Enantioselective Intermolecular [2 + 2] Photocycloaddition Reactions of 2(1H)-Quinolones Induced by Visible Light Irradiation

Article abstract of DOI:10.1021/jacs.6b03221

In the presence of a chiral thioxanthone catalyst (10 mol %) the title compounds underwent a clean intermolecular [2 + 2] photocycloaddition with electron-deficient olefins at λ = 419 nm. The reactions not only proceeded with excellent regio- and diastereoselectivity but also delivered the respective cyclobutane products with significant enantiomeric excess (up to 95% ee). Key to the success of the reactions is a two-point hydrogen bonding between quinolone and catalyst enabling efficient energy transfer and high enantioface differentiation. Preliminary work indicated that solar irradiation can be used for this process and that the substrate scope can be further expanded to isoquinolones.

Full text of DOI:10.1021/jacs.6b03221

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Communication
Enantioselective Intermolecular [2+2] Photocycloaddition
Reactions of 2(1H)-Quinolones Induced by Visible Light Irradiation
Andreas Tröster, Rafael Alonso, Andreas Bauer, and Thorsten Bach
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03221 • Publication Date (Web): 06 Jun 2016
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Enantioselective Intermolecular [2+2] Photocycloaddition Reactions
of 2(1H)-Quinolones Induced by Visible Light Irradiation
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Andreas Tröster,†Rafael Alonso,†Andreas Bauer, and Thorsten Bach*
Department Chemie and Catalysis Research Center (CRC), TechnischeUniversitätMünchen, Lichtenbergstrasse 4,
85747 Garching, Germany
Supporting Information Placeholder
thone, which required irradiation by UV-A light (λ = 366
ABSTRACT:In the presence of a chiral thioxanthone catalyst
nm).
(10 mol%) the title compounds underwent a clean intermo-
lecular [2+2] photocycloaddition with electron deficient
olefins at λ = 419 nm. The reactions proceeded not only with
excellent regio- and diastereoselectivity but delivered the
respective cyclobutane products also with significant enanti-
omeric excess (up to 95% ee). Key to the success of the reac-
tions is a two-point hydrogen bonding between quinolone
and catalystenabling efficient energy transfer and high enan-
tioface differentiation. Preliminary work indicatedthat solar
irradiation can be used for this process and that the substrate
scope can be further expanded to isoquinolones.
Scheme 1.Previous Work on Enantioselective Inter-
molecular [2+2] Photocycloaddition Reactions
The [2+2] photocycloaddition reaction1 has emerged over the
last decades as a powerful tool in organic synthesis2 and
offers a straightforward access to cyclobutanes generating up
to four stereogenic centers in a single transformation. Inter-
molecular [2+2] photocycloaddition reactions offer a wide
flexibility regarding the choice of substrates but frequently
suffer from relatively poor regio- and stereocontrol.1In con-
trast to thermal cycloaddition reactions, the intermediate of
a [2+2] photocycloaddition is short-lived and requires effi-
cient trapping by its reaction partner.3In recent years, inter-
est in enantioselective photochemical reactions has signifi-
cantly increased and it is therefore not surprising that at-
tempts have been made to perform the reaction enantiose-
lectively by the use of a chiral auxiliary or a chiral tem-
plate.4Catalytic enantioselective photochemical reactions5
are still scarce, however, and Scheme 1 provides the two only
examples, in which notable enantioselectivities were
achieved in an intermolecular [2+2] photocycloaddition
reaction6,7under catalytic conditions.The first example,
which led to the formation of cyclobutanes1, was reported in
2014 by the Yoon group.8Itscharacteristic feature is the use of
a ruthenium photoredox catalyst under visible light condi-
tions, which generates in the presence of a chiral Lewis acid a
radical anion that in turn can add enantioselectively to an-
otherenone. The relative configuration of the products could
be controlled by the chiral ligand of the Lewis acid. In the
same year it was found by our group that triplet energy
transfer is a viable concept for asymmetric induction by a
chiral triplet sensitizer in the intermolecular addition of
pyridones to certain alkynes.9 The catalyst was a chiral xan-
In the present study, we have attempted to apply a chiral
sensitizer to an intermolecular [2+2] photocycloaddition
under visible light irradiation. We found the title compounds
to be suitable substrates to react with a variety of olefins
upon sensitization with a chiral thioxanthone at λ = 419 nm.
Enantioselectivities exceeded in several cases 90% ee and it
was possible to substantiate the hypothesis that the reaction
rate of the respective olefin with the photoexcited substrate
is decisive for a successful chirality transfer. Our preliminary
results are summarized in this communication.
Initial work was performed with parent 2(1H)-quinolone10
as the substrate and methyl or ethyl acrylate as the reaction
partner (Table 1). Previous experiments on the intramolecu-
lar [2+2] photocycloaddition reaction of quinolones had
shown that the reactions are best performed at a concentra-
tion of c = 2.5 mM in trifluorotoluene solution and with 10
mol% of the catalyst.7a,b,e,f As in most intermolecular [2+2]
photocycloaddition reactions, the photochemically inactive
olefin was used in excess to avoid [2+2] photodimerization.
The triplet energy of 2(1H)-quinolone is tabulated as 276 kJ
1
mol− and seemed sufficiently close to the triplet energy of
thioxanthones11 to expect an energy transfer. This expecta-
tion was gratifyingly confirmed, as a smooth reaction was
observed already with 10 equivalents of methyl acrylate at λ =
419 nm.12The reaction was complete after ten hours and
product 4a13 was obtained in 74% ee. Remarkably, the regio-
and simple diastereoselectivity of the reaction was high and a
single isomer was obtained. The product is the formal head-
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to-tail (HT) product14 with the methoxycarbonyl substituent
positions C5 to C8 of the quinolone core (products 4i, 4k, 4l,
4n).
1
2
3
4
5
6
7
8
in exo-position. An increase in the number of acrylate equiv-
alents (entries 1-3) led to an increase in rate and an increase
in enantioselectivity. The reaction with 50 equivalents of
methyl acrylate was complete after six hours and delivered
the product with 81% ee. A further raise ofthe olefin concen-
tration was not attempted for practical purposes (removal of
excess olefin, olefin polymerization, solubility).A decrease in
temperature to −40 °C turned out to be equally impractical as
the rate decreased significantly (entry 4). The same observa-
tion was made for ethyl acrylate (entries 5, 6), which deliv-
ered at −40 °C a slightly improved enantioselectivity for
product 4b at the expense of space-time yield. There was no
background reaction in the absence of a sensitizer (entry 7),
which indicated that the thioxanthone is involved in the
catalytic cycle (vide infra).
Table2.Influence of Substituents on the Catalytic
Enantioselective [2+2] Photocycloaddition Reactions
between 2(1H)-Quinolones and Olefinsa
9
10
11
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Table 1. Optimization ofthe Catalytic Enantioselec-
tive [2+2] Photocycloaddition of 2(1H)-Quinolone
with Acrylates
eq.
(alkene)
temp.
(°C)
yield
ee
entry
R
t (h)a
product
(%)b (%)c
1
2
Me
Me
Me
Me
Et
10
20
50
50
50
50
50
10
7
4a
4a
4a
4a
4b
4b
4b
79
74
76
85
82
79

74
80
81
−25
−25
−25
−40
−25
−40
−25
3
6
4
5
22
6
83
78
80

a
6
7d
Et
45
24
Irradiation times varied between six and 18 hours. The
reactions were performed on a scale of 25 ꢀmol. For detailed
information, see the SI. The reaction was performed on a
scale of 0.15 mmol.
Et
b
aIrradiation time at λ = 419 nm in trifluorotoluene solution
b
c
(c = 2.5 mM). Yield of isolated product. The enantiomeric
excess was calculated from the ratio of enantiomers (4/ent-4)
as determined by chiral HPLC analysis.dNo thioxanthone (3)
was added to the reaction mixture.
Enantioselectivities remained high and reached a peak for
substitution at position C7 with product 4l being formed in
95% ee. A decrease in selectivity was noted for product 4m
derived from 8-methylquinolone. Notably, the [2+2] photo-
cycloaddition was compatible with a bromine substituent at
the quinolone core (product 4j). Even the sensitive olefin
acrolein could be brought to react in the enantioselective
[2+2] photocycloaddition. Product 4n was isolated in 44%
yield and with 91% ee.
Further studies were concerned with a preliminary evalua-
tion of the substrate scope (Table 2). Expectedly, the ester
substituent at the acrylate did not change yield or enantiose-
lectivity and the benzyl acrylate [2+2] photocycloaddition
product 4c was obtained in 83% yield and 82% ee. A positive
influence on the enantioselectivity was noted upon employ-
ing anα-substituted acrylate (product 4d) or a stronger elec-
tron withdrawing group at the olefinic double bond. Indeed,
methyl vinyl ketone and ethyl vinyl ketone turned out to be
excellent olefin components, providing the quinolone prod-
ucts 4e and 4f with enantioselecitivities exceeding 90% ee.
Methylsubstitution at the β-position of the α,β-unsaturated
ketone had little impact on the enantioselectivity (product
4g) but the reaction remained incomplete even after an irra-
diation time of eight hours. 4-Pentylquinolone reacted
smoothly with methyl vinyl ketone to produce product 4h
(94%, 90% ee). Methylsubstitution was further probed at
Scheme 2.Apparatus for Solar Irradiation and Result
of an Intermolecular [2+2] Photocycloaddition
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Journal of the American Chemical Society
O
more electron rich olefins such as vinyl acetate produced the
respective products with lower selectivity. Product 4o10c was
the formal HT product of the vinyl acetate [2+2] photocy-
cloaddition to quinolone and was formed as an exo/endo
mixture. Under the conditions given in Scheme 2, the exo-
product (42% yield) was obtained with 58% ee, and the endo-
product (36% yield) with 43% ee. In order to support the
hypothesis that a lower reaction rate might be responsible
for the decrease in enantioselectivity as compared for exam-
ple to product 4f (92% ee), a competition experiment was
performed (Scheme 4). The reaction was conducted at room
temperature in acetonitrile solution, which facilitated the
isolation and quantification of suitable samples in short time
intervals. Triplet sensitization was achieved with the tert-
butyl analogue 7 (10 mol%) of the chiral catalyst 3.
1
2
3
4
5
6
7
8
HN
O
+
solar irradiation
−25 °C
(PhCF3)
3
(10 mol%)
O
4f
H
H
86% ee
HN
O
9
10
11
Given the fact that visible light enables the enantioselec-
tive [2+2] photocycloaddition it seemed desirable to attempt
the reaction also with solar irradiation. A parabolic reflector
was employed to focus the sun beam on the reaction vessel
(Scheme 2). A Fe2(SO4)3 filter solution15 was applied to avoid
undesired direct excitation by short wavelength photons.
Due to the low sunlight intensity in winter, the reaction was
slower than with the artificial light sources. After three
hours, the yield for 4f was 81% at 21% conversion but the
enantioselectivity remained high (86% ee).
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Scheme 4.Competing Intermolecular [2+2] Photocy-
cloaddtion of Vinyl Acetate vs. Ethyl Vinyl Ketone
and 2(1H)-Quinolone
Y
hν (λ = 419 nm)
r.t. (MeCN)
O
O
H
H
HN
HN
Y
The absolute configuration of the photocycloaddition
products was derived from their specific rotation. It has been
earlier reported that the helical arrangement of the conjugat-
ed π-system in dihydro-2-quinolones is responsible for the
chiroptical properties of this compound class.7b,16The specific
rotation of 3,6-dihydrocyclobuta[c]-2-quinolones4b, 4c, 4d,
4f,and 4j was determined and they were found to be levoro-
tatory suggestingan (R)-configuration at carbon atom
C3(Scheme 2). This absolute configuration indicates an attack
at the prostereogenicquinolone carbon atom C3 from the Re
face. Indeed, based on previous results,7b,e it is assumed that
quinolone is excited into its reactive triplet state by triplet
energy transfer in complex 5 (Scheme 3). In line with the
mode of action of related templates,17 the approach to the
photoexcited quinolone in 5* is only feasible for the olefin to
occur from the Re(bottom) face relative to carbon atom C3
leading to the putative 1,4-diradical 6, from which product
formation occurs by C-C bond formation at C4.
O
4f
Y = COEt rac- + isomers
4o
N
Y = OAc rac- + isomers
tBu
kCOEt
O
S
= 11.2
kOAc
7 (10 mol%)
One equiv. of parent 2(1H)-quinolone were reacted in the
presence of 25 equiv. of vinyl acetate and ethyl vinyl ketone.
Product analysis was performed by GLC employing dodecane
as internal standard. It is evident from the rate profile
(Scheme 4) that formation of product rac-4f was significantly
faster than formation of product rac-4o. Quantification of
the data delivered a relative reaction rate kCOEt/kOAc of 11.2 in
favor of the former reaction, which is in line with the higher
enantioselectivity obtained with ethyl vinyl ketone as olefinic
reaction partner. If steric hindrance interferes with the hy-
drogen bonding event, the enantioselectivity of the [2+2]
photocycloaddition can also decrease. The comparably low
enantioselectivity for product 4m (Table 2) is likely due to
the methyl group at carbon atom C8 of the quinolone core.
Scheme 3.Mechanistic Picture of the Enantioselective
[2+2] Photocycloaddition and Origin for the For-
mation of Racemic Product rac-4
*
O
O
N
O
N
O
S
S
hν (λ = 419 nm)
3
N H
O
O
N H
O
O
4
H
N
H N
5
5*
X
dissociation
O
*
N
O
X
Scheme 5.Enantioselective Intermolecular [2+2] Pho-
tocycloaddition of 1(2H)-Isoquinolone and Methyl
Vinyl Ketone
O
S
H
X
HN
4
4
rac-
N H
O
O
N
H
T1
6
hν (λ = 419 nm)
3 (10 mol%)
H
N
H
H
N
O
O
We have previously speculated that dissociation of the tri-
−25 °C (PhCF3)
O
O
+
plet quinolone (T1) from complex 5* leads to a deterioration
of the enantioselectivity as the former species will not en-
counter any asymmetric induction thus forming racemic
products rac-4.7b In the present reactions, we noted that
H
86%
8
(91% ee)
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Page 4 of 6
chem.1996, 21, 135-216. (h) Fleming, S. A.; Bradford, C. L.; Gao J. J.
The kinetic data show that insufficient enantioface differ-
entiation in complex 5* is not responsible for a lack of enan-
tioselectivity with certain olefins but their low reaction rates.
With this in mind, other substrates which contain a lactam
binding motif and which show a high intermolecular reac-
tion rate should be equally suitable for enantioselectively
catalyzed intermolecular [2+2] photocycloaddition reaction.
A preliminary experiment with parent 1(2H)-isoquinolone19
and methyl vinyl ketone revealed that a high enantioselectiv-
ity can be achieved also with isoquinolone substrates
(Scheme 5). Product 817d was obtained as a single isomer in
91% ee. The conversion remained incomplete after nine
hours and varying amounts of starting material were recov-
ered. In the best case, the conversion was 86% and the yield
of product was 74% (86% based on conversion).
Regioselective and Stereoselective [2+2] Photocycloadditions. In
Organic Photochemistry,Molecular and Supramolecular Photochemis-
try, Vol. 1;Ramamurthy, V.; Schanze, K. S., Eds.; Dekker: New York,
1997; pp 187-244. (i) Bach, T. Synthesis1998, 683-703. (j) Margaretha,
P. Photocycloaddition of Cycloalk-2-enones to Alkenes. In Synthetic
Organic Photochemistry, Molecular and Supramolecular Photochem-
istry, Vol. 12; Griesbeck, A. G.; Mattay J., Eds.; Dekker: New York,
2005; pp 211-237. (k) Hehn, J. P.; Müller, C.; Bach, T. Formation of a
Four-Membered Ring: From a Carbonyl-Conjugated Alkene. In
Handbook of Synthetic Photochemistry; Albini, A.; Fagnoni, M., Eds.;
Wiley-VCH: Weinheim, 2010; pp 171-215. (l) Poplata, S.; Tröster, A.;
Zou, Y.-Q.; Bach, T. Chem. Rev.2016, 116, in press, doi:
10.1021/acs.chemrev.5b00723.
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(2) Reviews: (a) Iriondo-Alberdi, J.; Greaney, M. F. Eur. J. Org.
Chem.2007, 4801-4815. (b) Hoffmann, N. Chem. Rev. 2008, 108, 1052-
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1045.
In summary, chiral thioxanthone3 was shown to be a com-
petent catalyst to mediate the enantioselective intermolecu-
lar [2+2] photocycloaddition of various quinolones and elec-
tron deficient alkenes. Association between the catalyst and
the substrate by hydrogen bonding is critical for the success
of the reaction and dissociation of the photoexcited substrate
from the catalyst is likely reponsible for a loss in enantiose-
lectivity as observed for vinyl acetate as the reaction partner.
The kinetic parameters of these processes are currently being
studied in more detail and will be reported together with
possible applications of the enantioselective [2+2] photocy-
cloaddition in due course.
(3) Schuster, D. I. Mechanistic Issues in [2+2]-Photocycloadditions
of Cyclic Enones to Alkenes. In CRC Handbook of Photochemistry
and Photobiology, 2nd ed.;Horspool, W. M., Lenci, F., Eds.; CRC Press:
Boca Raton, 2004; pp 72/1-72/24.
(4) (a) Inoue, Y. (ed.) Chiral Photochemistry, Molecular and Su-
pramolecular Photochemistry, Vol. 11; Dekker: New York, 2004. (b)
Ramamurthy, V.; Inoue, Y., Eds. Supramolecular Photohemistry;
Wiley: Hoboken, 2011.
(5) Reviews: (a) Yang, C.; Inoue, Y. Chem. Soc. Rev.2014, 43, 4123-
4143. (b) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. Angew.
Chem. Int. Ed.2015, 54, 3872-3890.
(6) For a recent review on catalytic enantioselective [2+2] cy-
cloaddition reactions, see: Xu, Y.; Conner, M. L.; Brown, M. K. An-
gew. Chem. Int. Ed.2015, 54, 11918-11928.
Supporting Information
(7) For catalytic enantioselective (≥90% ee) intramolecular [2+2]
photocycloaddition reactions, see: (a) Müller, C.; Bauer, A.; Bach, T.
Angew. Chem. Int. Ed. 2009, 48, 6640-6642. (b) Müller, C.; Bauer, A.;
Maturi, M. M.; Cuquerella, M. C.; Miranda, M. A.; Bach, T. J. Am.
Chem. Soc.2011, 133, 16689-16697. (c) Brimioulle, R.; Guo, H.; Bach, T.
Chem. Eur. J.2012, 18, 7552-7560 (d) Brimioulle, R.; Bach, T. Sci-
ence2013, 342, 840-843. (e) Maturi, M. M.; Wenninger, M.; Alonso,
R.; Bauer, A.; Pöthig, A.; Riedle, E.; Bach, T. Chem. Eur. J.2013, 19,
7461-7472. (f) Alonso, R.; Bach, T. Angew. Chem. Int. Ed. 2014, 53,
4368-4371. (g) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Sibi, M. P.;
Sivaguru, J. Angew. Chem. Int. Ed.2014, 53, 5604-5608. (h) Vallavoju,
N.; Selvakumar, S.; Jockusch, S.; Prabhakaran, M. T.; Sibi, M. P.;
Sivaguru, J. Adv. Synth. Catal. 2014, 356, 2763-2768. (i) Brimioulle, R.;
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R.; Bauer, A.; Bach, T. J. Am. Chem. Soc.2015, 137, 5170-5176.
(8) (a) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science2014,
344, 392-396. (b) Neier, R. Science2014, 344, 368-369.
Experimental procedures, analytical data for all new com-
pounds, proof of constitution and configuration, competition
experiment, NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Corresponding Author
thorsten.bach@ch.tum.de
Notes
The authors declare no competing financial interests.
†These authors contributed equally to the project.
ACKNOWLEDGMENT
Financial support by the European Research Council under
the European Union’s Horizon 2020 research and innovation
programme (grant agreement No 665951 − ELICOS) and the
Deutsche Forschungsgemeinschaft (Reinhart Koselleck pro-
gram) is gratefully acknowledged. AT thanks the research
training group (Graduiertenkolleg) 1626 “ChemicalPhotoca-
talysis” for a scholarship. AR acknowledges the Alexander
von Humboldt foundation for a research fellowship. Dr. S.
Breitenlechner is acknowledged for his help with the rate
measurements.
(9) Maturi, M. M.; Bach, T. Angew. Chem. Int. Ed. 2014, 53, 7661-
7664.
(10) For early work on racemic intermolecular [2+2] photocy-
cloaddition reactions of 2(1H)-quinolones, see: (a) Evanega, G. R.;
Fabiny, D. L. Tetrahedron Lett. 1968, 9, 2241-2246. (b) Loev, B.;
Goodman, M. M.; Snader, K. M. Tetrahedron Lett. 1968, 9, 5401-5404.
(c) Evanega, G. R.; Fabiny, D. L. J. Org. Chem. 1970, 35, 1757-1761. (d)
Buchardt, O.; Christensen, J. J.; Harrit, N. Acta Chem. Scand. B1976,
30, 189–192. (e) Kaneko, C.; Naito, T. Somei, M. J. Chem. Soc. Chem.
Commun.1979, 804-805. (f) Kaneko, C.; Naito, T. Chem. Pharm. Bull.
1979, 27, 2254-2256.
(11) The triplet energy (ET) of parent thioxanthone is tabulated as
ET = 265 kJ mol−1 (Murov, S. L., Carmichael, I.; Hug, G. L. Handbook
of Photochemistry, 2nd ed., Dekker: New York, 1993, p. 80).
(12) For an emission spectrum of the irradiation lamps, see ref.7f.
(13) All compounds 4a-4n have not yet been reported and were
therefore prepared in racemic form for comparison (see Supporting
Information).
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(14) Parent 2(1H)-quinolone (carbosytril) has been previously re-
ported to react with acrylonitrile exclusively to the HT product: (a)
ref.10c. (b) Lewis, F. D.; Reddy, G. D.; Elbert, J. E.; Tillberg, B. E.;
Meltzer, J. A.; Kojima, M. J. Org. Chem.1991, 56, 5311-5318.
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(15) Pellicori, S. F. Appl. Opt.1964, 3, 361-366.
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(18) For some key references on intermolecular isoquinolone [2+2]
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(e) Coote, S. C.; Pöthig, A.; Bach, T. Chem. Eur. J.2015, 21, 6906-6912.
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