Enantioselective Lewis Acid Catalysis in Intramolecular [2 + 2] Photocycloaddition Reactions: A Mechanistic Comparison between Representative Coumarin and Enone Substrates

Article abstract of DOI:10.1021/jacs.5b01740

The intramolecular [2 + 2] photocycloaddition of three 4-(alk-4-enyl)coumarins and three 1-(alk-4-enoyl)-2,3-dihydropyridones was studied in the absence and in the presence of Lewis acids (irradiation wavelength = 366 nm). Spectral and kinetic data were collected for the respective parent compounds with a pent-4-enyl and a pent-4-enoyl chain. For the substrates with a methyl group in cis- or trans-position of the terminal alkene carbon atom (hex-4-enyl and hex-4-enoyl substitution), the stereochemical outcome of the [2 + 2] photocycloaddition was investigated. The mechanistic course of the uncatalyzed coumarin reactions was found to be a singlet pathway, whereas Lewis acid-catalyzed reactions proceeded with higher reaction rates in the triplet manifold. Contrary to that, the dihydropyridones underwent a fast triplet reaction in the absence of the Lewis acid. In the presence of a chiral Lewis acid the reactions slowed down but, due to the high extinction coefficient of the Lewis acid/dihydropyridone complexes at = 366 nm, still resulted in high enantioselectivity.

Full text of DOI:10.1021/jacs.5b01740

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Article
Enantioselective Lewis Acid Catalysis in Intramolecular [2+2]
Photocycloaddition Reactions: A Mechanistic Comparison
between Representative Coumarin and Enone Substrates
Richard Brimioulle, Andreas Bauer, and Thorsten Bach
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b01740 • Publication Date (Web): 25 Mar 2015
Downloaded from http://pubs.acs.org on April 7, 2015
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Enantioselective Lewis Acid Catalysis in Intramolecular [2+2] Photocycloaddition
Reactions: A Mechanistic Comparison between Representative Coumarin and Enone
Substrates
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a
a
a*
Richard Brimioulle, Andreas Bauer, and Thorsten Bach
a
Department Chemie and Catalysis Research Center (CRC)
Technische Universität München,
D-85747 Garching, Germany
thorsten.bach@ch.tum.de
Received
Abstract. The intramolecular [2+2] photocycloaddition of three 4-(alk-4-enyl)coumarins and
three 1-(alk-4-enoyl)-2,3-dihydropyridones was studied in the absence and in the presence of
Lewis acids (irradiation wavelength  = 366 nm). Spectral and kinetic data were collected for the
respective parent compounds with a pent-4-enyl and a pent-4-enoyl chain. For the substrates with
a methyl group in cis- or trans-position of the terminal alkene carbon atom (hex-4-enyl and hex-
4
-enoyl substitution), the stereochemical outcome of the [2+2] photocycloaddition was
investigated. The mechanistic course of the uncatalyzed coumarin reactions was found to be a
singlet pathway, whereas Lewis acid-catalyzed reactions proceeded with higher reaction rates in
the triplet manifold. Contrary to that, the dihydropyridones underwent a fast triplet reaction in the
absence of the Lewis acid. In the presence of a chiral Lewis acid the reactions slowed down but,
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due to the high extinction coefficient of the Lewis acid/dihydropyridone complexes at  = 366
nm, still resulted in high enantioselectivity.
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Introduction
It has been known for a long time that Lewis acids can alter the course of [2+2]
photocycloaddition reactions. More than a century ago, in 1910, Praetorius and Korn reported
that dibenzylideneacetone was converted into a dimeric product when its solution in glacial acetic
1
acid was exposed to sunlight. The reaction – which was almost quantitative (4.5 g crystalline
product from 5.0 g substrate) – proceeded only in the presence of stoichiometric quantities of
uranyl chloride as the Lewis acid. In the absence of the uranyl salt, polymeric material was
observed. The reaction could also be performed in the solid state upon irradiation of the 2:1:2
complex of dibenzylideneacetone, (UO )Cl and acetic acid. The product was suggested to be a
2
2
cyclobutane with head-to-tail regioselectivity (“truxillic” type dimer). Later it was shown that
2
SnCl shows a similar effect on the [2+2] photodimerization of dibenzylideneacetone and the
4
solid state reaction was further investigated by Alcock et al., who confirmed the structure of the
3
[2+2] photodimer. While the influence of metal catalysts on various photochemical reactions
4
was investigated in the 1970s and 1980s, specific studies regarding the influence of Lewis acids
on [2+2] photocycloaddition reactions of -unsaturated carbonyl compounds in solution were
5
reported by Lewis et al. in 1983. It was found that the photodimerization of coumarin was
catalyzed by BF ·OEt and the syn head-to-tail dimer was obtained as a single product upon
3
2
irradiation of an equimolar solution of coumarin and BF ·OEt in >85% yield. The
3
2
regioselectivity was different from the uncatalyzed reaction, in which the syn head-to-head dimer
6
is the major reaction product. The results were confirmed by Shim et al., who – like Lewis et al.

3
–
noted the increase in quantum yield upon Lewis acid addition from 10 (without BF ·OEt ) to
3 2
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.13 (with one equiv. BF ·OEt ). In a simultaneously performed study by Ogawa et al. on the
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photodimerization of 2-cyclopentenone it was found that the addition of SnCl as Lewis acid
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changes the regioselectivity but leads to a lower reaction rate. In 1989, Lewis and Barancyk
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observed that the Lewis acid catalysis by BF ·OEt and EtAlCl was also applicable to [2+2]
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0
photocycloaddition reactions of coumarin and olefins such as cyclopentene and 2-butene. Based
on the lack of stereospecificity in the EtAlCl -catalyzed reactions at low 2-butene concentration
2
(five-fold excess relative to coumarin) it was concluded that the reaction proceeded under these
conditions mainly by a triplet-state mechanism. At higher concentrations a stereospecific singlet
pathway was suggested to operate. In a comprehensive time-resolved UV-vis spectroscopy study,
Görner and Wolff compiled evidence for the fact that the BF -catalyzed photodimerization of
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1
1
coumarin is a triplet process. They showed that the quantum yield for coumarin triplet
formation increases from 0.03 to 0.3 upon addition of BF ·OEt .
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Figure 1. Structures of chiral Lewis acid 1 and of [2+2] photocycloaddition precursors 2 and 3.
The observation of a significant rate increase in coumarin [2+2] photocycloaddition chemistry
1
2,13
invited attempts to achieve enantioselective reactions
with appropriately chosen Lewis acids.
In 2010, it was found in our laboratories that Lewis acid 1 was suitable to enantioselectively
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(
82% ee) catalyze the intramolecular [2+2] photocycloaddition of coumarin 2a (Figure 1). The
reaction was later extended to other coumarins (up to 90% ee) and investigations regarding the
1
5
mode of action of the Lewis acid were performed.
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Given the above-mentioned observations that Lewis acids slow down the reaction rate of an
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enone dimerization, it was surprising that the same Lewis acid 1 was capable to induce also a
high enantioselectivity (88% ee) in the intramolecular [2+2] photocycloaddition of
dihydropyridone 3a. This reaction is applicable to related dihydropyridones and it was
1
6
successfully employed in the total synthesis of lupin alkaloids. Recently, it was shown in our
laboratories that the [2+2] photocycloaddition of 3-alkenyloxy-2-cycloalkenones can be
1
7
performed enantioselectively with an oxazaborolidine-based Lewis acid related to 1 and it was
found by the Sivaguru group that the intramolecular [2+2] photocycloaddition of coumarin 1a
18,19
and related coumarins can be enantioselectively catalyzed by a chiral Brønsted acid.
The purpose of the present study was to disclose the similarities and differences of the two
substrate classes 2a and 3a in [2+2] photocycloaddition reactions. Substrates 2b/3c and 3b/3c
were used to investigate the stereochemical reaction course of the photocycloaddition reactions.
Stereospecific reactions are indicative of a singlet-state mechanism while a non-stereospecific
2
0,21
transformation is expected for photochemical reactions which occur in the triplet manifold.
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As achiral Lewis acids BF ·OEt , BCl and EtAlCl were employed. Results of previous studies
3
2
3
2
are implemented where required but are clearly marked.
Results and Discussion
Spectral data. Coumarin 2a is in its physical properties very similar to the parent compound,
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which has been previously studied extensively. To summarize the most relevant data, coumarin

1
2
a exhibits (c = 0.8 mM in CH Cl ) two strong UV/Vis absorptions at  = 272 nm (=11100 M
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1
1
1
cm ) and at  = 313 nm (= 6400 M cm ). The extinction coefficients at  = 300 nm are =

1
1
1
1
5300 M cm and at  = 366 nm  ≤ 10 M cm . At an excitation wavelength of  = 300 nm
15
there is essentially no fluorescence. Addition of Lewis acids changes the spectra in full
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0
agreement with the work of Lewis and Baranczyk. They had determined the equilibrium

1
constant (K) for the coumarin-EtAlCl complex in CD Cl as 140 M at room temperature. The
2
2
2
complex showed different UV/Vis spectra and a significant fluorescence. The UV/Vis spectra for
the EtAlCl -complex of coumarin 2a at various EtAlCl concentrations are shown in the SI in
2
2
comparison to the same data for 4-methylcoumarin. The absence of defined isosbestic points in
the former data set – as compared to the latter – indicates the high photochemical reactivity of the
complex (vide infra). The complex 2a·EtAlCl exhibits a strong UV/Vis absorption at  = 313
2

1
1
nm (=15500 M cm ), while the intensity of the short wavelength absorption decreases. The

1
1
extinction coefficient at  = 366 nm is  = 84 M cm .
Lewis acid 1 is in situ prepared from the respective oxazaborolidine and AlBr . While
3
satisfactory NMR spectra of the oxazaborolidine were obtained, the Lewis acid itself could – in
2
4
line with previous experience – not been fully characterized. The solution of 1 in CH Cl is
2
2
orange-colored and its UV/Vis spectrum is depicted in the SI. Upon treatment of coumarin 2a
with Lewis acid 1, the absorption change in the long wavelength region of the UV/Vis spectrum

1
1
is similar to the EtAlCl complex. Due to a very broad band at   260 nm (= 4600 M cm ),
2
the long wavelength region appears as a shoulder. The extinction coefficient (10 equiv. 1) at  =

1
1 25
3
66 nm is  = 3500 M cm . Fluorescence of the complex is observed with an emission
1
5
maximum at  = 436 nm.
The intermolecular [2+2] photocycloaddition of 2,3-dihydropyridin-4(lH)-ones has been studied
2
6
by the group of Neier and there is a detailed study on the N-methoxycarbonyl analogue of
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compound 3a as chromophor in these reactions. However, Lewis acid coordination of this
compound class has not been previously investigated. The UV/Vis spectrum of 3a in CH Cl (c =
2
2

1
1
0
.5 mM) reveals one strong absorption at 291 nm (= 17400 M cm ) and a weak broad
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absorption at   360 nm (= 70 M cm ). Upon addition of EtAlCl , a new strong band
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evolves at  = 343 nm and the UV/Vis spectra reveal an isosbestic point at  = 311 nm (Figure
2
). In this concentration range, Lewis acid coordination occurs at the enone carbonyl oxygen
1
3
atom but not at the amide carbonyl oxygen atom. Chemical shift changes in the C-NMR spectra
are observed exclusively at the former but not at the latter position (Figure 2).
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.5 eq
.0 eq
.5 eq
eq
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,5
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.5 eq
eq
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Figure 2. UV/Vis spectra of compound 3a (c = 0.5 mM in CH Cl ) in the presence of variable
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concentration of EtAlCl and selected C-NMR data for 3a and its complex with
2
EtAlCl (2.2 equiv.) in CD Cl .
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The maximum absorption for the Lewis-acid induced band at  = 343 nm was obtained with 20
1
1
equiv. EtAlCl (= 21400 M cm ). With BCl (20 equiv.) the band was observed at  = 348
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3
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1
nm (= 24200 M cm ). With chiral Lewis acid 1 (20 equiv.) the band appears at  = 346 nm

1
1
1
(= 19300 M cm ). The extinction coefficient (10 equiv. 1) at  = 366 nm is  = 12600 M

1
cm . If the concentration of EtAlCl was further increased, the absorption maximum was shifted
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to a slightly shorter wavelength and a defined isosbestic point could not be longer detected. It
appears likely that coordination of a second equivalent EtAlCl to the 1:1 complex 3a·EtAlCl
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becomes feasible at high Lewis acid concentration. UV/Vis titration data corroborate this
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assumption and delivered an equilibrium constant (K) of 4300 M for the complex 3a·EtAlCl in
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CH Cl at ambient temperature (see the SI for further details). Apparently, the compound is
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significantly more Lewis basic than coumarin and shows a much higher affinity to Lewis acids.
Kinetic studies. Irradiation experiments with substrates 2a and 3a were performed at a substrate
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concentration of 20 mM and at an irradiation wavelength of = 366 nm. The reaction solution
in CH Cl was pre-cooled to 70 °C and the temperature was kept constant by a cryostat. These
2
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conditions were found optimal in previous experiments to achieve the highest enantioselectivity
in the presence of Lewis acid 1 (50 mol%). The photocycloaddition reactions proceed for both
substrates with excellent diastereoselectivity and the products are formed as single
diastereoisomers. In the absence of a chiral source the racemic products rac-4a and rac-5a
(Figure 3) are obtained, i.e. there is no selectivity for either enantiomer. The chiral catalyst
1
4
induces a high enantioselectivity in favor of 4a and 5a as major enantiomers (vide infra).
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Figure 3. Structures of chiral [2+2] photocycloaddition products 4a and 5a and their respective
enantiomers ent-4a and ent-5a.
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Substrate 2a showed a very slow reaction in the absence of the catalyst (Figure 4a). After an
irradiation time of five hours the product concentration was 2.2 mM (11% conversion). Side
reactions were not observed, as indicated by the equally low decrease in substrate concentration.
In the presence of catalyst 1, the reaction rate significantly increased (Figure 4b). 50% conversion
was achieved after 25 min and the reaction followed a zero-order rate law in this time interval.
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0
Employing a ferrioxalate actinometer to quantify the photon flux and assuming complete
photon absorption by the substrate, the quantum yield for the latter reaction was determined as 
=
0.09. In the former reaction (Figure 4a) a lower barrier for the quantum yield was estimated to
3 31
be   2·10 .
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,02
,01
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200
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t [min]
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,02
,01
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Figure 4. Rate profile for the intramolecular [2+2] photocycloaddition of substrate 2a in the
absence (Figure 4a) and in the presence (Figure 4b) of chiral Lewis acid 1 (50 mol%;

= 366 nm, T = 70 °C, c = 20 mM in CH Cl ).
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In stark contrast to substrate 2a, substrate 3a underwent a fast [2+2] photocycloaddition upon
irradiation at = 366 nm (Figure 5a). The reaction was complete within one hour and followed a
first-order rate law. No significant background reaction was observed. The quantum yield of the
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reaction was high and it was shown to exceed   0.23 by ferrioxalate actinometry. For the
intermolecular reaction of related dihydropyridones quantum yields between 0.5 and 0.9 have
27
been reported at room temperature. In the presence of Lewis acid 1, the reaction rate slowed
down significantly (Figure 5b). A zero-order reaction was observed and the conversion after ten
3
hours was ca. 50%. The quantum yield was determined as  = 4·10 .
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Figure 5. Rate profile for the intramolecular [2+2] photocycloaddition of substrate 3a in the
absence (Figure 5a) and in the presence (Figure 5b) of chiral Lewis acid 1 (50 mol%;

= 366 nm, T = 70 °C, c = 20 mM in CH Cl ).
2
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Stereochemical reaction course. Irradiation experiments performed with the methyl substituted
substrates 2b, 2c, 3b, and 3c lead to products which bear an additional stereogenic center as
compared to products 4a and 5a (Figure 3). While the relative configuration around the
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5
5
5
5
5
5
6
cyclobutane is determined by the rigidity of the attached rings, the methyl group at the additional
stereogenic center can be positioned either cis to the photo-anellated ring (products 4b and 5b) or
trans to it (products 4c and 5c). In Figure 6, the relative configuration is drawn for one
enantiomer of the respective products.
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Figure 6. Structures of chiral [2+2] photocycloaddition products 4b, 4c, 5b, and 5c.
Upon irradiation at  = 366 nm, substrate 2b with a cis-configuration of the olefinic double bond
in the alkenyl tether, reacted slowly to form racemic products rac-4 (Table 1, entries 1 and 2). At

70 °C (entry 1), a conversion of 55% was reached after 22 hours. The product was isolated in
5
3% yield and consisted mainly of cis-diastereoisomer rac-4b (d.r. = 92/8). The relative
configuration of the recovered starting material was shown to be essentially unchanged (2b/2c =
87/13). At ambient temperature (entry 2), the reaction was interrupted after five hours resulting in
1
7% yield of rac-4b (d.r. = 92/8) and in 74% of recovered starting material (2b/2c = 98/2). If the
trans-diastereoisomer 2c was used (entry 3) under the same conditions ( = 366 nm, ambient
temperature), diastereoisomer rac-4c was shown to be the major product (d.r. = 14/86) and the
starting material was recovered unchanged (2b/2c = 1/99). The reaction proceeded very slowly as
already observed for the uncatalyzed photocycloadditions of coumarins 2a and 2b. Addition of
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chiral Lewis acid changed the situation and the reactions of substrates 2b and 2c were complete
1
5
after ten hours (entries 4, 5). Enantiomerically enriched products 4 were obtained. In contrast to
the uncatalyzed reactions, both substrates delivered mainly the same product diastereoisomer, i.e.
trans-product 4c, in 72% and 78% ee, respectively. Although the diastereomeric ratio for
products 4b/4c varied slightly (38/62 vs. 23/77), the stereoconvergent reaction course is clearly
evident.
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54
55
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Table 1. Yields and product configuration for the [2+2] photocycloaddition reactions of
substrates 2b-2c and 3b-3c in the presence and absence of chiral Lewis acid 1.
[
a]
[b]
[c]
entry substrate
1 [mol%] t [h] yield [%] d.r.
ee [%]
[d]
[e]
1
2
3
4
5
6
7
8
9
2b
2b
2c
2b
2c
3b
3c
3b
3c



50
50


50
50
22
53
17
22
92/8
92/8

[
f]
[g]
[h]
[e]
5

[
f]
[e]
10
14/86
38/62
23/77
<5/95
<5/95
<5/95
<5/95

10
10
89
85
72
78
[i]
[e]
1.5
1.5
20
70

[
e]
75
76

87
53
[
j]
20
70
[
a]
Unless noted otherwise, the reactions were performed under anhydrous and oxygen-free
conditions at an irradiation wavelength of  = 366 nm and at a substrate concentration of 20 mM
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15 [b]
in CH Cl as the solvent at 70 °C. Entries 4 and 5 have been recorded in a previous study.
2
2
The diastereomeric ratio (d.r. = 4b/4c for entries 1-5, 5b/5c for entries 6-9) was determined by
1
H-NMR spectroscopy; the values were confirmed by chiral GC (4b/4c) and after derivatization
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[
c]
by chiral HPLC (5b/5c). The ee was calculated from the enantiomeric ratio, which in turn was
determined for the respective major diastereoisomer (4c for entries 4,5; 5c for entries 8,9) after
[d]
[e]
derivatization by chiral HPLC. 45% of the starting material (2b/2c = 87/13) was recovered.
[
f]
[g]
Racemic products were obtained. The reaction was performed at ambient temperature. 74%
[
h]
of the starting material (2b/2c = 98/2) was recovered. 74% of the starting material (2b/2c =
[i]
[j]
1
/99) was recovered. 27% of the starting material (3b/3c = >95/5) was recovered. 16% of the
starting material (3b/3c = <5/95) was recovered.
Perfect stereoconvergence was observed in all photocycloaddition reactions, in which
dihydropyridones 3b and 3c were involved (entries 6-9). Irrespective of the substrate
configuration only a single diastereoisomeric product 5c was observed. In the absence of Lewis
acid 1, the reaction was fast. The conversion after 90 minutes was 73% for substrate 3b (entry 6)
and quantitative for substrate 3c (entry 7). Recovered starting material in the former case was
shown to be exclusively cis-configured (3b/3c = >95/5). The racemic product rac-5c was in both
cases exclusively trans-configured (d.r. = <5/95). In the presence of chiral Lewis acid 1, the
reaction was notably retarded. Substrate 3b reacted slightly faster (entry 8) than substrate 3c
(
entry 9) and was completely converted to trans-product 5c (d.r. = <5/95, 87% ee) after an
irradiation time of 20 hours. Substrate 3c (3b/3c d.r. = <5/95) was partially recovered after 20
hours (entry 9) and delivered the product with lower enantioselectivity (53% ee) but also
exclusively as the trans-product 5c.
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Discussion. A clear mechanistic difference between the coumarin and dihydropyridone substrates
in the uncatalyzed [2+2] photocycloaddition reaction is the fact that the former substrate class
reacts via its singlet state while the latter substrate class reacts via its triplet state. As a result,
stereospecific photocycloaddition products rac-4b, rac-4c were obtained from coumarins 2b, 2c
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(
Table 1, entries 1-3). The dihydropyridones 3b, 3c produced stereoconvergently a single
diastereoisomer rac-5c (Table 1, entries 6, 7). Both substrate classes absorb weakly at = 366
nm but the dihydropyridones still react efficiently (Figure 5a) because rapid intersystem crossing
(ISC) enables them to access the typical reaction manifold of enones. The coumarins decay
23
rapidly to the ground state by internal conversion avoiding an ISC. Lewis acid coordination
changes the nature of the respective excited states. The coumarin photocycloaddition becomes
rapid (Figure 4b) and occurs with relatively high quantum yield at the triplet hypersurface (Table
10,11
1
, entries 3, 4). As pointed out earlier by others,
the Lewis acid seems to stabilize the S state
1
against internal conversion and facilitates ISC. In the presence of a Lewis acid, the
dihydropyridone photocycloaddition remains at the triplet hypersurface (Table 1, entries 8, 9) but
the reaction rate drops significantly (Figure 5b). A possible explanation for the latter effect could
be a decreased ISC rate. Lewis acid coordination occurs at the nonbonding oxygen orbitals and
lowers their energy. Thus, the triplet energy of the n* triplet state, which is in typical enones
2
1a
close to the triplet state of the * triplet state, is significantly increased. As a consequence,
ISC from the S state, which has * character in the complex (vide infra) is not feasible since
1
the energetically feasible ISC from S (*) to T (*) is symmetry forbidden according to El
1
1
32
Sayed’s rule.
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Figure 7. Excited state properties and reaction pathways for coumarins (a,b) and dihydro-
pyridones (c,d) in the absence and presence of a Lewis acid (L.A.) at  = 366 nm.
Regarding the bathochromic spectral shift upon Lewis acid coordination, it is evident that only
the respective * transitions are concerned while any n* transition will be shifted
hypsochromically or will disappear. Simplistically, the effect is based mainly on a decrease of the
3
3
energy of the * orbitals upon Lewis acid coordination. Indeed, the extent of the bathochromic
shift on coumarins and dihydropyridones is comparable for the * transition. For coumarin 2a,

1
1
the absorption at  = 272 nm (= 11100 M cm ) is shifted upon EtAlCl coordination to  =
2
1
1
3
13 nm (= 15500 M cm ). For dihydropyridone 3a, the absorption at  = 291 nm (=17400
M cm ) is shifted upon EtAlCl coordination to  = 343 nm (= 21400 M cm ). The
1
1
1
1
2
wavelength difference is thus  = 43 nm in the former and  = 52 nm in the latter case. In the
former case, however, the shift leads to an overlap with the relatively intense n* absorption of
1
1
the uncomplexed substrate at  = 313 nm (= 6400 M cm ) and in essence the bathochromic
shift at longer wavelength is detectable but minor. At  = 366 nm, the absorption of the Lewis
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acid complex remains low. In stark contrast, the Lewis acid coordination of the dihydropyridone
causes a high cross-section * transition at  = 366 nm, which is eventually responsible for the
enantioselective reaction course in the latter reaction. The otherwise rapid reaction of
uncomplexed substrate (Figure 4a) is completely suppressed because excitation becomes
impossible given its low extinction coefficient. Due to the high association constant of the
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complex 3a·EtAlCl (vide supra), the percentage of complexed vs. uncomplexed substrate in the
2
typical concentration range of the reaction is close to 50%, even at room temperature. Upon
initiation of the reaction at  = 366 nm, the absorption of 3a·EtAlCl is thus 180 times higher
2
34
than the absorption of uncomplexed substrate 3a.
The absolute product configuration of enantioselective [2+2] photocycloaddition reactions has
1
4-16
been elucidated in previous work.
From these results, the conformations shown in Figure 8
are postulated to be responsible for enantioface differentation. The additional hydrogen bond
between the respective -CH bond of the carbonyl compound and the oxazaborolidine oxygen
atom has been suggested in thermal Lewis acid-catalyzed process to account for the fixation of
35
the substrate. C-C bond formation is likely to occur first between the internal -carbon atom of
3
6
the -unsaturated carbonyl chromophor and the internal carbon atom of the alkene. The
absolute configuration is determined in this step. A major difference between 2a·1 and 3a·1 is the
fact that the tether which connects the alkene with the chromophor is positioned exo to the
existing ring in the former case but endo in the latter case. The opposite arrangements may be
possible but will be unproductive, because the resulting cyclobutane rings would be too strained.
According to molecular models a substituent at the terminal carbon atom of the alkene interferes
with the ortho-trifluoromethylphenyl group at the boron atom if positioned cis in the coumarin
case or trans in the dihydropyridone case. Indeed, the enantioselectivity drops for substrates of
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this type as seen for the reaction of coumarin 2b (Table 1, entry 4) and dihydropyridone 3c
(Table 1, entry 9).
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Figure 8. Suggested conformation of the substrates 2a and 3a in the complex with Lewis acid 1
prior to the first step of the [2+2] photocycloaddition.
3
7
Given the importance of enone [2+2] photocycloaddition reaction chemistry for organic
38
synthesis, the observation that chiral Lewis acids can render these reactions enantioselectively
is undoubtedly more important than the relatively limited enantioselective Lewis acid catalysis of
coumarin photocycloaddition reactions. In search for ways to improve the catalytic performance
of chiral Lewis acids, it is clear from the present study, that it would be desirable to identify
enone substrates, which show a relatively slow [2+2] photocycloaddition in a wavelength region,
which can be accessed by Lewis acid coordination and by a bathochromic shift of the *
transition. More importantly, based on the assumption that the rate decrease caused by the Lewis
acid is linked to a slow ISC, the ISC rate to the enone triplet needs to be enhanced. These
considerations should be useful for the development of new chiral Lewis acids.
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Conclusion
In summary, this investigation has revealed new information regarding the interaction of Lewis
acids and [2+2] photocycloaddition substrates. Most notably, the hypothesis that the
complexation of Lewis acids to typical enone substrates has other photochemical consequences
than the complexation to coumarins was further corroborated. In the former case, the [2+2]
photocycloaddition proceeds in the absence and in the presence of Lewis acids on the triplet
hypersurface. In the latter case, the Lewis acid induces a change of the reaction mode
10
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1
5
(singlet/triplet) and it induces a rate increase. As already discussed in previous work, we assign
the rate increase by the Lewis acid to several factors, i.e. a stabilization of the singlet state, a
higher ISC rate and an enhanced absorption at the irradiation wavelength ( = 366 nm). For
dihydropyridone 3a as a typical enone substrate, the mode of action of the chiral Lewis acid rests
exclusively on the fact that the strong * transition of the complex overlays with the weak n*
transition of the uncomplexed substrate. This overlay channels the reaction in an enantioselective
manifold with a highly selective C-C bond formation occurring in the Lewis acid complex. The
enantioselective reaction occurs at the expense of a lower reaction rate, which is proposed to be
due to a decreased ISC rate.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (Graduiertenkolleg
GRK 1626 Chemical Photocatalyis) and by Fonds der Chemischen Industrie (Ph.D. scholarship
to R. B.). The help of Olaf Ackermann, Marcus Wegmann and Florian Mayr in conducting the
HPLC analyses is gratefully acknowledged.
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Supporting Information Available: Supporting Information. Detailed experimental procedures,
characterization data for new compounds, rate profiles, and UV/Vis data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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References
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Praetorius, P.; Korn, F. Ber. Dtsch. Chem. Ges. 1910, 43, 2744-2746.
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Alcock, N. W.; Herron, N.; Kemp, T. J.; Shoppee, C. W. J. Chem. Soc. Chem. Commun.
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Lewis, F. D.; Howard, D. K.; Oxman, J. D. J. Am. Chem. Soc. 1983, 105, 3344-3345.
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S. C.; Lee, S. S. Bull. Korean Chem. Soc. 1989, 10, 324-326.
10
Lewis, F. D.; Barancyk, S. V. J. Am. Chem. Soc. 1989, 111, 8653-8661.
1
1
1
2
Görner, H.; Wolff, T. Photochem. Photobiol. 2008, 84, 1224-1230.
For the enantioselective photodimerization of coumarin in the presence of a
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For reviews on enantioselective photochemistry, see: (a) Rau, H. Chem. Rev. 1983, 83,
1
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35-547. (b) Inoue, Y. Chem. Rev. 1992, 92, 741-770. (c) Wessig, P. Angew. Chem. Int.
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Maturi, M. M.; Bach, T. Angew. Chem Int. Ed. 2015, 54, 3872-3890.
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Guo, H.; Herdtweck, E.; Bach, T. Angew. Chem. Int. Ed. 2010, 49, 7782-7785.
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Brimioulle, R.; Guo, H.; Bach, T. Chem. Eur. J. 2012, 18, 7552-7560
Brimioulle, R.; Bach, T. Science 2013, 342, 840-843.
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Brimioulle, R.; Bach, T. Angew. Chem. Int. Ed. 2014, 53, 12921-12924.
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Ed. 2014, 53, 5604-5608.
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For other recent approaches towards catalytic enantioselective [2+2] photocycloaddition
reactions, see: (a) Müller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.; Miranda, M.;
Bach, T. J. Am. Chem. Soc. 2011, 133, 16689-16697. (b) Du, J.; Skubi, K. L.; Schultz, D.
M.; Yoon, T. P. Science 2014, 53, 392-8396. (c) Alonso, R.; Bach, T. Angew. Chem. Int.
Ed. 2014, 53, 4368-4371. (d) Maturi, M. M.; Bach, T. Angew. Chem. Int. Ed. 2014, 53,
7
661-7664.
a) Becker, D.; Nagler, M.; Hirsh, S.; Ramun, J. J. Chem. Soc., Chem. Commun. 1983,
371-373. (b) Becker, D.; Nagler, M.; Sahali, Y.; Haddad, N. J. Org. Chem. 1991, 56,
537-4543. (c) Becker, D.; Klimovich, N. Tetrahedron Lett. 1994, 35, 261-264.
20
(
4
2
1
For reviews on the mechanism of the [2+2] photocycloaddition, see: (a) Schuster, D. I.
The photochemistry of enones in The chemistry of enones; Patai, S., Rappoport, Z., Eds.;
Wiley: Chichester, 1989, pp 623-756. (b) Schuster, D. I.; Lem, G.; Kaprinidis, N. A.
Chem. Rev. 1993, 93, 3-22. (c) Schuster, D. I. Mechanistic Issues in [2+2]-
Photocycloadditions of Cyclic Enones to Alkenes in CRC Handbook of Organic
nd
Photochemistry and Photobiology, 2 ed.; Horspool, W., Lenci, F., Eds.; CRC Press:
Boca Raton, 2004, pp 72/1-72/-24.
2
2
For selected references on the influence of Lewis acids on the photophysical and
photochemical properties of other compound classes but coumarins and enones, see: (a)
Lewis, F. D.; Howard, D. K.; Barancyk, S. V.; Oxman, J. D. J. Am. Chem. Soc. 1986, 108,
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016-3023. (b) Cavazza, M.; Zandomeneghi, M.; Pietra, F. J. Chem. Soc., Chem.
Commun. 1990, 1336-1337. (c) Cavazza, M.; Cimiraglia, R.; Persico, M.; Zandomeneghi,
M.; Pietra, F. J. Photochem. Photobiol. A: Chem. 1991, 61, 329-342. (d) Lewis, F. D.;
Barancyk, S. V.; Burch, E. L. J. Am. Chem. Soc. 1992, 114, 3866-3870. (e) Fukuzumi, S.;
Okamoto, T.; Otera, J. J. Am. Chem. Soc. 1994, 116, 5503-5504. (f) Fukuzumi, S.; Satoh,
N.; Okamoto, T.; Yasui, K.; Suenobu, T.; Seko, Y.; Fujitsuka, M.; Ito, O. J. Am. Chem.
Soc. 2001, 123, 7756-7766. (g) Fukuzumi, S.; Ohkubo, K. J. Am. Chem. Soc. 2002, 124,
10270-10271. (h) Yuasa, J.; Ohkubo, K.; Guldi, D. M.; Fukuzumi, S. J. Phys. Chem. A
10
11
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48
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54
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004, 108, 8333-8340.
For a review, see: Kuznetsova, N. A.; Kaliya, O. L. Russ. Chem. Rev. 1992, 61, 683-696.
a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808-3809. (b)
2
2
3
4
(
Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992-9993. (c) Ryu, D.
H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388-6390. (d) Ryu, D. H.; Zhou, G.;
Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800-4802. (e) Zhou, G.; Corey, E. J. J. Am.
Chem. Soc. 2005, 127, 11958-11959. (f) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem.
Soc. 2007, 129, 1498-1499. (g) Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
1
2686-12687.
2
2
5
6
1
1
Given that Lewis acid 1 has an extinction coefficient of ca. 430 M cm at  = 366 nm,
most of the absorption is due to the Lewis acid.
(a) Guerry, P.; Neier, R.; Chimia 1987, 41, 341-342. (b) Guerry, P.; Neier, R. J. Chem.
Soc., Chem. Commun. 1989, 1727-1728. (c) Aeby, D.; Eichenberger, E.; Haselbach, E.;
Suppan, P.; Guerry, P.; Neier, R. Photochem. Photobiol. 1990, 52, 283-292.
Guerry, P.; Blanco, P.; Brodbeck, H.; Pasteris, O.; Neier, R. Helv. Chim. Acta 1991, 74,
163-178.
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For an emission spectrum of the light source, see: Maturi, M. M.; Wenninger, M.; Alonso,
R.; Bauer, A.; Pöthig, A.; Riedle, E.; Bach, T. Chem. Eur. J. 2013, 19, 7461-7472.
The water- and air-sensitivity of the Lewis acids and its complexes has not allowed us to
acquire meaningful transient absorption spectra at 70 °C.
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(a) Baxendale, J. H.; Bridge, N. K. J. Phys. Chem. 1955, 59, 783-788. (b) Kuhn, H. J.;
Braslavsky, S. E.; Schmidt, R. Pure Appl. Chem. 2004, 76, 2105-2146.
A lower barrier is given because the criterion of complete photon absorption might in this
case not be fulfilled due to the low extinction coefficient of the substrate at  = 366 nm.
3
2
(
a) El-Sayed, M. A. Acc. Chem. Res. 1968, 1, 8-16. (b) Klán, P.; Wirz, J. Photochemistry
of Organic Compounds; Wiley: Chichester, 2009, pp 38-39.
a) Houk, K. N.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95, 4094-4096. (b) Alston, P. V.
33
(
J. Org. Chem. 1975, 40, 1111-1116. (c) Guner, O. F.; Ottenbrite, R. M.; Shillady, D. D.;
Alston, P. V. J. Org. Chem. 1987, 52, 391-394. (d) Lewis, F. D.; Reddy, G. D.; Elbert, J.
E.; Tillberg, B. E.; Meltzer, J. A.; Kojima, M. J. Org. Chem. 1991, 56, 5311-5318. (e)
Lipshutz, B. H.; Aue, D. H.; James, B. Tetrahedron Lett. 1996, 37, 8471-8474. (f) Avalos,
M.; Babiano, R.; Bravo, J. L.; Cintas, P.; Jiménez, J. L.; Palacios, J. C.; Silva, M. A. J.
Org. Chem. 2000, 65, 6613-6619.
3
4
If the catalyst concentration decreases this ratio also decreases and the racemic
background reaction leads to a deterioration of enantioselectivity. For the reaction 3a →
5
a, the ee decreased to 64% ee if performed with 40 mol% of Lewis acid and to 50% ee
1
7
with 30 mol%. For the influence of the light intensity on the ee, see ref. .
35
Review: Corey, E. J. Angew. Chem. Int. Ed. 2009, 48, 2100-2117.
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a) Srinivasan, R.; Carlough, K. H. J. Am. Chem. Soc. 1967, 89, 4932–4936. (b) Liu,
R. S. H.; Hammond, G. S. J. Am. Chem. Soc. 1967, 89, 4936–4944. (c) Maradyn, D.
J.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 5359–5360.
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Reviews: (a) Hehn, J. P.; Müller, C.; Bach T. Formation of a Four-Membered Ring:
From a Conjugate Alkene in Handbook of Synthetic Photochemistry; Albini, A.,
Fagnoni, M., Eds.; Wiley-VCH: Weinheim, 2009, pp 171-215. (b) Fleming, S. A.
Photocycloaddition of Alkenes to Excited Alkenes in Molecular and Supramolecular
Photochemistry; Vol. 12; Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker: New
York, 2005, pp 141-160. (c) Margaretha, P. Photocycloaddition of Cycloalk-2-enones
to Alkenes in Molecular and Supramolecular Photochemistry; Vol. 12; Griesbeck, A.
G., Mattay, J., Eds.; Marcel Dekker: New York, 2005, pp 211-237. (d) Pete, J. P.
[
2+2]-Photocycloadditions of Cyclopentenones with Alkenes in CRC Handbook of
nd
Organic Photochemistry and Photobiology, 2 ed.; Horspool, W., Lenci, F., Eds.;
CRC Press: Boca Raton, 2004, pp 71/1-71/14. (e) Bach, T. Synthesis 1998, 683-703.
(f) Pete, J.-P. Adv. Photochem. 1996, 21, 135-216. (g) Mattay, J.; Conrads, R.;
Hoffmann R. [2+2] Photocycloadditions of -Unsaturated Carbonyl Compounds
th
in Methoden der Organischen Chemie (Houben-Weyl), 4 ed, Vol. E 21c; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995,
3
087-3132. (h) Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297-588.
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Reviews: (a) Iriondo-Alberdi, J.; Greaney, M. F. Eur. J. Org. Chem. 2007, 4801-
4815. (b) Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103. (c) Bach, T.; Hehn, J. P.
Angew. Chem. Int. Ed. 2011, 50, 1000-1045.
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