Enantioselective catalysis of the intermolecular [2+2] photocycloaddition between 2-pyridones and acetylenedicarboxylates

Article abstract of DOI:10.1002/anie.201403885

Intermolecular [2+2] photocycloadditions represent the most versatile and widely applicable of photochemical reactions. For the first time, such intermolecular reactions have been carried out in a catalytic fashion using a chiral triplet sensitizer, with high enantioselectivity (up to 92 % ee). The low catalyst loading (2.5-5 mol %) underlines the high efficiency of the process both in terms of reaction acceleration and differentiation of the enantiotopic faces of the substrate. The substrate is anchored to the chiral catalyst through noncovalent interactions (hydrogen bonds), thus providing a chiral environment in which the enantioselective photocycloaddition proceeds. The densely functionalized products present numerous possibilities for further synthetic transformations.

Full text of DOI:10.1002/anie.201403885

Angewandte
Chemie
DOI: 10.1002/anie.201403885
Photochemistry Very Important Paper
Enantioselective Catalysis of the Intermolecular [2+2] Photo-
cycloaddition between 2-Pyridones and Acetylenedicarboxylates**
Mark M. Maturi and Thorsten Bach*
Abstract: Intermolecular [2+2] photocycloadditions represent
the most versatile and widely applicable of photochemical
reactions. For the first time, such intermolecular reactions have
been carried out in a catalytic fashion using a chiral triplet
sensitizer, with high enantioselectivity (up to 92% ee). The low
catalyst loading (2.5–5 mol%) underlines the high efficiency of
the process both in terms of reaction acceleration and differ-
entiation of the enantiotopic faces of the substrate. The
substrate is anchored to the chiral catalyst through noncovalent
interactions (hydrogen bonds), thus providing a chiral envi-
ronment in which the enantioselective photocycloaddition
proceeds. The densely functionalized products present numer-
ous possibilities for further synthetic transformations.
As shown in Scheme 1, in an idealized catalytic process
there is no direct excitation of the substrate A!A* at a given
wavelength l = c/n. Instead, only sensitized excitation of the
type A-B!*A-B occurs, which can take place only within the
complex of the substrate and chiral sensitizer B. This
U
nder thermal conditions, the main challenge in enantio-
selective catalysis involves the stabilization of a transition
state that arises from a relatively unreactive prochiral starting
material, and which leads subsequently to a defined product
[
1]
enantiomer. In contrast, such an approach is not applicable
to the enantioselective catalysis of photochemical reactions.
After excitation through irradiation with a light source,
further reaction of the substrate is generally very fast, such
that no additional catalyst is required. Thus it is generally
difficult to stabilize consecutive transition states of an already
excited substrate and to channel it into an enantioselective
reaction pathway. Instead, the chiral catalyst must maintain
communication with the substrate in the excitation step, so
that formation of an enantiomerically pure or enantiomeri-
cally enriched product is made possible through the formation
Scheme 1. Photochemical reaction of the prochiral substrate A in the
presence of chiral sensitizer B. It is assumed that sensitization occurs
exclusively in complex A-B, whereas the reaction with a reagent C can
occur either in the complex or after its dissociation. In the latter case,
the reaction is not enantioselective, and products D and ent-D are
obtained as a racemic (rac-D) mixture (top), whilst in the former case,
the reaction can proceed with enantioselective product formation
(bottom).
[
2,3]
of diastereoisomeric transition states.
In line with this
prerequisite is not at all trivial, and the situation is further
complicated since the sensitizer must also ensure excellent
differentiation of enantiotopic faces or groups, and since
conversion of the substrate to product must occur faster than
the dissociation of the substrate–sensitizer complex *A-B!
A* + B. The former complication is the main reason that
many viable sensitizers (e.g. chiral ketones for triplet energy
approach, the idea of using chiral sensitizers for the enantio-
selective catalysis of photochemical reactions was introduced
in the 1960s. The first studies in this area were published by
Hammond and Cole, and dealt with the isomerization of
achiral 1,2-cis-diphenylcyclopropane into chiral trans-1,2-
[4]
diphenylcyclopropane.
[
5]
transfer) do not deliver high enantioselectivities, despite
being catalytically active. The latter complication is most
likely the reason that a recently described chiral triplet
sensitizer delivers high enantioselectivites in some cases but
low enantioselectivities in other cases in the intramolecular
[
*] M. Sc. M. M. Maturi, Prof. Dr. T. Bach
Lehrstuhl fꢀr Organische Chemie I and Catalysis Research Center
(
CRC), Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
[
2+2] photocycloaddition of closely related substrate
[6]
classes.
In the case of an intermolecular reaction involving
[
**] This project was supported by the Deutsche Forschungsgemein-
schaft (DFG) and by the Fonds der Chemischen Industrie. M.M.M.
received a scholarship from the Graduiertenkolleg 1626 “Chemical
Photocatalysis”. We thank Olaf Ackermann, Florian Mayr, and
Marcus Wegmann for help with the HPLC analysis, as well as Dr.
Andreas Bauer for useful discussions.
a reagent C, the dissociation of the excited species A*
becomes a critical factor, because high enantioselectivities
can only be achieved if the reaction with C is very fast, or if
the complex *A-B is very stable. For a long time, it seemed
that the intermediacy of singlet exciplexes represented the
only approach capable of generating significant enantiose-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403885.
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lectivities in a catalytic intermolecular photochemical reac-
m-xylene (HFX) and trifluorotoluene (TFT) has a lower
melting point than either of the pure components; using this
mixture as the reaction solvent, reactions could be carried out
at lower temperatures (up to ꢀ658C; Table 1, entries 7–9).
Under these conditions, the catalyst loading could be lowered
to 2.5 mol% without any significant loss in yield and
enantioselectivity (Table 1, entry 10). Entries 8 and 10 were
identified as the optimal conditions, and these conditions
were applied in further reactions.
[
7]
tion. Herein, we now show that by the appropriate choice of
reaction partner and catalyst, triplet reactions that proceed
[8]
with high enantioselectivities are indeed possible.
Our interest in triplet-sensitized intermolecular [2+2]
photocycloaddition reactions led us to the work of Somekawa
et al., which dealt with the reaction between 2-pyridones and
[11]
acetylenedicarboxylates. Upon irradiation of 2-pyridones
in acetonitrile with a high-pressure mercury lamp (pyrex
filter) in the presence of benzophenone as a triplet sensitizer,
the authors obtained poor yields of the [2+2] and [4+2]
adducts (12–18%). We repeated these experiments under
In a first set of experiments, the size of the ester
substituent was investigated, and 2-pyridone (2) was reacted
with a range of esters 3b–d (Scheme 2). In comparison with
[12]
modified conditions, using chiral triplet sensitizer 1
Table 1). Starting with the reaction between 2-pyridone (2)
(
Table 1: Reaction optimization for the enantioselective, intermolecular
2+2] photocycloaddition of pyridone 2 with alkyne 3a in the presence of
chiral xanthone 1.
[
[
a]
[b]
[c]
[d]
[e]
Entry
c
1
3a
Solvent
T
t
Yield
ee
[
mm] [mol%] [equiv] [%TFT]
[8C] [h] [%]
[%]
[
f]
1
2
3
4
5
6
7
8
9
10
10
10
10
10
20
20
20
20
15
–
10
10
10
50
100
100
50
50
50
50
100
100
100
100
100
100
33
33
33
33
30
30
1
1
2
1
1
3
1
4
4
4
–
–
6
10
10
10
10
10
10
5
42
42
40
42
61
55
71
55
70
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ65
ꢀ65
ꢀ65
ꢀ65
22
42
42
44
48
48
49
49
Scheme 2. Enantioselective intermolecular [2+2] photocycloaddition of
2-pyridone (2) and 6-methyl-2-pyridone (5) with alkynes 3. All reactions
were carried out in a Rayonet RPR-100 reactor with 16 fluorescence
lamps (8 W, emission maximum at l=366 nm) as the light source
[
g]
2.5
2.5
[9]
under the given reaction conditions. [a] The ee value was determined
1
0
after acidic hydrolysis (CF COOH in CH Cl ) and methylation
3
2
2
[a] All reactions were carried out in a Rayonet RPR-100 reactor with 16
(TMSCHN in PhH/MeOH) through HPLC analysis of the correspond-
2
fluorescence lamps (8 W, emission maximum at l=366 nm) as the light
ing dimethylester.
[
9]
source under the given reaction conditions. [b] Trifluorotoluene (TFT)
and hexafluoro-m-xylene (HFX) were employed as the reaction solvent in
the volume ratios given. [c] Irradiation time required for complete
conversion. [d] Yield of isolated product. [e] The enantiomeric excess (ee)
was calculated from the enantiomer ratio, which was determined
through HPLC analysis. [f] No conversion. [g] Incomplete conversion.
the dimethyl ester product 4a (Table 1, entry 10, 49% ee), the
use of the diisopropyl ester variant gave a significant increase
in enantioselectivity (product 4c, 75% ee). Since a clear steric
influence was not apparent, four acetylenedicarboxylates
(R = Me, Et, iPr, tBu) were employed in subsequent experi-
and dimethyl acetylenedicarboxylate (3a), which was pre-
viously studied by Somekawa et al., we observed no back-
ground reaction upon irradiation at l = 366 nm (Table 1,
entry 1). Under otherwise identical conditions, we were
pleased to note that in the presence of the catalyst, a catalytic
enantioselective photoreaction took place (Table 1, entry 2),
forming the photoproduct 4a with high selectivity, through
addition to the 5,6 double bond of the pyridone.
ments, and a full summary of the experiments carried out can
be found in the Supporting Information. Diethyl acetylene-
dicarboxylate (3b) emerged as the optimal ester substrate for
the reaction of 6-methyl-2-pyridone (5), and the correspond-
ing product 6b was isolated in 53% yield and 88% ee
(Scheme 2).
For other pyridones, the use of a 2.5 mol% catalyst
loading required irradiation times of over four hours in order
to reach full conversion. In view of the moderate stability of
the sensitizer (which decomposes in the excited state through
At lower temperatures, the enantioselectivity increased
(
Table 1, entry 3), and as expected, increasing the amount of
[
9,13]
alkyne also improved the enantioselectivity (Table 1, entries 4
and 5). Meanwhile, increasing the substrate concentration led
to a considerable increase in yield (Table 1, entry 6). Through
empirical studies, we found that a 2:1 mixture of hexafluoro-
intermolecular hydrogen atom abstraction)
an increase in
catalyst loading was necessary for such pyridones, and for
these cases the conditions described in entry 8 of Table 1 were
employed. Under these conditions, the high enantioselectivity
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Scheme 4. Byproduct rac-11 from the reaction between 2 and 3c in the
presence of benzophenone as the sensitizer; proposed model to
account for enantioface differentiation in complex 1·2; product 12
from the reaction of 3-methoxy-2-pyridone with diester 3a.
form. The binding mode shown (Scheme 4) has already been
established for other pyridones and dihydropyridones that
bind to templates containing a 1,5,7-trimethyl-3-azabicyclo-
[
3.3.1]nonane-2-one scaffold, and is consistent with the
[
17]
absolute configuration determined for these substrates. In
Scheme 3. Enantioselective intermolecular [2+2] photocycloadditions
of various methyl-substituted 2-pyridones with alkynes 3 at higher
concentration and catalyst loading. All reactions were carried out in
a Rayonet RPR-100 reactor with 16 fluorescence lamps (8 W, emission
[
18]
an analogous fashion, in complex 1·2 an attack from the top
face is preferred, resulting in the absolute configuration
shown in Table 1 and Schemes 2 and 3. It is likely that the
presence of a methyl substituent results in a change in
orientation, which is mirrored by a change in the enantiose-
lectivity of the photoreaction. Particularly significant is the
introduction of the methyl substituent at the 4-position of the
pyridone, since this methyl group points towards the carbonyl
group of the xanthone moiety of the catalyst, and is ideally
positioned for a hydrogen atom abstraction, resulting in rapid
decomposition of the catalyst. Similarly, the catalyzed reac-
tion between 3-methoxy-2-pyridone and dimethyl acetylene-
dicarboxylate (3a) stalls after only low conversion to product
12 (16% yield), which we attribute to decomposition of the
catalyst.
[
9]
maximum at l=366 nm). [a] The ee value was determined after
acidic hydrolysis (CF COOH in CH Cl ) and methylation (TMSCHN in
3
2
2
2
PhH/MeOH) through HPLC analysis of the corresponding dimethyl
ester.
already observed for product 6b could be further increased to
9
0% ee, and the yield was also increased significantly (79%;
Scheme 3). The best yields and selectivities were observed for
-methyl-2-pyridone (7) with the isopropyl and tert-butyl
3
acetylenedicarboxylates, furnishing the corresponding prod-
ucts 9c and 9d in very good yields (75% and 88%,
respectively) and good enantioselectivity (66% ee and
7
2% ee, respectively). In terms of enantioselectivity, the
In summary, we have shown for the first time that
intermolecular [2+2] photocycloadditions can be carried out
with high enantioselectivity by using a catalytic amount of
a chiral triplet sensitizer. The low catalyst loading is
particularly noteworthy; with 2.5 mol% of catalyst, enantio-
selectivities of up to 88% ee were recorded, whilst with
5 mol% of catalyst, products with up to 92% ee were
obtained. This result is attributed to the interplay between
several factors, the most important of which seem to include
the effective binding of the substrate to the catalyst through
hydrogen bonds, the rapid addition of the alkyne to the
excited substrate, and the high enantioface differentiation
ensured by the 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonane-2-
one scaffold. Further study of the mechanistic details should
help to clarify the reaction pathway, as well as broaden the
application of enantioselective catalysis through triplet sensi-
tization to other substrate classes.
best results were obtained using 5-methyl-2-pyridone (8):
photocycloaddition of 8 with alkyne 3a gave product 10a in
9
2% ee (Scheme 3), and high enantioselectivities were also
observed using esters 3b and 3d (90% ee and 86% ee,
respectively).
As demonstrated in the above examples, in addition to the
fact that catalyst 1 is able to effect an unprecedented level of
chirality transfer, it is of particular note that the reaction
conditions of the catalysis experiments also influence the type
and the regioselectivity of the photoreaction. In order to
obtain racemic photoproducts for HPLC analysis, the reac-
tions were also carried out using benzophenone as sensitizer.
In these reactions, a side reaction involving [2+2] addition to
the 3,4 double bond of the pyridone was often observed. Thus,
upon photocycloaddition of pyridone 2 and diester 3c,
dihydropyridone rac-11 was obtained as a byproduct in
addition to the major product rac-4c (Scheme 4), in an
approximate 1:3 ratio. Such 3,4-addition products (as well as
the [4+2] addition products described by Somekawa et al.)
were only produced in very small quantities in our catalysis
experiments.
Received: April 1, 2014
Published online: June 2, 2014
Keywords: cycloaddition · enantioselectivity · hydrogen bonds ·
.
organocatalysis · photochemistry · sensitizers
The absolute configuration was assigned based on the
assumption that the pyridones bind to catalyst 1 as shown for
2
-pyridone (2) in Scheme 4. Luminescence measure-
[
14,15]
[16]
ments
and calculations display a clear preference for
[
1] P. J. Walsh, M. C. Kozlowski, Fundamentals of Asymmetric
Catalysis, University Science Books, Sausalito, 2009.
the 2-pyridone form over the tautomeric 2-hydroxypyridine
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[
2] Reviews: a) H. Rau, Chem. Rev. 1983, 83, 535 – 547; b) Y. Inoue,
Chem. Rev. 1992, 92, 741 – 770; c) P. Wessig, Angew. Chem. 2006,
Methoden der Organischen Chemie (Houben-Weyl), 4th ed.,
Vol. E21c (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, pp. 3085 – 3132; d) J.-P.
Pete, Adv. Photochem. 1996, 21, 135 – 216; e) P. Margaretha in
Molecular and Supramolecular Photochemistry, Vol. 12 (Eds.:
A. G. Griesbeck, J. Mattay), Marcel Dekker, New York, 2005,
pp. 211 – 237; f) J. Iriondo-Alberdi, M. F. Greaney, Eur. J. Org.
Chem. 2007, 4801 – 4815; g) N. Hoffmann, Chem. Rev. 2008, 108,
1052 – 1103; h) T. Bach, J. P. Hehn, Angew. Chem. 2011, 123,
1032 – 1077; Angew. Chem. Int. Ed. 2011, 50, 1000 – 1045.
[11] K. Somekawa, Y. Okumura, K. Uchida, T. Shimo, J. Heterocycl.
Chem. 1988, 25, 731 – 734.
118, 2224 – 2227; Angew. Chem. Int. Ed. 2006, 45, 2168 – 2171;
d) C. Mꢀller, T. Bach, Aust. J. Chem. 2008, 62, 557 – 564; e) C.
Yang, Y. Inoue, Chem. Soc. Rev. 2014, 43, in press, DOI: 10.1039/
c3cs60339c.
[
3] For a recent review on photoorganocatalysis, see: D. Ravelli, M.
Fagnoni, A. Albini, Chem. Soc. Rev. 2013, 42, 97 – 113.
4] a) G. S. Hammond, R. S. Cole, J. Am. Chem. Soc. 1965, 87, 3256 –
[
3257; b) S. L. Murov, R. S. Cole, G. S. Hammond, J. Am. Chem.
Soc. 1968, 90, 2957 – 2958.
[
5] Examples: a) C. Ouannꢁs, R. Beugelmans, G. Roussi, J. Am.
Chem. Soc. 1973, 95, 8472 – 8474; b) L. Horner, J. Klaus, Liebigs
Ann. Chem. 1979, 1232 – 1257; c) M. Demuth, P. R. Raghavan, C.
Carter, K. Nakano, K. Schaffner, Helv. Chim. Acta 1980, 63,
[12] C. Mꢀller, A. Bauer, T. Bach, Angew. Chem. 2009, 121, 6767 –
6769; Angew. Chem. Int. Ed. 2009, 48, 6640 – 6642.
[13] R. Alonso, T. Bach, Angew. Chem. 2014, 126, 4457 – 4460;
Angew. Chem. Int. Ed. 2014, 53, 4368 – 4371.
2434 – 2439; d) D. F. Cauble, V. Lynch, M. J. Krische, J. Org.
Chem. 2003, 68, 15 – 21.
[14] From the phosphorescence maximum for 2 (lmax = 476 nm) at
77 K in EtOH/MeOH (9/1), the triplet energy can be estimated
[
6] C. Mꢀller, M. M. Maturi, A. Bauer, M. C. Cuquerella, M. A.
Miranda, T. Bach, J. Am. Chem. Soc. 2011, 133, 16689 – 16697.
7] Examples: a) J.-I. Kim, G. B. Schuster, J. Am. Chem. Soc. 1990,
ꢀ1
as 251 kJmol : K. Kimura, R. Nagai, Bull. Chem. Soc. Jpn. 1976,
49, 3343 – 3344.
[
1
12, 9635 – 9637; b) S. Asaoka, T. Wada, Y. Inoue, J. Am. Chem.
[15] M. Kuzuya, A. Noguchi, T. Okuda, J. Chem. Soc. Perkin Trans. 2
1985, 1423 – 1427.
[16] V. Barone, C. Adamo, J. Photochem. Photobiol. A 1994, 80, 211 –
219.
Soc. 2003, 125, 3008 – 3027; c) G. Fukuhara, T. Mori, Y. Inoue, J.
Org. Chem. 2009, 74, 6714 – 6727.
[
8] For alternative strategies for the enantioselective catalysis of
[
2+2] photocycloadditions, see: a) R. Brimioulle, T. Bach,
[17] a) T. Bach, H. Bergmann, K. Harms, Org. Lett. 2001, 3, 601 – 603;
b) T. Bach, H. Bergmann, H. Brummerhop, W. Lewis, K. Harms,
Chem. Eur. J. 2001, 7, 4512 – 4521; c) D. Albrecht, F. Vogt, T.
Bach, Chem. Eur. J. 2010, 16, 4284 – 4296.
[18] For reviews on template-directed photoreactions, see: a) J.
Svoboda, B. Kçnig, Chem. Rev. 2006, 106, 5413 – 5430; b) B.
Bibal, C. Mongin, D. M. Bassani, Chem. Soc. Rev. 2014, 43, in
press, DOI: 10.1039/c3cs60366k.
Science 2013, 342, 840 – 843; b) J. Du, K. L. Skubi, D. M. Schultz,
T. P. Yoon, Science 2014, 344, 392 – 396.
[
9] M. M. Maturi, M. Wenninger, R. Alonso, A. Bauer, A. Pçthig, E.
Riedle, T. Bach, Chem. Eur. J. 2013, 19, 7461 – 7472.
[
10] Reviews: a) M. T. Crimmins, T. L. Reinhold, Org. React. 1993,
4, 297 – 588; b) D. I. Schuster, G. Lem, N. A. Kaprinidis, Chem.
Rev. 1993, 93, 3 – 22; c) J. Mattay, R. Conrads, R. Hoffmann,
4
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