Intermolecular 2 + 2 Carbonyl-Olefin Photocycloadditions Enabled by Cu(I)-Norbornene MLCT

Article abstract of DOI:10.1021/jacs.9b03775

Photocycloadditions are often typified by the oxetane-forming Paternò-Büchi reaction. However, the mechanistic constraints of carbonyl excitation and olefin interception have limited this attractive oxetane-forming pathway. Here we describe the use of a Cu(I) precatalyst that achieves selective olefin activation via coordination to the metal center. Significantly, this intermolecular 2 + 2 carbonyl-olefin photocycloaddition engages alkyl ketones, which are more challenging to accommodate via direct irradiation pathways. Mechanistic investigations support the in situ formation of a Cu-norbornene resting state that undergoes a MLCT leading to oxetane formation.

Full text of DOI:10.1021/jacs.9b03775

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Communication
Intermolecular 2+2 Carbonyl-Olefin Photocycloadditions
Enabled by Cu(I)-Norbornene MLCT
Daniel M. Flores, and Valerie A. Schmidt
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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Intermolecular 2+2 Carbonyl-Olefin Photocycloadditions Enabled by
Cu(I)-Norbornene MLCT
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Daniel M. Flores and Valerie A. Schmidt*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
Supporting Information Placeholder
ABSTRACT: Photocycloadditions are often typified by
the oxetane forming Paternò-Büchi reaction. However,
the mechanistic constraints of carbonyl excitation and
olefin interception have limited this attractive oxetane
forming pathway. Here we describe the use of a Cu(I) pre-
catalyst that achieves selective olefin activation via
coordination to the metal center. Significantly, this
intermolecular 2+2 carbonyl-olefin photocycloaddition
engages alkyl ketones which are more challenging to
accommodate via direct irradiation pathways.
Mechanistic investigations support the in situ formation
of a Cu-norbornene resting state that undergoes a MLCT
leading to oxetane formation.
complexes were design features selected to promote
MLCT and generate relatively long-lived excited states
capable of intermolecular electron or energy transfer.
1
2
Radical-type reactivity occurring at the highly conjugated
ligands is uncommon although recent examples have
emerged where the active species that undergoes
1
3-16
excitation is
a
substrate-metal complex.
We
envisioned that inverting many of the properties that
make Ru- or Ir-based photoredox catalysts successful
could unlock the potential for new mechanistic pathways
featuring MLCT and access new reactivity modes.
Scheme 1. Selected Previous 2+2 Photocycloadditions.
A. Paterno-Buchi Reactiona
H
O
O
1
25 W Hg lamp
+
PhH, 40-80 h
Ph
The photochemically allowed 2+2 cycloaddition of two
-components is a straightforward, atom-economical
Ph
Ph
Ph
H

via: direct carbonyl excitation
80% yield
>95:5 dr
approach to 4-membered ring construction. The premier
example of such a reaction is the photocycloaddition of
carbonyl and alkene -bonds to form oxetanes, known as
B. Cu-catalyzed alkene photodimerizationb
H
H
CuOTf (1 mol %)
4
50 W Hg lamp
1
,2
+
the Paternò-Büchi reaction (Scheme 1A).
Despite the
THF, 144 h
name recognition of this reaction and the utility of
H
H
3
,4
oxetanes in drug discovery, its strategic application to
the general synthesis of oxetanes has been
mechanistically limited to specific substrate pairings
because they proceed via direct carbonyl excitation or
via: excitation of a Cu-olefin complex
8
8% yield
c
C. Cu-catalyzed norbornadiene valence isomerization
[
Cu]
Hg lamp
5
,6
photosensitization followed by alkene interception.
Consequently, the majority of reports feature aryl ketones
hexanes
via: excitation of a Cu-olefin complex
7
-9
or aldehydes paired with electron-rich alkenes, while
examples of alkyl ketone substrates are more limited and
rely on UVC irradiation and quartz reaction vessels,
D. Cu-catalyzed carbonyl-olefin 2+2 photocycloaddition (COPC)
This work
H
TpCu (10 mol %)
O
O
1
0
reducing their practicality and user friendliness.
100 W Hg lamp
Et2O, 12 - 48 h
R = alkyl
+
Catalyst controlled approaches have not been widely
developed.
R
R
R
R
H
via: excitation of a Cu-olefin complex
6
The ability of d octahedral transition metal compounds
to undergo metal to ligand charge transfer (MLCT) upon
irradiation is the fundamental photophysical property that
a
b
c
See ref. 2a. See ref. 17b. See ref. 22.
has propelled the burgeoning field of photoredox
Mackor and Kochi were among the first to report that
catalytic copper(I) triflate significantly improved the
efficiency of simple alkene photodimerizations via
11
catalysis.
The geometries, oxidation states, and
relatively slow ligand exchange kinetics of these
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excitation of an in situ formed Cu(I)-olefin complex
Page 2 of 7
the conventional 2+2 photocycloadditive oxetane
forming pathway of the Paternò-Büchi reaction (Scheme
1D). By activation of a metal-olefin complex rather than
direct excitation of either substrate, this approach could
alter the reactivity of the excited state and allow a more
diverse range of carbonyls to participate in 2+2 carbonyl-
olefin photocycloadditions (2+2 COPC). We selected
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17-20
(
Scheme 1B).
These examples required prolonged
reaction times (~days) and high wattage (450 W)
immersion well photoreactor setups to achieve even
moderate reaction efficiencies. Salomon and co-workers
initially proposed that excitation of an in situ formed
Cu(I)-olefin complex resulted in a charge transfer event
between the metal center and the alkene ligand leading to
cyclobutane formation. Budzelaar and coworkers later
computationally confirmed that the directionality of the
charge transfer event is metal (Cu) to ligand (olefin)
MLCT). Analogously, the valence isomerization of
23
tris(pyrazolyl)borate (Tp) for our investigations as we
20
anticipated that the monoanionic state could mimic the
electronic influences of the weakly coordinating triflate
anion commonly used, and the tridentate facial
coordination mode could simultaneously allow for olefin
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(
24
norbornadiene to quadricyclane was reported using a
range of pre-catalysts including Cu(I)-halides
coordination and inhibit non-productive quenching via
22a
22b,c
25-27
and
flattening.
other Cu(I) compounds bearing neutral mono- and bi-
Irradiation of a 1:3 mixture of methyl isobutyl ketone
and norbornene in the presence of 10 mol %
tris(pyrazolyl)borate copper(I) (TpCu) in diethyl ether
22d-j
22k
dentate phosphines,
and tris(pyrazolyl)borate
mono-anionic oxoquinolinato
22l
chelates (Scheme 1C).
28
Spectroscopic studies by Kutal and coworkers also
confirmed that Cu(I) mediated norbornadiene to
quadricyclane valence isomerization occurred by
with a 100W Hg lamp for 12 h resulted in 49% yield of
oxetane 1 as a 55:45 mixture of diastereomers at C2 with
exclusive cis-exo disposition at the ring junction (Table 1,
entry 1). In the absence of TpCu or light, 1 was not
detected (entries 2 and 3). The reaction efficiency
decreased when an equimolar ratio of ketone and alkene
were used, requiring a longer 36 h reaction time to
produce 1 in only 33% yield (entry 4). Using 10 mol %
copper(I) triflate in place of TpCu resulted in only 13%
yield of 1 and 11% yield of a mixture of norbornene
dimers (entry 5). Notably, alkene dimers were not
detected when TpCu was used. In lieu of using pre-
formed TpCu, an equimolar mixture of copper(I) triflate
and potassium tris(pyrazolyl)borate (10 mol % each) was
successful but produced 1 with diminished reaction
efficiency (31 vs. 49% yield, entry 6 vs 1).
2
excitation of an in situ generated Cu- -norbornadiene
2
2l
complex and proceeds via a MLCT.
Table 1. 2+2 COPC Reaction conditions effects.a
H
O
TpCu (10 mol %)
00 W Hg lamp
O
(C2)
1
+
iBu
equiv
Me
Me
Et O (0.15M), 12 h
2
iBu
H
1
3 equiv
standard conditions
1
Entry
Deviation from standard conditions
none
Yield of 1a
49%b
1
2
3
4
5
6
Scheme 2. Aryl ketone dimerizationa
No TpCu
n.d.
No lightc
n.d.
TpCu (10 mol %)
OH
O
Ph
Ph
100 W Hg lamp
Ph
Ph
+
33%d
1 equiv norbornene
CuOTf in place of TpCu
CuOTf + KTp (10 mol % each)e
Ph
Ph
Et O, 24 h
2
OH
2% yield
without TpCu: 53% yield
13%d
31%
1 equiv
3 equiv
4
aYields determined via 1H-NMR of crude reaction
mixtures using durene as an internal standard; a 55:45
aYields determined from 1H-NMR of crude reaction
mixtures using durene as an internal standard.
diastereomeric
ratio
was
determined
via
gas
chromatography of the crude reaction mixture; OTf =
b1
triflate. H-NMR yield calculated as the average over 3
Aryl ketones, such as benzophenone, are prototypical
carbonyls in Paternò-Büchi reactions. When subjected to
our standard conditions, benzophenone with excess
norbornene resulted in benzopinacol formation in 42%
yield without detection of the corresponding oxetane
c
independent trials, standard deviation >3% yield. In the
absence of light, the reaction mixture was heated to 43 C to
d
replicate the temperatures reached during irradiation. 36 h
e
reaction time. 11% yield of norbornene dimers were also
e
isolated. CuOTf and KTp were mixed in diethyl ether for 20
(Scheme 2). A control experiment without added TpCu
min prior to addition of substrates and irradiation.
resulted in similar reaction efficiency and selectivity for
ketone dimerization. Selectivity for benzophenone
dimerization in ethereal solvents rather than oxetane
formation with norbornene in benzene solutions has been
We envisioned that with an appropriate supporting
ligand, excitation of a Cu(I)-olefin compound in the
presence of a carbonyl could form an oxetane – inverting
2
previously reported. We attribute the lack of background
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Paternò-Büchi reactivity to the diethyl ether solvent used
and the failure of aryl ketones to produce oxetanes in our
observed reactivity.31 Cyclic ketones proved to be
outstanding carbonyl substrates, generating oxetanes 4-
10 in good to excellent yields and in each case,
exclusively as the cis-exo diastereomers. These examples
showcase the tolerance of acid sensitive acetal (7), ether
(8), basic tertiary amine (9), and thio-ether (10)
functionality during 2+2 COPC.
1
2
3
4
5
6
7
8
9
study to the inability of the Cu-mediated pathway to
29,30
outcompete ketone dimerization.
Also, the excitation
of alkyl ketones generally requires the use of quartz
reaction vessels to ensure adequate transmission
however, we exclusively used borosilicate reaction
vessels in our study which significantly block light at
wavelengths shorter than 280 nm (see Fig. 1). This
suggests that the traditional Paternò-Büchi mechanism of
direct carbonyl excitation is not operative in this 2+2
COPC and highlights the opportunities that become
available when a suitable catalyst is used.
To interrogate the mechanism by which this Cu-
catalyzed 2+2 COPC occurs, we carried out a series of
spectroscopic studies. We collected the electronic
absorption spectra of diethyl ether solutions of TpCu
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
(green line, Figure 1) and an equimolar mixture of TpCu
and methyl isobutyl ketone (gold line). Both spectra are
nearly identical and lack any distinct absorption features
Scheme 3. 2+2 COPC Scope of alkyl carbonyls.a
2
00 – 400 nm. Conversely, an ethereal solution of TpCu
and norbornene (1:1 molar ratio, pink line) has a broad
absorption feature with a maximum at 272 nm, suggesting
the formation of a new species in solution. A 1:1:1
mixture of TpCu, norbornene, and methyl isobutyl
ketone (orange line) displays the same absorption features
as without added ketone, suggesting that this new species
is the resting state species.
O
TpCu (10 mol %)
100 W Hg lamp
O
+
R1
equiv
Et2O, 12 - 48 h
R
R
R1
1
3 equiv
H
O
H
H
O
(C2)
2
3
Me
Me
5
1% yield
95:5 exo:endo
45% yield
55:45 dr at C2
95:5 exo:endo
Me
H
>
>
H
H
H
O
n = 1 4 66% yield
n = 2 05 81% yield
n = 3 06 67% yield
O
H
O
7
b
>95:5 exo:endo
76% yield
95:5 exo:endo
n
O
>
H
H
O
H
O
O
H
H
H
N
S
O
8
9
10
60% yield
>95:5 exo:endo
b
75% yield
95:5 exo:endo
69% yield
>95:5 exo:endo
>
Figure 1. Electronic absorption spectra. All samples were
collected at 0.5 mM in diethyl ether and as equimolar
mixtures of the compounds indicated with each component
being 0.5 mM. The transmission spectrum of the reaction
vessels used in this study is overlaid for reference (right
vertical axis).
aYields determined by 1H-NMR of crude reaction
mixtures using durene as an internal standard;
1
diastereomeric ratios were determined via H-NMR of the
crude reaction mixtures with the structure of the major
diastereomer shown; see the SI for additional details.
b
Isolated yields following purification via silica gel
chromatography.
The borosilicate reaction vessels used, transmit very
little light <280 nm indicating that oxetane formation is
the result of absorption >280 nm (see Figure 1). Oxetane
Next, a variety of alkyl ketones were investigated using
these Cu-catalyzed 2+2 COPC conditions (Scheme 3).
Irradiation of acetone, a common organic photosensitizer,
reacted to form oxetane 2 in 51% yield. 5-Hexen-2-one
which contains a terminal alkene was smoothly converted
to 3 in 45% yield as a 55:45 mixture of diastereomers at
C2. No intra- or intermolecular reactivity was observed
as a result of the -olefin. The absence of reactivity for
other alkenes in this 2+2 COPC suggests that norbornene
interaction with TpCu is preferred and is the source of
1
was detected in only 60% conversion after 12 h of
irradiation when a long pass 300 nm cut-on filter was
applied compared to >98% conversion without the filter.
Transmission through the cut-on filter ranges from <1%
below 295 nm to >22% above 300 nm. The correlation
between the decreased amount of light that reaches the
reaction mixture between 280-300 nm and the decreased
conversion to 1 suggests that oxetane forming excitation
occurs in this region.
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In agreement with the electronic absorption data, a
mixture of TpCu and methyl isobutyl ketone does not
result in the appearance of a new compound as
of additional norbornene or methyl isobutyl ketone in the
presence of TpCu(Norb). The absence of an observed
quenching relationship does not definitively exclude the
possibility that an additional sensitization process may
contribute to oxetane formation. The spin state of 2+2
1
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9
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33
1
determined by H-NMR (Figure 2, spectrum C).
However, in the presence (spectrum A) or absence of
methyl isobutyl ketone (spectrum B), mixtures of TpCu
and norbornene resulted in the formation of a Cu-olefin
compound as evidenced by the downfield chemical shift
change from 7.10 to 7.43 ppm of the proton at the C5
pyrazole position and a broadening of the signals
corresponding to norbornene (comparing spectra D to B
photocycloadditions is commonly inferred based on the
34,35
stereochemistry of the products detected.
However,
the use of norbornene in our present work precludes an
analogous interpretation because geometric constraints
would result in identical products irrespective of spin
state.
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and A). The H-NMR spectrum of a 1:10:30 ratio of
Scheme 4. Mechanistic proposal.
TpCu, methyl isobutyl ketone, and norbornene showed
the same characteristic C5 pyrazole proton chemical shift
that was observed from stoichiometric mixing of TpCu
and norbornene, suggesting that TpCu(Norb) is formed
under the reaction conditions and is the resting state
species.
In conclusion, we have developed a Cu-catalyzed 2+2
carbonyl-olefin photocycloaddition of alkyl ketones and
norbornene that accesses the corresponding oxetanes via
a mechanistically distinct pathway from conventional
Paternò-Büchi reactions. Our approach allows for
traditionally more challenging alkyl ketones to engage in
4
-membered ring formation because direct carbonyl
excitation is avoided. Mechanistic investigations support
that in situ formed TpCu(Norb) is the photoactive
species that upon excitation leads to oxetane formation.
This intermolecular 2+2 COPC process disrupts the
traditional Paternò-Büchi oxetane forming mechanistic
paradigm and was achieved using a MLCT approach
enabled through alkene substrate coordination.
Additional examples of substrate dependent MLCT
catalysis for use in chemical synthesis are under active
investigation in our laboratory and will be disclosed in
due course.
1
Figure 2. H-NMR spectra of reaction components. All
6
samples were prepared in benzene-d . A shows 1:10:30
mixture of TpCu:methyl isobutyl ketone: norbornene
(
(
0.11M with respect to ketone). B shows TpCu(Norb)
0.11M). C shows a 1:1 mixture of TpCu and methyl
isobutyl ketone (0.11M in each component). D shows TpCu
(0.11M). E shows norbornene (0.11 mM). F shows methyl
isobutyl ketone (0.11M).
In alignment with the previously reported mechanisms
1
8-21
of Cu-mediated alkene photodimerization,
valence
2
2
ASSOCIATED CONTENT
isomerization, and our collected data we propose that
Cu-catalyzed 2+2 COPC proceeds via initial olefin
coordination to TpCu to form TpCu(Norb) (Scheme 4).
Excitation 280-300 nm results in MLCT to generate a
Cu(II) metal center and an alkene radical anion. Trapping
of this polarized intermediate by the carbonyl unit of the
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental details; characterization data including NMR
spectra of novel compounds; methods and results (PDF)
3
2
AUTHOR INFORMATION
Corresponding Author
alkyl ketone can result in oxetane formation.
Luminescence data collected by excitation 280-300 nm
did not exhibit a relationship between the concentration
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*
vschmidt@ucsd.edu
(12) For a recent examples of Cu-based photoredox catalysis, see: (a)
1
2
3
4
5
6
7
8
9
Reiser, O. Shining Light on Copper: Unique Opportunities for
Visible-Light-Catalyzed Atom Transfer Radical Addition
Reactions and Related Processes. Acc. Chem. Res., 2016, 49,
ORCID
Daniel M. Flores: 0000-0002-7260-0860
Valerie A. Schmidt: 0000-0001-9647-6756
1
990 – 1996. DOI: 10.1021/acs.accounts.6b00296. (b) Michelet,
B.; Deldaele, C.; Kajouj, S.; Moucheron, C.; Evano, G. A General
Copper Catalyst for Photoredox Transformations of Organic
Notes
Halides.
Org.
Lett.,
2017,
19,
3576
–
3579.
(c)
The authors declare no competing financial interest.
https://pubs.acs.org/doi/10.1021/acs.orglett.7b01518.
Minozzi, C.; Caron, A.; Grenier-Petel, J. C.; Santandrea, J.;
Collins, S. K. Angew. Chem., Int. Ed., 2018, 57, 5477 – 5481.
DOI: 10.1002/anie.201800144. (d) Larsen, C. B.; Wenger, O. S.
ACKNOWLEDGMENT
This work was supported by start-up funds provided by the
University of California San Diego. D.M.F. thanks a
USDoEd GAANN Fellowship (P200A150251-17) for
support. We thank Profs. Joshua Figueroa and Clifford
Kubiak for helpful discussions.
Chem.
–
Eur. J., 2018, 24, 2039
–
2058. DOI:
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