Cu(II)-Catalyzed 6π-Photocyclization of Non-6πSubstrates

Article abstract of DOI:10.1021/acs.orglett.0c01854

This research successfully achieved a Cu(II)-catalyzed 6π-photocyclization of non-6πsubstrates. The photoenolization converts ortho-alkylphenyl alkynl ketones into a triene-type intermediate which undergoes the subsequent 6π-photocyclization to give napht

Full text of DOI:10.1021/acs.orglett.0c01854

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Cu(II)-Catalyzed 6π-Photocyclization of Non-6π Substrates
Yanbin Zhang, Ruiwen Jin, Wenjie Kang, and Hao Guo*
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ABSTRACT: This research successfully achieved a Cu(II)-
catalyzed 6π-photocyclization of non-6π substrates. The photo-
enolization converts ortho-alkylphenyl alkynl ketones into a triene-
type intermediate which undergoes the subsequent 6π-photo-
cyclization to give naphthol as the final product. Cu(II) catalyst
facilitates both photoenolization and 6π-photocyclization. This
research highlighted the tandem reaction strategy and the importance of metal catalysis in photochemistry.
Scheme 1. Previous 6π-Photocyclizations and Working
Hypothesis
6π-Photocyclization has become one of the well-established
photocyclization reactions since its discovery in the 1980s.1 It
provides a convenient way to construct 1,3-cyclohexadiene and
aromatic rings by further dehydrogenation or elimination.
Thus, 6π-photocyclization is widely used in total synthesis,2,3
medicine discovery,4 and photoresponsive material design.5
One of the typical 6π-photocyclization substrates is triene with
an s-cis,Z,s-cis conformation (Scheme 1A, top).6 The π system
of s-cis,Z,s-cis triene has a similar conformation as the 6-
membered transition state of 6π-photocyclization, and the
termini of the π system are close enough to form a new σ
bond.7 For other conformers of triene, the isomerization of the
triene system is inevitable before the 6π-photocyclization.8 For
the dienyne-type substrate, the 6π-photocyclization is much
more difficult (Scheme 1A, bottom).9,10 The termini of the
dienyne π system are far away, leading to a higher kinetic
barrier to form both a 6-membered transition state and the
new σ bond. In addition, the corresponding primary 6π-
photocyclization product is 6-membered cyclic allene, which is
highly unstable.9 The subsequent aromatization via 1,5-H shift,
H abstraction, or protonation is necessary to achieve this
transformation, affording aromatic rings as final products.10 In
most cases, O2 and amines can facilitate the H abstraction,10a
while protic solvent may provide proton for the proto-
nation.10d Compared with those two pathways, the 1,5-H shift
has dramatically higher kinetic barrier, which is normally the
minor aromatization pathway.10a,b Overall, the 6π-photo-
cyclization of dienyne is conformationally disfavored, and
extra reagents are necessary for the transformation from the
highly unstable primary product to the final aromatic product.
Considering the broad application of 6π-photocyclizations,
new methods for 6π-photocyclization of dienyne is highly
desired yet challenging.
Received: June 2, 2020
In 2016, we reported a Cu(II)-catalyzed 6π-photocyclization
of dienynes (Scheme 1B).11 The Cu(II) catalyst showed dual
functions in this reaction: (1) The Cu(II)−alkyne complex has
a twisted “alkene-like” conformation. Thus, the coordination of
Cu(II) can transfer disfavored dienyne type substrate into
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© XXXX American Chemical Society
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favored triene type intermediate. (2) The Cu(II)−alkyne
complex has enhanced absorption toward the uncoordinated
substrate. Thus, the quantum yield of the reaction is also
improved. With such a Cu(II) catalysis strategy established, we
further questioned whether we could use this method to
achieve more challenging 6π-photocyclizations.
unidentified decompositions (Table 1, entries 4 and 5). Thus,
Cu(OTf)2 was chosen as catalyst for further studies. Solvent
screening demonstrated that THF showed the highest yield
among the tested solvents (Table 1, entries 6−11). Decreasing
the loading of Cu(OTf)2 to 1 mol % gave slightly higher yield
of 2a (Table 1, entries 12−14). Finally, control experiments
were carried out (Table 1, entries 15 and 16). Light was
proved to be necessary for this transformation, while the
absence of Cu(OTf)2 led to unidentified decomposition of all
of the starting material. Thus, conditions A (1 and 1 mol % of
Cu(OTf)2 in THF (0.02 M) irradiated by purple LED under
argon atmosphere at rt for 24 h) were chosen as the optimized
conditions for further studies.
The photochemical property of o-alkyl aromatic ketone is
very interesting. Upon proper photoirradiation, it can isomer-
ize to photoenol via 1,5-H transfer and intersystem crossing
(ISC).12 The photoenol is a unique intermediate and shows
dual reactivity as a diene and an enol.13,14 Many interesting
transformations were developed on the basis of this process.
However, as a diene, the reactivity exploration of photoenol
was limited to Diels−Alder reaction.14 With our continued
interest in 6π-photocyclization, we questioned whether the
reactivity exploration could be expanded to 6π-photocycliza-
tion (Scheme 1C). If o-alkylaromatic alkynyl ketone is used as
the starting reactant, the in situ generated photoenol may
provide an additional π system to form a transient dienyne type
6π intermediate. On the basis of our previous results, the
incorporation of proper Cu(II) catalyst may transfer this
disfavored dienye-type intermediate into a favored triene-type
species. Hence, we may achieve a new 6π-photocyclization
using a non-6π substrate. Herein, we report our recent results
on Cu(II)-catalyzed 6π-photocyclization of o-alkylphenyl
alkynyl ketones.
With the optimized conditions in hand, we next examined
the substrate scope of this reaction (Scheme 2). Functional
a
Scheme 2. Substrate Scope
The initial attempt was carried out using o-tolyl 4-
methoxyphenylacetylenyl ketone (1a) as the model substrate.
A series of Cu(II) salts were first screened (Table 1, entries 1−
3). The results revealed that Cu(OTf)2 showed remarkable
catalytic activity compared to other Cu(II) salts. Other π acids,
like AgOTf and PPh3AuCl, were also tried, but only led to
a
Table 1. Screening of the Conditions.
entry
cat. (mol %)
solvent
2a (%)
14
10 (2)
89
1
2
3
4
CuSO4 (10)
THF
THF
THF
THF
b
Cu(OAc)2 (10)
Cu(OTf)2 (10)
AgOTf (10)
nd
5
6
7
8
PPh3AuCl (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (3)
Cu(OTf)2 (1)
−
THF
EA
nd
b
b
b
nd (26)
nd (26)
nd (65)
6 (20)
26 (15)
nd (43)
88
90
91 (90)
nd
nr (100)
CH3CN
CH3OH
CH2Cl2
Toluene
Acetone
THF
THF
THF
THF
THF
b
9
b
b
10
11
12
13
14
15
a
Conditions: 1 (0.2 mmol) and 1 mol % of Cu(OTf)2 in THF (10
c
mL) was irradiated by purple LED under argon atmosphere at rt for
a
24 h. Isolated yield was reported. Isolated yield of gram-scale (4
mmol) reaction.
d
b
16
Cu(OTf)2 (1)
a
A solution of 1a (0.2 mmol) and catalyst in anhydrous solvent (10
groups at R were first studied (2a−k). Strong electron-
donating groups (EDG), such as methoxy (2a) and acetoxy
(2b), as well as weak EDG, such as tert-butyl (2c) and methyl
(2d), were tolerant in the formation of 2. Halogens (F, Cl, Br)
were also tested and gave good results (2f-h). Substrates with
strong electron-withdrawing groups (EWG), like methoxycar-
mL) was irradiated by a purple LED light under argon atmosphere at
rt. Yield and recovery was determined by H NMR analysis (400
1
MHz) of the crude reaction mixture using CH2Br2 (0.2 mmol) as the
b
c
d
internal standard; Recovery of 1a; Isolated yield of 2a; The
reaction was carried out without light. nd = not detected. nr = no
reaction.
B
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bonyl (2i), formyl (2j), and trifluormethyl (2k), also worked
well. Next, substituents at the linking phenyl ring were
examined. The tested substrates showed good reactivity (2l−
p). Disubstituted substrates were synthesized and tried. Di-
EDG (2q), EDG-EWG (2r-t), and EWG-EDG (2u) also gave
good yield (2v). Substrates where Ar was replaced by n-Bu
(2w) or TMS (2x) did not show good reactivity. Thus, this
reaction showed good substrate scope and functional group
tolerance.
After the substrate scope exploration, we next focused on
mechanistic studies. First, UV−vis spectroscopy was con-
ducted to identify what is excited during the reaction process.
As shown in Scheme 3A, the addition of 1 equiv of Cu(OTf)2
among the three simulated species. This observation is in
consistent with the fact that 6π-photocyclization of dienyne is
conformationally disfavored.9 The longer distance caused a
higher energy barrier in the new C1−C6 σ bond formation. To
our surprise, the C1−C6 distance of the favored triene type
intermediate II is even longer than that of III. The main reason
might be the rigid bond angle (126.9° and 124.2°) of the
alkene, which dramatically decreased the coplanner property of
II. The dihedral angle between the two phenyl is 48.3°. On the
contrary, the bond angles in III are 151.5° and 156.6°, and the
dihedral angle is only 22.5°. With less tortuosity in III, the
distance between C1−C6 is shorter than that in II. This
observation suggested that this Cu(II)-enabled 6π-photo-
cyclization of triene may have an even lower kinetic barrier
than the typical triene-type reaction. Experimentally, only
alkene isomerization occurred when a triene-type substrate was
applied under the same conditions (for a detailed discussion,
see Scheme S1).
Scheme 3. Mechanism Studies
Next, deuterium labeling and KIE experiments were carried
out to gain insight to the H atom transfer in this reaction
(Scheme 3C). Methyl-deuterated substrate 1a-d3 was synthe-
sized and tried under standard conditions. Then 65% of 2a-d
was generated with both 2- and 4-positions deuterated; 20% of
1a-d3 was recovered with 62% deuterium content at methyl.
The deuterium content loss of 1a and 2a was mainly due to the
de-excitation pathways during formation of photoenol (for a
detailed discussion, see Scheme S2).12 The D atom transfer
from the starting methyl to 2-position in 2a could be a strong
evidence for the 1,5-H shift during the cyclization process. The
lower deuterium content at the 2-position than 4-position
could be reasoned in other aromatization pathways, such as
protonation.9 The kH/kD was calculated to be 2.0, which
indicated the C−H bond cleavage or formation is the rate-
determining step (RDS). Since both photoenolization and 6π-
photocyclization processes contained C−H bond cleavage
and/or formation, it is hard to determine which step is the
RDS with the evidence so far.
With the evidence above and literature precedent, a possible
reaction mechanism was proposed in Scheme 4. With the
coordination of a catalytic amount of Cu(II) to starting
material 1, there are two existing species in the reaction
mixture: Cu(II)−alkyne complex 3 and uncoordinated 1. Both
Scheme 4. Proposed Mechanism
into the 1a solution induced a new absorption peak at a low
wavelength region. This observation suggested that a new
ground-state complex was formed upon the complexation of
Cu(OTf)2 to 1a. Furthermore, the Cu(II)−1a complex
showed slightly enhanced absorption compared to pure 1a at
the purple LED emitting region (for the emission spectra of
purple LED, see Figure S1). This result indicated that the
Cu(II)−1a complex is easier to be excited than pure 1a under
purple LED irradiation.
To gain a better understanding of the behavior of Cu(II) in
this reaction, DFT calculations of the enolized intermediates
(I, II, and III) were then carried out (Scheme 3B). Clearly,
with the coordination of Cu(OTf)2, the triple bond in III was
twisted (bond angle was 151.5° and 156.6°). Further
comparison of the C1−C6 distance revealed that the enolized
intermediate I has the longest C1−C6 distance (3.490 Å)
C
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species can be excited by purple LED light, while 3 showed
enhanced absorption than 1 (Scheme 3A). Upon excitation, 1
can be converted to photoenol 4 (for a detailed process, see
Scheme S3). Intermediate 4 is a disfavored dienyne-type
intermediate for 6π-photocyclization. The lifetime of 4 is
around 50 μs,15 which means it has little chance to coordinate
with 1 mol % of Cu(II) to form a favored triene-type
intermediate. Thus, the majority of 4 may de-excite and return
to 1. The excitation of Cu(II)−alkyne complex 3 leads to 5,
which is a favored triene-type intermediate. Then 6π-
photocyclization of 5 occurs, and primary product 6 is
generated. Subsequently, 1,5-H shift or protonation−deproto-
nation gives 7. The dissociation of Cu(II) yields the naphthol
2 as the final product.
In conclusion, a Cu(II)-catalyzed 6π-photocyclization
reaction of o-alkylphenyl alkynyl ketone was developed. This
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favored triene type intermediate. This reaction showed broad
substrate scope and function group tolarance. Mechanistic
studies indicated that the Cu(II) catalyst facilitated both
photoenolization and 6π-photocyclization processes. Further
photophysical investigation and application of this strategy are
ongoing in our group.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01854.
■
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Figure S1, Schemes S1−S3, experimental procedures,
and characterization of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
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(11) Jin, R.; Chen, J.; Chen, Y.; Liu, W.; Xu, D.; Li, Y.; Ding, A.;
Guo, H. J. J. Org. Chem. 2016, 81, 12553−12558.
Hao Guo − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China; orcid.org/0000-0003-3314-
4564; Email: hao_guo@fudan.edu.cn
(12) Cuadros, S.; Melchiorre, P. Eur. J. Org. Chem. 2018, 2018,
2884−2891.
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T. Angew. Chem., Int. Ed. 2003, 42, 3693−3696. (b) Nicolaou, K. C.;
Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613−627.
Authors
Yanbin Zhang − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China; orcid.org/0000-0002-
4087-420X
Ruiwen Jin − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China
Wenjie Kang − Department of Chemistry, Fudan University,
Shanghai 200438, P.R. China
(c) Dell’Amico, L.; Vega-Penaloza, A.; Cuadros, S.; Melchiorre, P.
̃
Angew. Chem., Int. Ed. 2016, 55, 3313−3317. (d) Yang, B.; Gao, S.
Chem. Soc. Rev. 2018, 47, 7926−7953. (e) Yang, B.; Lin, K.; Shi, Y.;
Gao, S. Nat. Commun. 2017, 8, 622.
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Soc. 2001, 123, 7931−7932. (b) Masuda, Y.; Ishida, N.; Murakami,
M. J. Am. Chem. Soc. 2015, 137, 14063−14066. (c) Shao, Y.; Yang, C.;
Gui, W.; Liu, Y.; Xia, W. Chem. Commun. 2012, 48, 3560−3562.
Complete contact information is available at:
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(d) Dell’Amico, L.; Fernandez-Alvarez, V. M.; Maseras, F.;
Melchiorre, P. Angew. Chem., Int. Ed. 2017, 56, 3304−3308.
(e) Cuadros, S.; Dell’Amico, L.; Melchiorre, P. Angew. Chem., Int.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly acknowledge financial support from Shanghai
Science and Technology Committee (18DZ1201607). We
thank Pan Huang at East China University of Science and
Technology for DFT calculations.
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