 kcal/mol) promoting the formation of
cyclobutane, whereas Ru(bpy) (PF ) has much lower triplet
3 6 2
energy (46.5 kcal/mol) than that of enone D leading to no
reaction, supported the triplet-triplet energy transfer pathway.
Form the viewpoint of generating enone in situ, the Witting
reaction of aldehyde and phosphorus ylides would be more
favourable to combine with photo[2+2]cycloaddition for
cyclobutanes formation (more details see SI). In addition, the
geometric isomerization[15] of enone D was observed to compete
with the cross[2+2]cycloaddition under visible light irradiation of
iridium catalyst. However, cyclobutane was the only isolated
product. Thus, the final cyclobutane is derived from E/Z isomers .
Scheme 5. Proposed mechanism.
Scheme 4. Summary of key mechanistic findings.
Strikingly, enone D enabled quenching the 3MLCT emission of
On the basis of the above experimental observation, we
proposed a plausible mechanism outlined in Scheme 5. Under
visible light irradiation, the excited photocatalyst Ir(ppy) *
3
transfers energy to the enone, generated in situ from aldehyde
and ketone via aldol condensation reaction or aldehyde and
Ir(ppy)
b, Figure S2 and S3 in Supporting Information). From these
attributes, we considered that the interaction of photoexcited
Ir(ppy) * with the acyclic enone D generated in situ is more
3
375 times greater than 1,1-diphenylethylene C (Figure
1
3
phosphorus ylide via Witting reaction, to yield the excited enone
favorable than the other olefin, 1,1-diphenylethylene C.
in triplet state via energy transfer process.[
9l]
The latter
To shed more light on the activation mechanism, we
selected several photocatalysts for this unique reaction. Good to
excellent yields were obtained when the template reaction was
undergoes [2+2] cycloaddition with olefin in the ground state to
produce the diradical intermediate. The stable diradical closes to
yield the cyclobutane product.
conducted in the presence of Ir(ppy)
Ir[dF(CF )ppy] (dtbbpy)(PF ) (Scheme 4). However, the use of
Ru(bpy) (PF , with the similar visible light absorption and redox
potential as Ir(ppy) (dtbbpy)(PF
), yielded no product, Conclusions
2
(dtbbpy)(PF
6
)
and
3
2
6
3
6 2
)
2
6
suggesting that the redox potential of photocatalyst was not the
key for the cycloaddition. When 1 equiv electron donor N,N-
diisopropylethylamine (DIPEA) was added into the solution, the
yield of cyclobutane product was decreased to 18%, indicating
the unfavorable single electron transfer (SET) pathway.
Considering no external additives presented in the reaction
solution, we speculated that the quenching of the excited
In conclusion, we have succeeded in developing
multicomponent cascade strategy to assemble cyclobutanes.
This reaction is accomplished by commercially available
a new
aldehydes,
ketones
and
olefins
via
aldol
condensation/photo[2+2] cycloaddition reaction sequence or by
aldehydes, phosphorus ylides and olefins via Witting
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Chemistry - A European Journal
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reaction/photo[2+2] cycloaddition reaction sequence, which
shows good compatibility of thermal and photochemical
procedures. Mechanistic study demonstrates that the enone
generated form aldehyde and ketone or phosphorus ylide was
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aldehyde, ketone and olefin: A 10 mL glass tube equipped with a
magnetic stir bar was charged with olefin (0.6 mmol), NaOH (0.4 mmol),
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Ir(ppy) (1 mol %), DCE (2 mL). This system was bubbled with Ar for 15
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syringe. This system was sealed and irradiated at room temperature by
blue LED for 11 hours. Then the mixture was evaporated under reduced
pressure to remove the solvent and the residue was purified by flash
chromatography on silica gel (Petroleum ether/ EtOAc) to afford the
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with a magnetic stir bar was charged with phosphorus ylide (0.4 mmol),
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blue LED for 12 hours. Then the mixture was evaporated under reduced
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Acknowledgements
10.1002/anie.201803102.
We are grateful for financial support from the Ministry of Science
and Technology of China (2014CB239402, 2017YFA0206903),
the National Natural Science Foundation of China (21390404),
the Strategic Priority Research Program of the Chinese
Academy of Science (XDB17000000) and Key Research
Program of Frontier Sciences of the Chinese Academy of
Science (QYZDY-SSW-JSC029).
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Keywords: multicomponent cascade reaction • aldol reaction •
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A new approach to synthesis of
cyclobutanes via multicomponent
cascade reactions is described.
An array of cyclobutanes with
high selectivity have been
Tao Lei, Chao Zhou, Xiang-Zhu Wei,
Bing Yang, Bin Chen, Chen-Ho Tung,
and Li-Zhu Wu*
Page No. – Page No.
achieved from commercially
available aldehydes, ketones or
phosphorus ylide, olefins with
visible light irradiation of a
To Construct Cyclobutanes by
Multicomponent Cascade Reactions
in Homogeneous Solution via Visible
Light Catalysis
catalytic amount of Ir(ppy)
room temperature.
3
at
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