Visible light photoredox catalysis: Generation and addition of N -aryltetrahydroisoquinoline-derived α-amino radicals to michael acceptors

Article abstract of DOI:10.1021/ol202857t

The photoredox-catalyzed coupling of N-aryltetrahydroisoquinoline and Michael acceptors was achieved using Ru(bpy)₃Cl₂ or [Ir(ppy)₂(dtb-bpy)]PF₆ in combination with irradiation at 455 nm generated by a blue LED,

Full text of DOI:10.1021/ol202857t

ORGANIC
LETTERS
2012
Vol. 14, No. 3
672–675
Visible Light Photoredox Catalysis:
Generation and Addition of
N-Aryltetrahydroisoquinoline-Derived
R-Amino Radicals to Michael Acceptors
Paul Kohls,† Deepak Jadhav,†,‡ Ganesh Pandey,*,‡ and Oliver Reiser*,†
€
€
Institut fu€r Organische Chemie, Universitat Regensburg, Universitatsstrasse 31,
93053 Regensburg, Germany, and Division of Organic Chemistry, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune-411 008, India
Oliver.Reiser@chemie.uni-regensburg.de; gp.pandey@ncl.res.in
Received October 23, 2011
ABSTRACT
The photoredox-catalyzed coupling of N-aryltetrahydroisoquinoline and Michael acceptors was achieved using Ru(bpy)3Cl2 or [Ir(ppy)2-
(dtb-bpy)]PF6 in combination with irradiation at 455 nm generated by a blue LED, demonstrating the trapping of visible light generated R-amino
radicals. While intermolecular reactions lead to products formed by a conjugate addition, in intramolecular variants further dehydrogenation occurs,
leading directly to 5,6-dihydroindolo[2,1-a]tetrahydroisoquinolines, which are relevant as potential immunosuppressive agents.
In recent years, there has been increasing interest in the
use of visible light to drive organic reactions because of its
infinite availability, ease of handling, and promising
application in industry.1 Generally, photosensitizers or
photocatalysts are required in such processes due to the
inability of many organic molecules to absorb in the range
between 400 and 800 nm.2 Photoredoxcatalysts induce
exchange of electrons with interacting substrates owing to
their well-defined redox potential differences and hence
generate potentially active ion radicals. The unique fea-
tures of these photosensitized and photocatalyzed
reactions are associated with the generation and subse-
quent facile cleavage of radical ions into radicals and ions,
providing the basis for the development of many new
and useful organic synthetic conversions.3 In particular,
one-electron oxidation of tertiary amines is known to
produce planar radical cations, which in polar solvents
(3) (a) DeLaive, P. J.; Lee, J. T.; Sprintschnik, H. W.; Abruna, H.;
Meyer, T. J.; Whitten, D. G. J. Am. Chem. Soc. 1977, 99, 7094. (b)
Nicewicz, D., A.; MacMillan, D. W. C. Science 2008, 322, 77. (c) Pham,
P. V.; Nagib, D. A; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2011,
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Chem. Soc. 2008, 130, 12886. (e) Du, J.; Ruiz Espelt, L.; Guzei, I. A.;
Yoon, T. P. Chem. Sci. 2011, 2, 2115. (f) Narayanam, J. M. R.; Tucker,
J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756. (g) Dai,
C.; Narayanam, J. M. R.; Stephenson, C. R. J. Nature Chem. 2011, 3,
†
€
Universitat Regensburg.
‡ National Chemical Laboratory.
(1) Leading reviews: (a) Narayanam, J. M. R.; Stephenson, C. R. J.
€
€
140. (h) Neumann, M.; Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem.,
Chem. Soc. Rev. 2011, 40, 102. (b) Yoon, T. P.; Ischay, M. A.; Du, J. N.
Nature Chem. 2010, 2, 527. (c) Teply, F. Collect. Czech. Chem. Commun.
2011, 76, 859. (d) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785.
(2) (a) Srinivasan, R. J. Am. Chem. Soc. 1963, 85, 3048. (b) Salomon,
R. G.; Kochi, J. K. J. Am. Chem. Soc. 1974, 96, 1137. (c) Kochi, J. K.
Angew. Chem., Int. Ed. 1988, 27, 1227.
Int. Ed. 2010, 123, 981.
ꢀ
(4) (a) Lewis, F. D.; Ho, T.-I.; Simpson, J. T. J. Org. Chem. 1981, 46,
1077. (b) Lewis, F. D.; Ho, T.-I.; Simpson, J. T. J. Am. Chem. Soc. 1982,
104, 1924. (c) Lewis, F. D. Acc. Chem. Res. 1986, 19, 401. (d) Chow,
Y. L.; Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Chem. Rev. 1978,
78, 243.
r
10.1021/ol202857t
Published on Web 01/19/2012
2012 American Chemical Society

undergo facile deprotonation, subject to kinetic acidity
and stereoelectronic factors, to produce R-amino radicals
(eq 1).4
ꢀeꢀ
ꢀHþ
ꢀeꢀ
•
• þ
þ
R2NCHR02 f R2 N CHR20 f R2N C R02 f R2 N ¼ CR20
ð1Þ
Depending on the reaction conditions, the generated
R-amino radicals could either react as a nucleophile with
a suitable substrate or could undergo further one-electron
oxidation due to their reduced ionization potential to form
iminium cations, thus serving as an electrophile. Stephen-
son et al.5a have demonstrated the latter concept in combi-
nation with visible light photoredox catalysis by trapping
the iminium cation of N-phenyltetrahydroisoquinoline
with nitromethane (Scheme 1), which was subsequently
demonstrated with other nucelophiles as well.5bꢀe
Figure 1. Photoredoxcatalysts used in this work.
We began our investigation by irradiating a mixture of
N-phenyltetrahydroisoquinoline (3a, 1 equiv) and methyl
vinyl ketone (4a, 3 equiv) in the presence of catalytic amounts
of Ru(bpy)3Cl2 6H2O (1, 2 mol %) in degassed acetonitrile
3
with a blue light emitting diode (LED; λmax = 455 nm)
gave rise to the conjugate addition product 5a in 58% yield
(Scheme 2). Increasing the amount of 4a (10 equiv) and the
ruthenium catalyst (10 mol %) resulted in an improvement of
yield for 5a (75%).
Scheme 1. Photocatalyzed R-Alkylation of Amines
The formation of 5a suggests R-amino radical 6as a viable
intermediate that subsequently undergoes conjugate addi-
tion to 7 followed by its reduction/protonation with con-
current regeneration of the ruthenium catalyst (Scheme 2).
Scheme 2. Photocatalyzed R-Functionalization of N-Phenyli-
soquinoline (3)
Given our interest in photoredox processes6 and
R-functionalization of pyrrolidines and piperidines,7
we were questioning if also the former process, i.e., the
utilization of R-amino radicals as synthetically useful
intermediates, can be realized by visible light driven
photoredox catalysis (Figure 1).8 We report here the
successful realization of this concept with the coupling
of teritiary amines and R,β-unsaturated carbonyl com-
pounds in conjugate additions, contrasting copper(I)
bromide catalyzed oxidative couplings of the same
reaction partners reported by Bohle et al.9
(5) (a) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J.
€
J. Am. Chem. Soc. 2010, 132, 1464. (b) Hari, D. P.; Konig, B. Org. Lett.
2011, 13, 3852. (c) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.;
Fabry, D. C. Chem. Commun. 2011, 47, 2360. (d) Rueping, M.; Zhu, S.;
Koenigs, R. M. Chem. Commun. 2011, 47, 8679. (e) Rueping, M.; Zhu,
S.; Koenigs, R. M. Chem. Commun. 2011, 47, 12709.
(6) (a) Pandey, G. Photoinduced Redox Reactions in Organic Synthe-
sis. In Molecular and Supramolecular Photochemistry; Ramamurthy, V.,
Ed.; Marcel-Dekker Inc.: New York, 1997; Vol. 1, p 245. (b) Pandey, G.
Photoinduced Electron Transfer (PET) in Organic Synthesis. Top. Curr.
Chem. 1993, 168, 175. (c) Pandey, G.; Rani, K. S.; Lakshmaiah, G.
Tetrahedron Lett. 1992, 33, 5107. (d) Pandey, G. Synlett 1992, 546. (e)
Maji, T.; Karmakar, A.; Reiser, O. J. Org. Chem. 2011, 76, 736.
€
(7) (a) Heimgartner, G.; Raatz, D.; Reiser, O. Tetrahedron 2005, 61,
643. (b) Bodmann, K.; Bug, T.; Steinbeisser, S.; Kreuder, R.; Reiser, O.
Tetrahedron Lett. 2006, 47, 2061. (c) Gheorghe, A.; Schulte, M.; Reiser,
O. J. Org. Chem. 2006, 71, 2173.
Further evidence for the occurrence of 6 was found by
analyzing the crude product mixture by mass spectrometry
Org. Lett., Vol. 14, No. 3, 2012
673

in which a prominent peak of 2-fold the mass of 6 was
observed. Irradiation of 3a under identical conditions in the
absence of methyl vinyl ketone indeed results in the forma-
tion of 8 as a mixture of diastereomers. One of those was
obtained in pure form allowing its structural assignment by
X-ray analysis (Scheme 3).
coupling product 5j with methyl vinyl ketone in low yields
and only in the presence of iridium catalyst 2, pointing
to the necessity of an activating substituent on the R-
position as also noted for the corresponding iminium
cation chemistry.5
There seems to be quite a delicate balance with respect
to electronic factors on both coupling partners, which
also seem to interplay with the type of catalyst used in the
process. While in all cases attack on the β-position of the
R,β-unsaturated carbonyl compound is observed, point-
ing toward the nucleophilic nature14 of 6, increasing the
donor character of the latter by switching the N-R-sub-
stituent from phenyl to p-methoxyphenyl resulted in a
pronounced decrease in yield when iridium catalyst 2 was
employed (5a/5b and 5d/5e). On the other hand, switching
from phenyl vinyl ketone to p-methoxyphenyl vinyl
Scheme 3. Photoredox-Catalyzed Reactions of N-Phenyltetra-
hydroisoquinoline (3a) in the Absence and Presence of Oxygen
Moreover, when the reaction solution was not deoxy-
genated, 9 was isolated instead, which can be explained by
initial coupling of 6 with ground-state oxygen or by
ꢀ
reaction with O2 generated through regeneratioþn of
2þ
Ru(bpy)3 via an electron transfer by Ru(bpy)3 to
dissolved air in the solvent (Scheme 3).10
These findings also support the intermediacy of 6 en
route to its corresponding iminium cation, being so far
the only species that could be trapped in a visible light
photo redox process.5 Very recently, compelling evidence
for 6 was given by ESR measurements;11 additionally,
new studies have been reported that prove R-amino
radicals as valuable synthetic intermediates in visible light
photoredox processes.12,13
A representative spread of N-aryltetrahydroisoquino-
lines and acceptor-substituted alkenes was investigated
(Figure 2) in this coupling reaction. In addition to Ru-
(bpy)3Cl2 (1), we also tested [Ir(ppy)2(dtb-bpy)]PF6 (2) as
photoredoxcatalyst, which proved to be superior in some
but not all cases. Using 2ꢀ5 mol % catalyst and irradia-
tion at 455 nm (blue LED), aldehydes and ketones gave
the expected conjugate addition products with moderate
to excellent yields (43ꢀ93%), while exo-methylene-γ-
butyrolactone and acrylonitrile, most likely due to com-
peting polymerization reactions, were less effective sub-
strates (31ꢀ33% yield). N-Phenylpyrrolidine gave the
(8) For pioneering work demonstrating the R-functionalization of
tertiary amines under UV light irradiation, see: (a) Bertrand, S.; Glapski,
C.; Hoffmann, N.; Pete, J.-P. Tetrahedron Lett. 1999, 40, 3169. (b)
Bertrand, S.; Hoffmann, N.; Pete, J.-P. Eur. J. Org. Chem. 2000, 2227. (c)
Harakat, D.; Pesch, J.; Marinkovic, S.; Hoffmann, N Org. Biomol.
Chem. 2006, 4, 1202. For the visible light generation and trapping of
R-glucosyl radicals, see: (d) Andrews, R. S.; Becker, J. J.; Gagne, M. R.
Angew. Chem., Int. Ed. 2010, 49, 7274. (e) Andrews, R. S.; Becker, J. J.;
Gagne, M. R. Org. Lett. 2011, 13, 2406.
(9) Li, Z. P.; Bohle, D. S.; Li, C. J. Proc. Nat. Acad. Sci. U.S.A. 2006,
103, 8928.
(10) Anderson, C. P.; Salmon, D. J.; Meyer, T. J.; Young, R. C.
J. Am. Chem. Soc. 1977, 99, 1980.
Figure 2. Photoredox-catalyzed coupling of N-arylamines (3)
and Michael acceptors 4.
674
Org. Lett., Vol. 14, No. 3, 2012

ketone, the latter being a weaker acceptor14 than the
former, resulted in an increase of yield when iridium
catalyst 2 was used, resulting in almost quantitative
product formation of 5f (93%).
Scheme 4. Synthesis of 5,6-Dihydroindolo[2,1-a]-
tetrahydroisoquinolines 13
When applicable, the products were formed as diaster-
eomeric mixtures: For 5dꢀi, the relative configuration of the
major diastereomer can be tentatively assigned on the basis
of the X-ray-structure of (R*,S*)-5d, which was obtained
diastereomerically pure by recrystallization (Figure 3).
intermolecular process apparently proceeds more effi-
ciently than the intramolecular variant.
In conclusion, we have developed a new visible light
driven photocatalytic CꢀC-coupling between N-aryl-tet-
rahydroisoquinolines and Michael acceptors, suggesting
R-amino radicals as key intermediates.
Figure 3. X-ray structure of (R*,S*)-5d.
Investigating the photocatalyzed coupling of 12, being
readily available from 10 and acetone (11a) or acetophe-
none (11b), respectively, as an example for substrates
poised for undergoing intramolecular couplings, fol-
lowed a different reaction pathway: We observed in
addition to the expeceted cyclization also dehydrogena-
tion, leading directly to the 5,6-dihydroindolo[2,1-a]-
tetrahydroisoquinoline 13 (Scheme 4), a class of com-
pounds that have been found to exhibit significant im-
munosuppresive activity against IL-2, IL-10, and IFN-γ.15
However, the yields in which 13 is obtained are clearly
not satisfactory, and it is surprising to note that the
Acknowledgment. This work was supported by the DFG
(Graduiertenkolleg 1626 Photocatalysis), Bayerische Gradu-
€
ietenforderung (fellowship PK) and the DAAD (Indigo). We
are grateful to Dr. M. Zabel and S. Stempfhuber for carrying
out X-ray structure analyses.
Supporting Information Available. Experimental pro-
cedures, characterization, 1H and 13C NMR spectra, and
details on X-ray structures. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) While this work was under review, the visible light mediated
reaction of 3a catalyzed by eosine was reported. By ESR-spectroscopy 6
could be characterized, which further broke down to its corresponding
iminium cation being trapped by nitroalkanes: Liu, Q.; Li, Y-N; Zhang,
H-H; Chen, B.; Tung, C-H; Wu, L-Z Chem.;Eur. J. 2012, 18, 620.
(12) While this work was under review, the visible light mediated
trapment of R-amino radicals and 1,4-dicyanobenzene catalyzed by
Ir(III) complexes was reported: McNally, A.; Proer, C. K.; MacMillan,
D. W. C. Science 2011, 334, 1114.
(13) While this work was under review, the oxidation of 6 by BrCCl3
as an efficent way to generate its corresponding iminium cation followed
by trapping with nucelophiles was reported: Freemen, D. B.; Furst, L.;
Condie, A. G.; Stephenson, C. R. J. Org. Lett. 2012, 14, 94.
(14) Cf. de Vleeschouwer, F.; van Speybroeck, V.; Waroquier, M.;
Gerrlings, P.; de Proft, F. Org. Lett. 2007, 9, 2721.
(15) Kraus, G. A.; Gupta, V.; Kohut, M.; Singh, N. Biorg. Med.
Chem. Lett. 2009, 19, 5539.
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