Enantioselective intramolecular [2 + 2]-photocycloaddition reactions of 4-substituted quinolones catalyzed by a chiral sensitizer with a hydrogen-bonding motif

Article abstract of DOI:10.1021/ja207480q

Six 2-quinolones, which bear a terminal alkene linked by a three- or four-membered tether to carbon atom C4 of the quinolone, were synthesized and subjected to an intramolecular [2 + 2]-photocycloaddition. The reaction delivered the respective products in high yields (78-99%) and with good regioselectivity in favor of the straight isomer. If conducted in the presence of a chiral hydrogen-bonding template (2.5 equiv) at low temperature in toluene as the solvent, the reaction proceeded enantioselectively (83-94% ee). An organocatalytic reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane, was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at -25 °C in trifluorotoluene as the solvent, three of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72-87% ee). In all catalyzed reactions, the yields based on conversion were moderate to good (40-93%).

Full text of DOI:10.1021/ja207480q

ARTICLE
pubs.acs.org/JACS
Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions
of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a
Hydrogen-Bonding Motif
Christiane M€uller,† Andreas Bauer,† Mark M. Maturi,† M. Consuelo Cuquerella,‡ Miguel A. Miranda,*,‡ and
Thorsten Bach*,†
†Lehrstuhl f€ur Organische Chemie I and Catalysis Research Center (CRC), Technische Universit€at M€unchen, D-85747 Garching,
Germany
‡Instituto de Tecnología Química (UPV-CSIC), Universidad Politꢀecnica de Valencia, 46022 Valencia, Spain
S Supporting Information
b
ABSTRACT: Six 2-quinolones, which bear a terminal alkene linked by a
three- or four-membered tether to carbon atom C4 of the quinolone,
were synthesized and subjected to an intramolecular [2 + 2]-photo-
cycloaddition. The reaction delivered the respective products in high
yields (78ꢀ99%) and with good regioselectivity in favor of the straight
isomer. If conducted in the presence of a chiral hydrogen-bonding
template (2.5 equiv) at low temperature in toluene as the solvent, the
reaction proceeded enantioselectively (83ꢀ94% ee). An organocatalytic
reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or
xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer
inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane,
was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-
membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash
photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation
of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under
optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at ꢀ25 °C in trifluorotoluene as the solvent, three
of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72ꢀ87% ee).
In all catalyzed reactions, the yields based on conversion were moderate to good (40ꢀ93%).
’ INTRODUCTION
Chirality1 is one of the most fascinating properties of matter.
The quest to create chiral molecules enantioselectively and the
desire to understand their interactions belong to the intellec-
tually most challenging tasks of chemistry.2 Photochemical,
enantioselective approaches to chiral molecules have been pur-
sued along different lines of research. Solid-state photochemistry
offers access to enantioselective products by irradiation of
homochiral crystals3 or by employing chiral cavities.4 In the
Figure 1. Chiral template (+)-1 and chiral sensitizers (+)-2 and (+)-3.
liquid phase, chirality can be induced either by transforming a
chiral solid-state conformation photochemically into a defined
pyridones,14 dihydropyridones,15 imidazolidinones,16 and aro-
absolute configuration5 or by irradiation with circularly polarized
light.6 An alternative approach is to employ noncovalent inter-
actions to provide a chiral environment, in which a photochemical
reaction takes place.7 Apart from other supramolecular interactions,8
hydrogen bonds have turned out to be a generally applicable means9
to coordinate photochemical substrates in a spatially distinct three-
dimensional fashion.10 For use on a stoichiometric scale, tem-
plate (+)-1 (Figure 1) and its enantiomer11 have proven to be useful
complexing agents to induce high enantioselectivities in photo-
chemical reactions of (dihydro)quinolones,12 isoquinolones,13
matic amides.17
It was envisaged that it might be possible to combine the
hydrogen-bonding ability of the 1,5,7-trimethyl-3-azabicyclo-
[3.3.1]nonan-2-one skeleton with a catalytically active sensitizing18
unit R attached to the 7-position of the scaffold. The distance
dependence of triplet energy19 or electron20 transfer would allow
for a sensitized intramolecular photochemical reaction to occur
Received: August 9, 2011
Published: September 28, 2011
r
2011 American Chemical Society
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Scheme 2
Figure 2. Substrates for the intramolecular [2 + 2]-photocycloaddition.
Scheme 1
synthetic routes were used in this study. One route is based on
easily accessible 4-chloroquinoline-N-oxide (10)26 as starting material
(Scheme 1). Nucleophilic displacement of the chlorine substituent is
facilitated by the electron withdrawing power of the N-oxide and
occurs readily either by an oxygen or by a sulfur nucleophile. Alcohols
1127 and 1228 were accessible by known procedures. Following the
substitution pathway, ether 13 and thioether 14 were directly obtained
from N-oxide 10 in very good yields.
The key transformation in the N-oxide route to 4-substituted
quinolones is the subsequent rearrangement, which is advanta-
geously conducted photochemically.29 A major improvement in
this reaction step was made recently12d by performing the
rearrangement in oxygen-purged methanol employing a contin-
uous flow system. The photochemical rearrangement occurs on
the singlet hypersurface and is consequently not sensitive to the
presence of oxygen, while the potentially possible, but at this
stage undesired intramolecular [2 + 2]-photocycloaddition of the
quinolone products occurs on the triplet hypersurface (vide
infra). The latter reaction is almost completely suppressed in
the presence of oxygen, which allows for the isolation of the
quinolones in high yields. Starting from N-oxide 13, quinolone 6
was obtained in quantitative yield at an irradiation wavelength of
λ = 366 nm. The thiosubstituted N-oxide 14 could be irradiated
at longer wavelength (λ = 419 nm) and delivered the desired
quinolone 7 in a yield of 76%.
selectively in a 1:1 complex of substrate and catalyst. Our first
successful experiment in this series was based on the use of catalyst
(+)-2 and its enantiomer, with which it was shown that a chirality
multiplication is possible in an enantioselective radical cyclization
initiated by a photoinduced electron transfer (70% ee with 30 mol %
of catalyst).21,22 In earlier work aiming at catalysis by triplet energy
transfer, Krische !et al. had used a hydrogen-bonding template
tethered to a benzophenone sensitizer to induce enantioselectivity
in the intramolecular [2 + 2]-photocycloaddition23 of 4-(but-3-
enyloxy)quinolone (4, Figure 2)24 (19% ee with 25 mol % of
catalyst).10a When revisiting this photocycloaddition, we found that
catalyst (+)-3 can be employed to achieve very high enantioselec-
tivities at low catalyst loadings (90% ee with 5 mol % catalyst).25
Prerequisites for a high chemo- and enantioselectivity were the use of
a nonpolar solvent (trifluorotoluene) at low temperature (ꢀ25 °C)
and long wavelength irradiation (λ = 366 nm). This intriguing result
led us to initiate a more extensive study on the enantioselective
intramolecular [2 + 2]-photocycloaddition of 4-substituted quino-
lones. To this end, various substrates 4ꢀ9 (Figure 2) were synthe-
sized and tested in photocycloaddition reactions mediated by
either the stoichiometric template (+)-1 or the catalyst (+)-3.
For some substrates, it was found that they show an equally good
performance as was previously observed for substrate 4.
A second route to quinolones relies on the synthetic modifica-
tion of preformed quinolones by functional group manipulation
and substitution. Oxidation30 of sulfide 7 (Scheme 2) proceeded
cleanly and furnished sulfone 8 in high yield.
The reactions of 4-(but-3-enyloxy)quinolone (4) and 4-
(pent-4-enyloxy)quinolone (5) were closely compared regarding
the different parameters, which influence the enantioselectivity.
Laser flash spectroscopic studies revealed that there are distinct
differences in the photocycloaddition kinetics of 4 and 5, which
nicely explain the difference in enantioselectivity observed in the
catalytic version of their enantioselective [2 + 2]-photocycload-
dition reactions. A mechanistic picture was developed, which
comprises the experimental facts so far obtained.
Known 4-methylquinolone (15)31 was transformed into the
pent-4-enyl substituted quinolone 9 by deprotonation and sub-
sequent electrophilic attack by but-3-enyl bromide as an alkylat-
ing agent. Amine 17 was prepared by nucleophilic displacement
of the triflate group in quinolone 16 with N-but-3-enylamine.32
The resulting product 17 was moisture sensitive, however, and
hydrolyzed quickly to 4-hydroxyquinolone. As discussed in the
next paragraph, its intramolecular [2 + 2]-photocycloaddition
turned out to be capricious.
’ RESULTS AND DISCUSSION
Preparation of Starting Materials. Among the different
possible approaches to 4-substituted quinolones, two major
Preliminary Studies and Template-Induced Enantioselec-
tivity. Intramolecular [2 + 2]-photocycloaddition reactions of
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Scheme 3
Table 2. Reaction Conditions, Enantioselectivities, and
Yields in the Enantioselective Intramolecular [2 + 2]-Photo-
cycloaddition of Quinolones 4ꢀ9 in the Presence of Chiral
Template (+)-1 (See Scheme 3)
entry substratea
X
R
product λ [nm] tb [h] eec [%] yieldd [%]
1
2e
3
4
5
6
7
8
9
O
H
18a
19a
300
300
300
366
366
366
3
1
6
1
1
2
89
>90
83
43
87
66
89
99
99
OCH2
O
H
Me 20a
4
S
H
H
H
21a
22a
23a
89
5
SO2
CH2
90
6
94
a All reactions were conducted at a substrate concentration of 5 mM with
2.5 equiv of template (+)-1 at ꢀ78 °C in toluene as the solvent.
b Irradiation time. c The enantiomeric excess of the straight photocy-
cloaddition products was determined by chiral HPLC analysis (see the
Supporting Information). d Yield of isolated product. e The reaction has
been studied in earlier work at ꢀ60 °C. The enantiomeric excess was
determined by chemical shift experiments, which have a relatively high
detection limit. The other enantiomer could not be detected.12a
Table 1. Reaction Conditions, Regioselectivities, and Yields
in the Intramolecular [2 + 2]-Photocycloaddition of Quino-
lones 4ꢀ9 (See Scheme 3)
there was no chiral information present, all products were racemic
(rac-18 to rac-23).
entry substratea
X
R
product tb [h]
r.r.c
yieldd [%]
1
2
3
4
5
6
4
5
6
7
8
9
O
H
rac-18
rac-19
9e
9
86/14
90/10
91/9
78
99
95
99
92
99
Although 4-(but-3-enylamino)quinolone (17) exhibits an
absorption band, which is significantly shifted to longer wave-
lengths (λ > 350 nm) as compared to the corresponding 4-
alkenyloxyquinolones 4 and 5, its photocycloaddition proceeded
sluggishly. There was a precipitate observed shortly after the
irradiation was initiated, and even after 10 h the reaction had not
gone to completion. The resulting product showed typical NMR
data of the expected straight photocycloaddition product but was
impossible to purify. Given these difficulties, the reaction was not
further studied.
OCH2
O
H
Me rac-20
7
S
H
H
H
rac-21
rac-22
rac-23
2
>95/5
>95/5
SO2
CH2
2
0.5 >95/5
a All reactions were conducted at a substrate concentration of 5 mM at
λ = 366 nm and ambient temperature in trifluorotoluene as the solvent.
b Time required for complete conversion. c The regioisomeric ratio (r.r.)
refers to the ratio of straight (a) to crossed (b) photocycloaddition
product and was determined by 1H NMR spectroscopy. d Yield of
isolated product. e The reaction remained incomplete after 9 h (83%
conversion).
The enantioselectivity in intramolecular reactions of lactams
in the presence of template (+)-1 depends mainly on two
parameters. The first parameter is the efficiency, with which
binding to the substrate occurs. The second parameter is the
intrinsic selectivity of the reaction in the bound substrate/
template complex. This selectivity depends on conformational
preferences for the ring-closing step and on the steric bias exerted
by the substituent R (Figure 1) in this step. On the basis of
previous studies with 4-substituted quinolones,12d it can be safely
assumed that they bind at low temperature (<0 °C) in a nonpolar
solvent quantitatively to template (+)-1 provided that the
template is present in superstoichiometric (2.5 equiv) amounts.
The enantioselectivity in the intramolecular [2 + 2]-photocy-
cloaddition of 4-substituted quinolones 4ꢀ9 in the presence of
template (+)-1 can consequently be considered a reliable way to
investigate the feasibility of a highly enantioselective catalytic
reaction assuming that the steric bias exerted by the substituents
R (Figure 1) in (+)-2 and (+)-3 is similar to the steric bias of the
10-oxa-30-azacyclopenta[b]naphthalene shield in (+)-1. Reac-
tions (Table 2) were performed in toluene at ꢀ60 °C at
wavelengths that guarantee rapid conversion. Although the
picture is only semiquantitative, it became evident that, for example,
alkenyloxyquinolone 6 (entry 3) exhibits a lower intrinsic enantios-
electivity. The regioselectivity was somewhat influenced by the
template with an increased preference for the straight product in
the previously less selective cases (entries 1ꢀ3). The absolute
configuration of product 19a12a and of the noranalogue of com-
pound 18b34 had been earlier proven. Both compounds were
quinolones33 can lead to a multitude of isomers with up to four
stereogenic centers being formed in a single reaction step.
Because of the steric constraints exerted by the cyclobutane ring,
the diastereoselectivity of the reactions is generally high. Conse-
quently, there are only four major isomers to be taken into
account (Scheme 3). Apart from one set of regioisomers, straight
(a) and crossed (b), a set of enantiomers is to be expected. In the
absence of any chiral information, the photocycloaddition pro-
ceeds racemically and the enantiomers are formed in equal
amounts. Indeed, the first set of experiments performed with
substrates 4ꢀ9 was to prove the general feasibility of the [2 + 2]-
photocycloaddition and to obtain racemic material for compar-
ison with enantiomerically enriched products (Table 1). Reac-
tions were performed at conditions later used for the catalyzed
reactions; that is, the solvent was trifluorotoluene at a relatively
long wavelength (λ = 366 nm). Given the spectroscopic proper-
ties of the substrates (for UVꢀvis data, see page S17 in the
Supporting Information), the long wavelength irradiation con-
ditions were the reason why the previously reported facile [2 + 2]-
photocycloaddition reactions24 of substrates 4 and 5 proceeded
slowly. In all cases (entries 1ꢀ6), yields and diastereoselectivities
were high. The regioselectivity was clearly in favor of the straight
products with the crossed photocycloaddition products resulting
from 7ꢀ9 (entries 4ꢀ6) being not detectable at all. Because
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Scheme 4
Table 4. Reaction Conditions, Enantioselectivities, and
Yields in the Enantioselective Intramolecular [2 + 2]-Photo-
cycloaddition of Quinolone 5 in the Presence of Chiral
Catalysts (+)-2 and (+)-3 (See Scheme 4)
entrya catalyst mol %
r.r.b
conv.c [%] eed [%] yielde [%]
1
2
3
4
5
(+)-2
(+)-3
(+)-3
(+)-3
(+)-3
10
5
82/18
80/20
76/24
80/20
70/30
60
55
58
65
69
12
21
27
35
41
45
39
42
48
62
10
20
30
a All reactions were conducted at a substrate concentration of 10 mM by
irradiation at λ = 366 nm for 4 h at ꢀ25 °C in trifluorotoluene as the
solvent. b The regioisomeric ratio (r.r.) refers to the ratio of straight
(19a) to crossed (19b) photocycloaddition product and was deter-
mined by 1H NMR spectroscopy. c The conversion is based on reisolated
starting material. d The enantiomeric excess of the straight photocy-
cloaddition product 19a was determined by chiral HPLC analysis. e Yield
of isolated product.
Table 3. Intramolecular [2 + 2]-Photocycloaddition of
4-(Pent-4-enyloxy)quinolone (5) in the Absence and
Presence of an Achiral Catalyst (See Scheme 4)
entry
catalysta
tb [h] product r.r.c conv.d [%] yielde [%]
1
2
3
4
4
4
rac-19
rac-19
rac-19
91/9
91/9
91/9
46
96
94
22
89
93
benzophenone
xanthone
a Reactions were conducted at a substrate concentration of 10 mM and
Scheme 5
at λ = 366 nm with 20 mol % of the respective catalyst at ꢀ25 °C in
c
trifluorotoluene as the solvent. b Irradiation time. The regioisomeric
ratio (r.r.) refers to the ratio of straight (rac-19a) to crossed (rac-19b)
photocycloaddition product and was determined by 1H NMR spectros-
copy. d The conversion is based on reisolated starting material. e Yield of
isolated product.
obtained by intramolecular [2 + 2]-photocycloaddition in
the presence of template (+)-1, and both products are levor-
otatory. The absolute configuration of products 18a, 20aꢀ23a
was assigned on the basis of an analogy and on the basis of com-
parison of the chiroptical product data with known data. Indeed,
dihydroquinolone products are expected to be levorotatory if the
dihedral angle along the nitrogen-aryl axis (atoms C2ꢀN1ꢀ
C8aꢀC4a) has a negative sign.21 According to molecular models,
the twist resulting from the cyclobutane annelated to carbon
atoms C3 and C4 of a dihydroquinolone should lead in com-
pounds 18ꢀ23 to negative dihedral angles (and to a negative
specific rotation) and for compounds ent-18ꢀ23 to positive
dihedral angles (and to a positive specific rotation). The specific
rotations measured for all products 18aꢀ23a were indeed found
to be negative.
Catalytic Reactions with Substrates 4 and 5. Initial studies
regarding a potential catalysis of the intramolecular [2 + 2]-
photocycloaddition were performed with 4-(pent-4-eny-
loxy)quinolone (5). The choice for this substrate, as opposed
to 4, was based on the fact that a single straight regioisomer
(compound rac-19a) was expected from its reaction. Indeed,
Kaneko et al. had reported that substrate 4 delivered a 7:1
mixture of regioisomers (in MeOH as the solvent), whereas 5
gave a single product.24 Our previous experiments12a alsosupported
the notion that the reaction of 5 was highly regioselective (in par-
ticular in the presence of template (+)-1) and hence easier
to analyze. Concerning catalysis, it was conceived that energy
transfer from photoexcited aromatic ketones might be possible
upon long wavelength (λ = 366 nm) irradiation. The electro-
philic nature of the triplet nπ*-state involved in the sensitization
led us to use trifluorotoluene instead of toluene as the solvent in
these and all subsequent studies. The absence of labile CH-bonds
in trifluorotoluene makes hydrogen abstraction reactions from
the solvent inefficient. A catalytic effect was detectable (Scheme 4,
Table 3) when using benzophenone or xanthone as a sensitizer. In
comparison to the uncatalyzed reaction, product formation was
significantly increased after 4 h of irradiation time. Benzophenone
and xanthone (entries 2 and 3) showed a similar rate enhancement,
which could also be quantified in more extensive kinetic experi-
ments (seepage S20intheSupportingInformation). The catalyzed
reaction was not only faster than the uncatalyzed reaction (entry 1)
but led also to less byproduct and delivered higher yields of the
respective cycloaddition product. The regioselectivity was in the
expected range (r.r. = 91/9).
Reactions with the chiral benzophenone (+)-2 and the
xanthone (+)-3 confirmed that both chromophores are similarly
well suited to induce the desired rate acceleration (Table 4).
However, benzophenone (+)-2 was less effective in the chirality
transfer from the catalyst to the product (entries 1 and 3). In
general, the enantioselectivities were lower than was hoped based
on the high enantioselectivities achieved with the superstoichio-
metrically used template (+)-1 (vide supra). An increasing
amount of catalyst (+)-3 gave expectedly a higher selectivity
(entries 2ꢀ5), but the result (41% ee at best) was not satisfac-
tory. There were some additional observations. Catalyst decom-
position was still severe despite the use of trifluorotoluene as the
solvent. Hydrogen abstraction cannot occur from the solvent but
rather occurs from the reaction products. As a consequence of
the product chirality, different decomposition rates were ob-
served for different enantiomers. After 1 h of irradiation time
(40% conversion), both regioisomers 19a and 19b were formed
with similar enantiomeric excess (37% ee and 38% ee). The ee of
the major regioisomer 19a, however, decreased as the reaction
progressed, resulting in 27% ee after 4 h (58% conversion, entry
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Table 5. Reaction Conditions, Enantioselectivities, and
Yields in the Enantioselective Intramolecular [2 + 2]-Photo-
cycloaddition of Quinolone 4 in the Presence of Chiral
Catalysts (+)-2 and (+)-3 (See Scheme 5)
entrya catalyst mol % tb [h] r.r.c conv.d [%] eee [%] yield f [%]
1
2
3
4
5
6
7
8
1
1
1
2
4
n.d.
19
57
5
51
58
75
50
46
48
53
(+)-2
(+)-3
(+)-3
(+)-3
(+)-3
(+)-3
(+)-3
10
10
10
10
10
5
84/16
78/22
77/23
>99/1
39
92
90
91
89
90
94
64
81
90
10 >99/1
100
50
1
1
78/22
79/21
20
73
Figure 3. Emission spectra of 4, 5, and MQ registered at low tempera-
ture (ꢀ190 °C) in an ethanol matrix.
a All reactions were conducted at a substrate concentration of 5 mM and
at a temperature of ꢀ25 °C by irradiation at λ = 366 nm in trifluor-
otoluene as the solvent. b Irradiation time. c The regioisomeric ratio (r.r.)
refers to the ratio of straight (18a) to crossed (18b) photocycloaddition
product and was determined by 1H NMR spectroscopy. d The conver-
sion is based on reisolated starting material. e The enantiomeric excess of
the straight photocycloaddition products was determined by chiral
HPLC analysis. f Yield of isolated product.
determination was possible and if the ee was measured, it never
exceeded the ee of the straight product 18a but was typically lower.
Representative values, as determined, for example, for entry 3 of
Table 5, were 90% ee for 18b versus 92% ee for 18a. In contrary to
the reaction 5 f 19a/19b, the enantiomeric excess of the major
product did not change in the course of the photocycloaddition.
Rather, the regioisomeric ratio changed as already discussed.
Photophysical Experiments. A possible explanation for the
striking substrate-dependent enantioselectivity was suspected to
be found in the kinetics of the reactions. To gain insight into this
aspect, the photophysics of 4 and 5 was studied and compared to
that of 4-methoxyquinolone (MQ), which shares the same
heterocyclic nucleus, but possesses a methoxy (instead of an
alkenoxy) substituent at position C4. Fluorescence spectra of the
three quinolones displayed a maximum at ca. 360 nm with
quantum yields (ϕF) of 0.10, 0.11, and 0.12 for 4, 5, and MQ,
respectively (Figure SI-3 in the Supporting Information). The
singlet excited-state energies were determined from the inter-
section between the excitation and the emission spectra (Figure
SI-4 in the Supporting Information) and were found to be the
same for the three compounds: 358 kJ/mol (86 kcal/mol). This
clearly indicates that the intramolecular [2 + 2]-photocycloaddi-
tion does not take place from the singlet excited state.
When emission was recorded at low temperature (ꢀ190 °C)
in an ethanol matrix, a small fluorescence component was still
observed. The position of the band was the same as in solution,
but the spectra were better resolved. Moreover, the fluorescence
intensity was comparable for the three quinolones (Figure 3).
Conversely, large intensity differences in the long-wavelength
phosphorescence band were observed. In particular, the phos-
phorescence of 4 was significantly lower than that of 5 (Figure 3).
The relative quantum yields (ϕPh) were determined by compar-
ing the areas of the phosphorescence spectra. Taking into
account that ϕPh = ϕISC ꢁ τPh ꢁ kPh, where kPh is the intrinsic
emission rate constant, and assuming that ϕISC (the intersystem
crossing quantum yield) is the same for the quinolones, the ratio
between the phosphorescence lifetimes and quantum yields of 4
and 5 is given by eq 1.
3, Table 4). The crossed regioisomer 19b showed after the same
period of time an ee of 50%. The result is in line with a preferred
decomposition of 19a (as compared to its enantiomer ent-19a) in
the case of the major regioisomer and of ent-19b (as compared to
its enantiomer 19b) for the minor regioisomer. From a practical
point of view, the reactions slowed in all cases significantly after
4 h, indicating a significant decomposition of the sensitizer. The
sensitizer could not be recovered.
When the same series of experiments conducted with sub-
strate 5 and catalysts (+)-2 and (+)-3 were performed with
4-(but-3-enyloxy)quinolone (4), a much higher enantioselectiv-
ity was found (Scheme 5, Table 5). In particular, xanthone (+)-3
showed a performance previously not encountered for a chiral
triplet sensitizer. In the absence of a catalyst, only 19% of the
starting material had reacted after 1 h of irradiation (Table 5,
entry 1). With 10 mol % of xanthone (+)-3, the conversion was
64% after the same time period with the major regioisomer 18a
being formed in 92% ee (entry 3). Benzophenone (+)-2 was
inferior (entry 2) to xanthone (+)-3 both in catalytic activity (57%
conversion) and in enantioselectivity (39% ee). The instability of
catalyst (+)-3 became again evident from the decreased reaction
rates at prolonged reaction times (entries 3ꢀ6). Byproducts were
formed after 2 h, and the enantioselectivity dropped if complete
conversion was to be achieved (entry 6). Remarkably, the decom-
position of the sensitizer appears in this case to go hand in hand
with the decomposition of the minor regioisomer 18b. While the
regioisomeric ratio 18a/18b was 77/23 after 2 h (entry 4), the
minor regioisomer had almost completely vanished after 4 h (entry 5).
As already mentioned previously, hydrogen abstraction is likely
to be the major reason for the decomposition, and one could
speculate the exposed CH2 protons at C2, C3, or C11 are readily
abstracted. The catalytic activity of xanthone (+)-3 was remarkable.
Even if used in only 5 mol % (entry 7), significant conversion and
high enantioselectivity (90% ee) were observed. Expectedly, a
higher amount of catalyst (entry 8) resulted in higher conversion
and an increase in enantioselectivity.
ϕPhð4Þ
ϕPhð5Þ
τPhð4Þ
τPhð5Þ
¼
¼ 0:38
ð1Þ
The minor regioisomer 18b was not in all cases isolated in
The reduced phosphorescence of quinolones 4 and 5 is
sufficient quantities to determine its enantiomeric excess. If the
consistent with the intramolecular [2 + 2]-photocycloaddition
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Figure 4. (A) Transient absorption spectra of a deaerated solution of MQ, 270 ns after laser excitation, and (B) decay profile of a deaerated solution of 5,
in trifluorotoluene upon laser excitation.
Scheme 6
reaction taking place from the triplet excited state. Besides, the
remarkable differences between the phosphorescence intensities
of 4 and 5 point to a higher reaction rate constant in the
intramolecular [2 + 2]-photocycloaddition of the former sub-
strate. Laser flash photolysis experiments performed at room
temperature supported this conclusion. The transient absorption
spectra of these quinolones showed a broad maximum centered
at 460 nm after laser excitation (λexc = 308 nm). This is shown in
Figure 4A for MQ; the spectra obtained with the other two
quinolones were poor, due to partial decomposition. The 460 nm
band was assigned to the triplet excited states, which was
confirmed by means of sensitization experiments, using xanthone
as triplet energy donor, and by oxygen quenching (Figure SI-6 in
the Supporting Information). In trifluorotoluene, MQ and 5
triplet excited state lifetimes (τT) were 1 μs and 57 ns, respec-
tively (Figure 4A, inset, and B). The triplet lifetime of 4 was too
close to the detection limit of our laser setup to be accurately
determined by direct measurement. Its value could be estimated,
however, by assuming that the τPh(4)/τPh(5) ratio is roughly the
same as that of τT(4)/τT(5). Hence, eqs 1 and 2 apply:
On the basis of the above data, the intramolecular photoreac-
tion rate constant can be calculated as given by eq 3:
1
1
kðiÞ ¼
ꢀ
ð3Þ
τTðiÞ τTðMQ Þ
Thus, the reaction constants, k(4) and k(5), can be estimated at
4.5 ꢁ 107 and 1.7 ꢁ 107 sꢀ1, respectively. Hence, at room
temperature, the butenyloxy derivative 4 is markedly more
reactive than the pentenyloxy analogue 5. The photophysical
studies corroborate the results obtained in the enantioselective
reactions of substrates 4 and 5. In the template-mediated
enantioselective reaction (Table 2), the degree of enantioselec-
tivities is only dependent on the thermodynamic parameters
(association constant Ka and dimerization constant Kdim), which
are expected to be identical for quinolones 4 and 5. In the
catalytic reactions, however, the rate of the [2 + 2]-photocy-
cloaddition has an essential impact on the enantioselectivity. An
excited substrate, which dissociates from the catalyst prior to
[2 + 2]-photocycloaddition, will not react enantioselectively because,
due to the low catalyst loading, it will not find a chiral template for
reassociation. Apparently, the rate of the intramolecular [2 + 2]-
photocycloaddition reactions of substrates 4 and 5 (or rather of
their first CꢀC bond step) is in the order of the dissociation rate
constant. The lower rate for cyclization to the six-membered ring
causes the lower enantioselectivity observed for quinolone 5.
τTð4Þ ¼ τTð5Þ ꢁ 0:38 ¼ 57 ns ꢁ 0:38 ¼ 22 ns
ð2Þ
The obtained value (22 ns) is actually feasible and could explain
the dispersity of the experimental decay measurements (not
shown).
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Table 6. Reaction Conditions, Enantioselectivities, and
Yields in the Enantioselective Intramolecular [2 + 2]-Photo-
cycloaddition of Quinolones 4ꢀ9 in the Presence of 10 mol %
of Chiral Catalyst (+)-3 (See Scheme 3)
xanthone (+)-3 acts as an independent compound in the
excitation step or whether the complex (+)-3 4 (S0) represents
3
an absorption complex35 needs to be further studied. In any case,
intramolecular [2 + 2]-photocycloaddition (step 3) within the
complex (+)-3 4 (T1) occurs highly enantioselectively from the
entrya substrate tb [h] product r.r.c conv.d [%] eee [%] yieldf [%]
3
bottom face of substrate 4, while the top face is shielded by
the oxazolo[4,5-b]xanthone part of catalyst (+)-3. Dissociation
of the photoexcited quinolone 4 (T1) is a competing pathway
leading to racemic products 18. In the case of substrate 5, the
lower photocycloaddition rate (relative to 4) favors the dissoca-
tion, and this fact has been identified as a major reason for the low
enantioselectivity observed in the conversion 5 f 19.
1
2
4
5
6
7
8
9
2
18
19
20
21
22
23
77/23
78/22
82/18
>95/5
>95/5
>95/5
81
41
79
53
31
84
90
38
85
72
6
75
34
73
21
28
70
1
3
1
4g
5g
6g
0.5
0.5
0.5
87
Enantioselective Reactions of Substrates 6ꢀ9. From the
mechanistic discussion in the previous section, it is apparent that
the major issue regarding an enantioselective [2 + 2]-photocy-
cloaddition of substrates 6ꢀ9 in the presence of xanthone (+)-3 is
the selective excitation (step 2). The rate of the [2 + 2]-photo-
cycloaddition (step 3) was of less concern as the formation of five-
membered rings was expected to be rapid. This is particularly true
for substrate 6, which bears a geminal dimethyl substitution
(ThorpeꢀIngold effect36). The outcome of the reactions is
summarized in Table 6, with the previously discussed reactions
of quinolones 4 and 5 included for comparison. Indeed, the
xanthone-catalyzed reaction of the dimethyl-substituted compound
6 was more rapid (Table 6, entry 3) than the reaction of the parent
substrate 4 (entry 1). After 1 h, the same conversion was observed
for 6 as for 4 after 2 h. The enantioselectivity was high (85% ee) but
did not completely match the selectivity achieved with quinolone 4.
The reason for the diminished selectivity appears to be the
intrinsically lower enantiotopic face differentiation of the catalyst
backbone as was already indicated by the reaction with stoichio-
metric amounts of template (+)-1 (Table 2, entry 3).
As is apparent from Table 1, the background reaction, that is,
the reaction occurring by direct excitation at λ = 366 nm, was
significant for substrates 7ꢀ9. Attempts to conduct the cata-
lyzed photocycloaddition of substrates 7ꢀ9 at longer wavelength
(λ =419nm) werenotsuccessful. However,itwaspossibletoreduce
the photon flux by reducing the number of fluorescent lamps. A
reduction by a factor of 8 (2 instead of 16 lamps) led to a low
conversion in the absence of a catalyst after 30 min. The reaction
of substrate 7, for example, went to 33% conversion with the
complete lamp set but only to 9% conversion with two lamps. As
a consequence, the catalytic effect of 10 mol % of catalyst (+)-3
was significant, leading to a more than 5-fold increase in
conversion (Table 6, entry 4) and to 72% ee. This procedure
was even more successful for substrate 9, which had given
complete conversion after 30 min if the complete lamp set was
used at ꢀ25 °C. The conversion was lowered to 22% under the
modified conditions, and the rate acceleration in the presence of
catalyst (+)-3 was notable, resulting in 84% conversion (70% of
isolated product) and a remarkable enantioselectivity of 87% ee
(Table 6, entry 6). Only with sulfone 8 was it impossible to
reduce the conversion significantly. Even more importantly, a
catalytic effect was not observed. Because of the electron-with-
drawing nature of the sulfone group, it is likely that the triplet
energy of substrate 8 is not appropriate for sensitization leading
to a disappointingly low enantiomeric excess (Table 6, entry 5).
a The reactions were conducted at a substrate concentration of 5 mM
and at a temperature of ꢀ25 °C by irradiation at λ = 366 nm (16 lamps)
in trifluorotoluene as the solvent. b Irradiation time. c The regioisomeric
ratio (r.r.) refers to the ratio of straight (a) to crossed (b) photocy-
1
cloaddition product and was determined by H NMR spectroscopy.
d The conversion is based on reisolated starting material. e The enantio-
meric excess of the straight photocycloaddition products was deter-
mined by chiral HPLC analysis. f Yield of isolated product. g The photon
flux was reduced by reducing the number of light sources (2 lamps
instead of 16 lamps).
Excitation and Turnover. If one sums up the previous results
on the catalytic cycle, a picture as drawn in Scheme 6 for the
reaction of quinolone 4 evolves. The enantioselectivity depends
on the association (step 1), on an efficient sensitization (step 2),
and on the rate of the subsequent cyclization (step 3). Associa-
tion data have been collected for substrate/template combina-
tion related to 4 and (+)-3,12d suggesting that the catalyst is at the
outset of the reaction completely bound to the substrate (vide
supra). In addition, from the data we have gathered by the spec-
troscopic studies mentioned above, there is a lower rate limit, at
which the cyclization (step 3) competes effectively with dissocia-
tion from the catalyst. Dissociation of product 18a from the
template (step 4) is important to guarantee efficient turnover.
Given that the product is considerably bulkier than the planar
substrate, it is expected that a disfavorable interaction between
the oxazolo[4,5-b]xanthone shield in catalyst (+)-3 and the
product facilitates an exchange from product to new substrate.
A similar scenario has been previously observed in enantioselec-
tive reactions12b mediated by template (+)-1.
Regarding the sensitization (step 2), the question why this
process is so effective and how it proceeds has not yet been
addressed. Looking at the absorption data (see page S17 in the
Supporting Information), it is apparent that xanthone (+)-3
virtually absorbs all photons at long wavelength (λ = 350ꢀ
370 nm). Its molar absorption coefficient ε is g3000 at 360 nm,
whereas ε360 for the substrate is only 144; that is, it is by a factor
of 20 smaller than ε360 of (+)-3. The significantly higher absorp-
tion of xanthone (+)-3 seems to be important for the enantios-
electivity. In the absence of the xanthone, 19% of starting material
4 (Table 5, entry 1) is converted after 1 h of irradiation into
racemic product. If this reaction, which occurs by direct excita-
tion of quinolone, was not suppressed, only a maximum ee of
81% could have been achieved. In other words, by harvesting all
available photons, xanthone (+)-3 channels the excitation of
ground state (S0) quinolone 4 into one possible mode occurring
in the complex (+)-3 4 (S0). We have speculated earlier25 that
3
’ CONCLUSION
the sensitization occurs by energy transfer in this complex, thus
generating the corresponding complex (+)-3 4 (T1), from
which the photocycloaddition occurs. The question of whether
The present study represents a first step toward a deeper
understanding of enantioselective photochemical reactions catalyzed
3
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Journal of the American Chemical Society
ARTICLE
by hydrogen-bonding sensitizers such as compounds (+)-2 and
(+)-3. It revealed the importance of kinetic factors in designing
an optimal catalytic cycle, and it showed the scope and limitations
regarding different 4-substituted quinolones. The reactions are
preparatively useful for oxygen-, carbon-, and sulfur-tethered
alkenes, which can react by rapid five-membered ring closure to
yield the respective cyclobutane products in the photocycloaddi-
tion step. Regarding the excitation, it remains to be elucidated
which mechanism accounts for the excitation of the quinolone in
its reactive triplet state. Regarding a potential extension of this
work, other substrates have to be found, which show a relatively
large singletꢀtriplet gap and which do not absorb at longer wave-
lengths (λ e 350 nm). In this respect, it will be revealing to study
the influence of various substituents at the quinolone chromo-
phore on the photophysical and photochemical behavior of these
substrates.
8574–8575. (b) Ke, C. F.; Yang, C.; Mori, T.; Wada, T.; Liu, Y.; Inoue,
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’ ASSOCIATED CONTENT
(12) (a) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem.
Soc. 2002, 124, 7982–7990. (b) Grosch, B.; Orlebar, C. N.; Herdtweck,
E.; Kaneda, M.; Wada, T.; Inoue, Y.; Bach, T. Chem.-Eur. J. 2004,
10, 2179–2189. (c) Selig, P.; Herdtweck, E.; Bach, T. Chem.-Eur. J. 2009,
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S
Supporting Information. Detailed experimental proce-
b
dures, characterization data for new compounds, and experi-
mental details of the photophysical measurements. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Austin, K. A. B.; Herdtweck, E.; Bach, T. Angew. Chem., Int. Ed.
2011, 50, 8416–8419.
’ AUTHOR INFORMATION
(14) Bach, T.; Bergmann, H.; Harms, K. Org. Lett. 2001, 3, 601–603.
(15) (a) Aechtner, T.; Dressel, M.; Bach, T. Angew. Chem., Int. Ed.
2004, 43, 5849–5851. (b) Albrecht, D.; Vogt, F.; Bach, T. Chem.-Eur.
J.2010, 16, 4284–4296. (c) See also: Bach, T.; Bergmann, H.; Brummerhop,
H.; Lewis, W.; Harms, K. Chem.-Eur. J. 2001, 7, 4512–4521.
(16) Bach, T.; Aechtner, T.; Neum€uller, B. Chem.-Eur. J. 2002,
8, 2464–2475.
Corresponding Author
mmiranda@qim.upv.es; thorsten.bach@ch.tum.de
’ ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsge-
meinschaft (DFG) in Germany (Schwerpunktprogramm Orga-
nokatalyse and Graduiertenkolleg GRK 1626 Chemical Photocatalyis).
Financial support from the Spanish Government is also acknowl-
edged (JAE-doc fellowship for M.C.C. and CTQ2009-13699).
(17) Bach, T.; Grosch, B.; Strassner, T.; Herdtweck, E. J. Org. Chem.
2003, 68, 1107–1116.
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