Chemo- and Regioselective Synthesis of Alkynyl Cyclobutanes by Visible Light Photocatalysis

Article abstract of DOI:10.1021/acs.orglett.8b02934

Here is the first visible light catalytic intermolecular cross [2 + 2] cycloaddition of enynes with alkenes to alkynyl cyclobutanes established with good functional group tolerance and high reaction efficiency and selectivity. Detailed studies reveal that

Full text of DOI:10.1021/acs.orglett.8b02934

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Chemo- and Regioselective Synthesis of Alkynyl Cyclobutanes by
Visible Light Photocatalysis
†
,‡
Tao Lei, Xiang-Zhu Wei, Zan Liu, Bin Chen,†,‡
†,‡
†,‡
†,‡
Chao Zhou,
Vaidhyanathan Ramamurthy, Chen-Ho Tung,
§
†,‡
,†,‡
and Li-Zhu Wu*
†Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, The
Chinese Academy of Sciences, Beijing 100190, China
‡
School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China
§
Department of Chemistry, University of Miami, Miami, Florida 33124-0431, United States
*
S Supporting Information
ABSTRACT: Here is the first visible light catalytic intermolecular cross
2 + 2] cycloaddition of enynes with alkenes to alkynyl cyclobutanes
[
established with good functional group tolerance and high reaction
efficiency and selectivity. Detailed studies reveal that enynes, including
nonaromatic ones, can be sensitized by fac-Ir(ppy) via an energy transfer
3
pathway. Addition of the Lewis acid PPh AuNTf enables the cross
3
2
photo[2 + 2] cycloaddition reaction to take place under both direct visible
light irradiation or sensitization by Ru(bpy) (PF ) .
3
6 2
lkynyl cyclobutanes, structures in which a strained
cyclobutane ring is connected to a potentially reactive
However, these additions were often accompanied by other
types of additions. Only a few terminal and cyclic enynone gave
7
A
acetylene unit, occupy an important place in organic chemistry
because these structures can be readily transformed to many
[2 + 2] adducts as the sole products with moderate efficiency
8
(Scheme 1b).
1
other useful and reactive molecular skeletons. As illustrated in
During the past few years, successful visible-light-induced
photocycloadditions of aryl olefins, enones, and 1,3-dienes have
been reported. In several of these studies, it was shown that
triplet sensitization is a successful way to facilitate the reaction,
Scheme 1a, conventional syntheses of 1-alkynyl cyclobutanes
Scheme 1. Synthesis of Alkynyl Cyclobutane
9
even in an enantioselective fashion. These studies motivated us
to examine the photocycloaddition between an enyne and an
olefin via visible-light-activated catalysis. We envisioned that by
extending the conjugation of an alkene with an alkynyl
substitution, the triplet energy of the substrate would be
lowered. Complexation of the alkyne part with Lewis acids
would possibly further decrease the triplet energy of the present
system. Such a decrease in triplet energy would allow the use of
visible-light-absorbing photosensitizers to accomplish the
intermolecular cross [2 + 2] cycloaddition of an excited enyne
with an olefin via an energy transfer pathway.
In the present work, we summarize our successful design for
the highly efficient intermolecular cross [2 + 2] cycloaddition of
enynes with olefins under visible light irradiation. To our
knowledge, such a type of addition by visible light photocatalysis
(
VLPC) has not been reported. We have found that enynes,
even the ones substituted with an aliphatic group, could be
2
sensitized efficiently by 1 mol % of fac-Ir(ppy) without any
3
involve transition-metal-catalyzed cross-coupling, nucleophilic
3
additive to react with terminal olefins to yield alkynyl
cyclobutanes with high chemo- and regioselectivity. Various
functional groups, including ester, ketone, aldehyde, carboxylic
acid, amide, and phenyl sulfone, were tolerated. Addition of
addition reactions, and strong base-catalyzed intramolecular
cyclizations of long-chain alkynyl halocarbons. It is well-known
that cyclobutanes can be readily constructed by light-induced [2
4
5
+
2] addition of olefins. Based on this, we envisaged that
irradiation of enynes in the presence of olefins would yield the
above 1-alkynyl cyclobutanes (Scheme 1b). Such UV-irradiated
Received: September 13, 2018
6
cross addition reactions have been reported by Hopf et al.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Conditions ,
a b
Lewis acids such as PPh AuNTf enabled the [2 + 2] reaction to
3
2
take place under both direct visible light irradiation and
sensitization by a photocatalyst with lower triplet energy.
Initial efforts were focused on exploring the feasibility of a
visible-light-induced energy transfer pathway for the cross [2 +
2
] reaction of enyne. We synthesized the ethyl (E)-5-
entry
1
2
photocatalyst
solvent
yield (%)
dr
phenylpent-2-en-4-ynoate 1a as a model substrate and explored
its photophysical properties (Figure 1). UV−vis absorption
fac-Ir(ppy)3
THF
THF
THF
THF
THF
THF
THF
85
83
76
74
0
2:1
2:1
2:1
2:1
c
fac-Ir(ppy)3
3
4
5
Ir(ppy) (dtbbpy)(PF )
2
6
Ir[dF(CF )ppy] (dtbbpy)(PF )
3
2
6
Ru(bpy) (PF )
3
6
2
d
6
e
0
0
7
fac-Ir(ppy)3
a
Conditions: 0.2 mmol (1 equiv) 1a (E/Z = 2:1), 1b, 1 mol %
b
Photocatalyst, 2 mL solvent, Ar, blue LEDs, room temperature. Yield
and dr (trans/cis) was determined by H NMR analysis of the
1
unpurified reaction mixture using 1,1-diphenylacetonitrile as the
internal standard, and the trans and cis diastereomers were identified
c
on the basis of the NOEDS spectrum. The absolute trans-1a (E/Z >
Figure 1. (a) Absorption spectra of fac-Ir(ppy) (Ps), 1a, PPh AuNTf ,
3
3
2
d
e
−5
−5
19:1) was used. No fac-Ir(ppy) . No light.
and 1a + PPh AuNTf . [Ir(ppy) ] = 2.0 × 10 M; [1a] = 2.0 × 10 M,
3
3
2
3
−
5
[
[
PPh AuNTf ] =2.0 × 10 M (high concentration: [1a] = 0.05 M,
3 2
PPh AuNTf ] = 0.05 M). (b) Normalized phosphorescence spectra of
3
2
Ir(ppy) , 1a, and 1a + PPh AuNTf at 77 K. Excitation wavelength was
any one of these components did not result in the product
(entries 6 and 7). If the triplet energy is above that of 1a, the
3
3
2
3
30 nm for 1a, 350 nm for 1a + PPh AuNTf , and 450 nm for fac-
3
2
Ir(ppy)3.
reaction worked independent of the electrochemical potentials
IV/ III
of the catalysts. In addition to fac-Ir(ppy) (E
* = −1.73 V
3
1/2
spectra showed that 1a has no obvious absorption above 400
nm. Direct excitation by 330 nm light at 77 K generated a
moderate phosphorescence emission with λmax at 532 nm (the
emission in the region less than 470 nm is attributed to
fluorescence; see Figure S1). The phosphorescence corresponds
to a triplet energy of 53.7 kcal/mol for 1a. Comparing the triplet
vs SCE), two other iridium photocatalysts, Ir(ppy) (dtbbpy)-
2
IV/ III
(PF ) (E
*
= −0.96 V vs SCE) and Ir[dF(CF )-
IV/ III
6
1/2
3
ppy] (dtbbpy)(PF ) (E
*
= −0.89 V vs SCE), having
2
6
1/2
lower redox ability and similar triplet energy, performed well as
sensitizers. In the presence of these two photocatalysts, the
reaction proceeded smoothly to yield the product in 76 and 74%
yields, respectively (entries 3 and 4). Consistent with the
conclusion that the catalyst used in this study functions as a
triplet sensitizer, no reaction occurred when Ru(bpy) (PF )
energy of 1a with that of commercial photocatalysts fac-Ir(ppy)
3
1
0
(
55.2 kcal/mol) and Ru(bpy) (PF ) (48.9 kcal/mol), it is
3 6 2
clear that fac-Ir(ppy)3 rather than Ru(bpy) (PF ) would
3
6 2
3
6 2
III/ II
sensitize the photoaddition of enyne with olefins via triplet−
(E1/2 * = −0.81 V vs SCE) with a lower triplet energy but
similar redox potential as Ir(ppy) (dtbbpy)(PF ) and Ir[dF-
triplet energy transfer. As expected, the emission of fac-Ir(ppy)
3
2
6
was quenched by 1a (Figure S2), and the lifetime was shortened
(CF )ppy] (dtbbpy)(PF ) were used as the catalyst (entry 5).
3 2 6
from 1140 to 326 ns (Figure S3). This corresponded to a
The generality of the above visible-light-induced energy
transfer strategy was established by exploring the substrate scope
of cycloaddition with fac-Ir(ppy)3 as the photosensitizer.
Examination of the reactivity of numerous enynes and alkenes
(Scheme 2) led to the following observations: (a) Good yields of
products were obtained regardless of the substituents on the yne
part of the enyne. Alteration of the para substituent on the
phenyl group present on the yne part (2c−5c) changed neither
the reactivity nor the yield of the product. (b) Similar to aryl-
substituted enynes, heteroaryl-substituted ones such as ethyl-
(E)-5-(pyridine-3-yl)pent-2-en-4-ynoate and ethyl-(E)-5-(thio-
phene-2-yl)pent-2-en-4-ynoate also readily afforded the corre-
sponding products with 85 and 78% yields (6c−7c). (c) On the
ene side of enynes, a variety of substituents are tolerated. For
example, the ester group of 1a can be readily replaced by a
ketone, aldehyde, amide, and carboxylic acid group without
losing reactivity (8c−13c). The carboxylic acid derivative was
converted into the [2 + 2] adduct in 90% yield (12c). (d) The
above photoaddition also tolerated a number of diarylethylene
derivatives (14c−18c) as reaction partners; both electron-
donating and electron-withdrawing groups showed excellent
reactivity. (e) An even more important observation relates to the
fact that the addition works even with nonaromatic enynes
(19c−28c). Although an unsubstituted enyne (19c) gave a
reduced yield of the addition product with diphenylethylene
9
−1
−1
quenching constant of 5.80 × 10 s
M
(Figure S4).
Considering the possibility that Lewis acid coordination would
further decrease the triplet energy of the substrate, PPh AuNTf
3
2
was selected due to its strong interaction with alkynyl groups. As
expected, the absorption of 1a in the presence of PPh AuNTf
3
2
was red-shifted to 450 nm in comparison to that in its absence.
Upon excitation, a new phosphorescence peak up to 610 nm was
detected, which matches the triplet energy of the photocatalyst
Ru(bpy) (PF ) . Thus, we expect Ru(bpy) (PF ) to act as a
3
6 2
3
6 2
suitable photosensitizer in the presence of PPh AuNTf .
3
2
With the information in mind, we first attempted the
intermolecular cross [2 + 2] cycloaddition of ethyl (E)-5-
phenylpent-2-en-4-ynoate 1a with 1,1-diphenylethylene 1b by
using fac-Ir(ppy) as the photocatalyst (Table 1). Irradiation of
3
the above mixture in THF for 5 h provided alkynyl cyclobutane
1
c in 85% yield and 2:1 dr (entry 1; for more details about the
optimization of solvent and dosage of olefin 1b, see Table S1)
trans/cis, identified by the NOEDS spectra, Figures S13 and
(
S14), accompanied by the homodimer formation of enyne 1a as
a byproduct. The experiments with pure (E)-1a and a mixture of
(E)- and (Z)-1a (2:1) gave identical products (entry 2),
suggesting that the geometry around the ene part of enyne does
not control the product distribution. Control experiments
established that light and photocatalyst were necessary; omitting
B
DOI: 10.1021/acs.orglett.8b02934
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Organic Letters
Letter
Scheme 2. Scope of Substrates
diphenylethylene, and PPh AuNTf were directly irradiated. In
3
2
this case, the product yield was dependent upon the initial
isomer (Scheme 3). We speculate that triplet generation might
have been favored by the heavy Au atom.
The above experimental data could be understood on the
basis of the mechanism illustrated in Scheme 4. When a mixture
Scheme 4. Proposed Mechanism
of enyne, alkene, and fac-Ir(ppy) is irradiated with blue light,
3
the last one absorbs the light and populates the enyne to the
excited triplet state via the well-known triplet−triplet energy
9b
transfer pathway. The triplet enyne reacts with the ground-
state alkene to yield the diradical 3 that closes to yield the
cyclobutene. This reaction also occurs in the presence of the
Lewis acid PPh AuNTf . Under this condition, PPh AuNTf
3
2
3
coordinates with the enyne to red-shift its absorption and lower
its triplet energy. Such a complexation allows the direct
irradiation with visible light and permits the use of normally
inactive Ru(bpy) (PF ) to act as a triplet sensitizer.
3
6 2
To illustrate the synthetic application of this reaction further,
a gram-scale reaction of enyne 1a and olefin 1b was conducted in
(
45%), introduction of an alkyl group at the terminal position
the presence of 1 mol % of fac-Ir(ppy) . The reaction proceeded
generally increased the yield to well above 70% (20c−23c). The
only exception was the tert-butyl-substituted enyne 24c. Both
aliphatic and alicyclic substituents were tolerated at the yne end.
Overall, the above VLPC cycloaddition was found to be general,
and the yields of the alkynyl cyclobutanes were good.
3
smoothly to give the isolated product 1c in 74% yield with 2:1 dr
(
Scheme 5, path a). Furthermore, 1c could be converted to
Scheme 5. Synthetic Applications
As argued above, anticipating that addition of PPh AuNTf
3
2
would further decrease the triplet energy of 1a, we irradiated a
mixture of 1a, diphenylethylene, Ru(bpy) (PF ) , and
3
6 2
PPh AuNTf . The cycloadducts were obtained in 53% yield
3
2
and 2:1 dr, as shown in Scheme 3. Neither the yield nor the dr
value changed when the initial isomer ratio was changed from E/
Z 19:1 to 1:19. Interestingly, we found that the dimerization,
albeit in low yield, could be achieved when a mixture of 1a,
Scheme 3. [2 + 2] Photocycloaddition of Enyne by Other
Photocatalysts
related 1,2-dicarbonyl cyclobutane in 65% yield via RuCl /
3
11
TBHP oxidization (29, Scheme 5, path b). The alkynyl group
in 1c could be reduced to an alkyl group by Pt/C under H (1
12
2
atm) in 80% yield (30, Scheme 5, path c). Treatment of 1c with
13
LiAlH4 afforded the cyclobutylmethanol 31 in 83% yield
(
Scheme 5, path d).
In summary, we have established the occurrence of a highly
efficient [2 + 2] reaction between an enyne and an alkene to
C
DOI: 10.1021/acs.orglett.8b02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield alkynyl cyclobutanes with high chemo- and regioselectivity
initiated by visible light. The reaction tolerated various
functional groups such as ester, ketone, aldehyde, carboxylic
acid, amide, and phenyl sulfone. Both aryl- and alkyl-substituted
enynes showed high reactivity and gave the corresponding
cyclobutanes in high yields. This simple and efficient method
provides a new method for the synthesis of alkynyl cyclobutanes.
Control and spectroscopic experiments established the reaction
to be initiated by an energy transfer process. By lowering the
triplet energy of the enyne through complexation with the Lewis
acid PPh AuNTf , the utility of lower triplet energy sensitizers
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ASSOCIATED CONTENT
Supporting Information
■
̈
*
S
J. Am. Chem. Soc. 2016, 138, 7808−7811. (g) Blum, T. R.; Miller, Z. D.;
Bates, D. M.; Guzei, I. A.; Yoon, T. P. Science 2016, 354, 1391−1395.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02934.
(
H.; Meng, Q.-Y.; Ramamurthy, V.; Tung, C.-H.; Wu, L.-Z. Angew.
Chem., Int. Ed. 2017, 56, 15407−15410.
Experimental and NMR data (PDF)
(10) Deng, H.-P.; Fan, X.-Z.; Chen, Z.-H.; Xu, Q.-H.; Wu, J. J. Am.
Chem. Soc. 2017, 139, 13579−13584.
AUTHOR INFORMATION
Corresponding Author
■
*
(11) Ren, W.; Liu, J.; Chen, L.; Wan, X. Adv. Synth. Catal. 2010, 352,
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424−1428.
12) Feng, Y. S.; Xu, Z. Q.; Mao, L.; Zhang, F. F.; Xu, H. J. Org. Lett.
013, 15, 1472−1475.
13) Man, Z.; Dai, H.; Shi, Y.; Yang, D.; Li, C. Y. Org. Lett. 2016, 18,
4962−4965.
(
2
(
E-mail: lzwu@mail.ipc.ac.cn.
ORCID
Chao Zhou: 0000-0003-4942-8422
Bin Chen: 0000-0003-0437-1442
Vaidhyanathan Ramamurthy: 0000-0002-3168-2185
Chen-Ho Tung: 0000-0001-9999-9755
Li-Zhu Wu: 0000-0002-5561-9922
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and Technology
of China (2017YFA0206903), the National Natural Science
Foundation of China (21390404), the Strategic Priority
Research Program of the Chinese Academy of Sciences
(
XDB17000000), and the Key Research Program of Frontier
Sciences of the Chinese Academy of Sciences (QYZDY-SSW-
JSC029) is gratefully acknowledged. V.R. acknowledges the
Chinese Academy of Sciences for a fellowship and the U.S.
National Science Foundation (CHE-1807729) for the research
support.
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DOI: 10.1021/acs.orglett.8b02934
Org. Lett. XXXX, XXX, XXX−XXX