only a few reports on (homogeneous) enantioselective ca-
talysis in microflow systems;9,10 especially examples dealing
with synergistic catalysis11 have not yet been described. For
instance, the merging of photoredox catalysis with organo-
catalysis as pioneered by MacMillan et al.12,13 provides
access to important chiral R-alkylated aldehyde building
blocks. Proceeding under the simultanous activation of both
the nucleophile and the electrophile (within two distinct
intersecting catalytic cycles) this powerful concept poses an
additional challenge for the transfer to flow systems due to
the inherent low concentration of the key intermediates.11a
The obvious benefits of microstructured reactors known
from classical photochemistry prompted us to investigate the
influence of microreactors on visible-light photoredox cata-
lysis. Herein, we disclose the successful development of flow
conditions to both enhance productivity of (enantioselective)
photocatalytic reactions and facilitate challenging transfor-
mations involving unstable intermediates.
Table 1. Acceleration of the Photocatalytic Reductive Dehalo-
genation within a Microreactora
We recently reported14 that the photoredox dehalogena-
tion15 of activated halogenides upon irradiation with
visible light can also be effected by simple organic dyes16
and therefore chose this Eosin Y mediated transformation
as a first benchmark reaction for the evaluation of flow
conditions using a commercially available microreactor
setup.17 In fact, within the flow regime, by employing similar
conditions as described previously,14 we noticed a tremen-
dous acceleration for the dehalogenation of R-bromoaceto-
phenone 1a (Table 1, entry 1). Full defunctionalization
yielding product 2a could be reached in less than 1 min.
Similarly, the conversion of the less activated R-carbonyl
chloride 1b (entry 2) was significantly increased without loss
of selectivity as the aromatic bromide remained untouched.
a Reaction conditions according to ref 14, cRHal = 0.5M. b Isolated yield.
We assume that in the presence of sacrificial electron
donors (such as diisopropylethylamine (DIPEA) and/or
Hantzsch ester) the strongly improved light penetration
results in the efficient formation of the excited 1EY* and
subsequent intersystem crossing to the corresponding
triplet state 3EY* and hence in a higher concentration of
the strong reductant Eosin Y radical anion EY•ꢀ being
capable of reducing the R-halogen carbonyl compounds.
The observed temporary decolorization of the usually
orange reaction mixture during irradiation might also
indicate the accumulation of this active catalyst species.18
Encouraged by these initial results we turned our atten-
tion to aza-Henry reactions, representing an example for
oxidative R-amino CꢀH functionalizations via visible-
light photoredox catalysis.19 Quite a number of related
transformations employing different nucleophiles20 and
also “follow-up” reactions21 with the help of various
photoredoxcatalysts22 havebeenpublishedrecently. Upon
irradiation, initial formation of an R-amino radical cation by
(9) (a) Rasheed, M; Elmore, S. C.; Wirth, T. In Catalytic Methods in
Asymmetric Synthesis: Advanced Materials, Techniques and Applications;
Gruttadauria, M., Giacalone, F., Eds.; Wiley: Hoboken, NJ, 2011; p 345. (b)
Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein J. Org. Chem. 2009, 5,
No. 19, DOI: 10.3762/bjoc.5.19. Selected recent examples of enantioselec-
tive flow chemistry: (c) Odedra, A.; Seeberger, P. H. Angew. Chem., Int. Ed.
2009, 48, 2699. (d) Fritzsche, S.; Ohla, S.; Glaser, P.; Giera, D. S.; Sickert,
M.; Schneider, C.; Belder, D. Angew. Chem., Int. Ed. 2011, 50, 9467.
(10) For a seminal example of enantioselective photochemistry in a
micoreactor (≈ 2% ee), see: Maeda, H.; Mukae, H.; Mizuno, K. Chem.
Lett. 2005, 34, 36.
(11) For recent reviews, see: (a) Allen, A. E.; MacMillan, D. W. C.
Chem. Sci. 2012, 3, 633. (b) Wende, R. C.; Schreiner, P. Green Chem.
2012, DOI: 10.1039/C2GC35160A.
(12) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 10875. (c) Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600.
(13) For another example of synergistic photoredox organocatalysis
(albeit with only poor enantioselectivity), see ref 3.
(18) (a) Neckers, D. C.; Valdes-Aguilera, O. M. Adv. Photochem.
1993, 18, 315. For recent spectroelectrochemical studies on redox
reactions of Eosin Y, see: (b) Zhang, J.; Sun, L.; Yoshida, T. J.
Electroanal. Chem. 2011, 662, 384.
ꢀ
ꢀ
(19) Condie, A. G.; Gonzalez-Gomez, J.-C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464.
€
€
(14) Neumann, M.; Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem.,
(20) For selected examples using Ir- or Ru-based catalysts, see: (a)
Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org. Lett.
2012, 14, 94. (b) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun.
2011, 47, 12709. (c) Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.;
Xiao, W.-J. Chem. Commun. 2011, 47, 8337. See also ref 3.
(21) (a) Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011,
47, 9615. (b) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen,
J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171.
Int. Ed. 2011, 50, 951.
(15) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. J. R. J. Am.
Chem. Soc. 2009, 131, 8756.
(16) For selected recent applications using organic photoredox cat-
alysts, see: (a) Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Green Chem.
2011, 13, 2682. (b) Pan, Y.; Wang, S.; Kee, C. W.; Dubuisson, E.; Yang,
Y.; Loh, K. P.; Tan, C.-H. Green Chem. 2011, 13, 3341. (c) Hari, D. P.;
€
Schroll, P.; Konig, B. J. Am. Chem. Soc. 2012, 134, 2958. (d) Hari, D. P.;
(22) Examples with organic photocatalysts, see refs 16a, 16b, 16d,
and 23a. For solid inorganic catalysts, see: (a) Rueping, M.; Zoller, J.;
Fabry, D. C.; Poscharny, K.; Koenigs, R. M.; Weirich, T. E.; Mayer, J.
Chem.;Eur. J. 2012, 18, 3478. (b) Cherevatskaya, M.; Neumann, M.;
€
B. Konig, B. Org. Lett. 2011, 13, 3852. (e) Zou, Y.-Q.; Chen, J.-R.; Liu,
X.-P.; Lu, L.-Q.; Davis, R. L.; Jørgensen, K. A.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2012, 51, 784. For a review, see: (f) Ravelli, D.; Fagnoni,
M. ChemCatChem 2012, 4, 169. (g) Pandey, G.; Ghorai, M. K.; Hajra, S.
Pure Appl. Chem. 1996, 68, 653.
€
€
Fuldner, S.; Harlander, C.; Kummel, S.; Dankesreiter, S.; Pfitzner, A.;
€
Zeitler, K.; Konig, B. Angew. Chem., Int. Ed. 2012, 51, 4062. (c) Xie, Z.;
(17) For details see Supporting Information.
Wang, C.; deKrafft, K. E.; Lin, W. J. Am. Chem. Soc. 2011, 133, 2056.
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