Eosin y catalyzed visible light oxidative C-C and C-P bond formation

Article abstract of DOI:10.1021/ol201376v

Eosin Y catalyzes efficiently the visible light mediated coupling of sp³ C-H bonds adjacent to the nitrogen atom in tetrahydroisoquinoline derivatives in the absence of an external oxidant. Nitroalkanes, dialkyl malonates, malononitrile, and di

Full text of DOI:10.1021/ol201376v

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3852–3855
Eosin Y Catalyzed Visible Light Oxidative
CꢀC and CꢀP bond Formation
€
Durga Prasad Hari and Burkhard Konig*
€
€
Institut fu€r Organische Chemie, Universitat Regensburg, Universitatsstrasse 31,
D-93053 Regensburg, Germany
Burkhard.Koenig@chemie.uni-regensburg.de
Received May 22, 2011
ABSTRACT
Eosin Y catalyzes efficiently the visible light mediated coupling of sp3 CꢀH bonds adjacent to the nitrogen atom in tetrahydroisoquinoline
derivatives in the absence of an external oxidant. Nitroalkanes, dialkyl malonates, malononitrile, and dialkyl phophonates were used as
pronucleophiles in this metal-free, visible light oxidative coupling reaction.
Sunlight is an abundant, renewable, and clean energy
resource for chemistry.1 Visible light accounts for the
major part of the incoming solar radiation, and therefore
visible light should be used to drive chemical transforma-
tions. However, most organic molecules do not absorb
light in the visible region of light. This restricts the appli-
cation of photochemical reactions and, thus, motivates
the development of efficient visible light photocatalysts
for chemical transformations in organic synthesis.2 Such
photoredox catalysts absorb visible light and utilize
the collected energy for electron transfer to or from
organic molecules to initiate chemical reactions.
catalysts in dehalogenation,2d,3 reduction,4 oxidation,5 and
asymmetric alkylation reactions.6 Yoon and co-workers
have used the same ruthenium complex as a photocatalyst
in inter- and intramolecular [2 þ 2] enone cycloadditions.2b,7
Currently, Stephenson used these catalysts for an oxidative
coupling reaction of nitroalkanes with N-arylamines in
visible light.8 However, the iridium and ruthenium catalysts
are expensive and toxic. The use of organic dyes, which are
environmentally friendly, inexpensive, and easy to handle as
photoredox catalysts, would be a superior alternative to
inorganic transition metal photocatalysts.
(4) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.;
Von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85–277.
(5) Kalyanasundaram, K. Coord. Chem. Soc. 1982, 46, 159–244.
(6) (a) Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360–1363.
(b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 10875–10877. (c) Narayanam, J. M. R.; Stephenson, C. R.
Chem. Soc. Rev. 2011, 40, 102–113. (d) Shih, H. W.; Vander Wal, M. N.;
Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
13600–13603.
(7) (a) Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 14604–14605.
(b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527–532.
(c) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–
8574.
In the past decade tris(bipyridine) ruthenium and iri-
dium complexes have been used as visible light photoredox
(1) Ciamician, G. Science 1912, 36, 385–394.
(2) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77–
80. (b) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem.
Soc. 2008, 131, 12886–12887. (c) Zeitler, K. Angew. Chem., Int. Ed. 2009,
48, 9785–9789. (d) Narayanam, J. M. R.; Tucker, J. W.; Stephenson,
C. R. J. Am. Chem. Soc. 2009, 131, 8756–8757. (e) Furst, L.; Matsuura,
B. S.; Narayanan, J. M. R.; Tucker, J. W.; Stephenson, C. R. Org. Lett.
€
€
2010, 10, 3104–3107. (f) Neumann, M.; Fuldner, S.; Konig, B.; Zeitler,
K. Angew. Chem., Int. Ed. 2011, 50, 951–954.
(3) Maji, T.; Karmakar, A.; Reiser, O. J. Org. Chem. 2011, 76, 736–
739.
(8) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J. Am.
Chem. Soc. 2010, 132, 1464–1465.
r
10.1021/ol201376v
Published on Web 07/11/2011
2011 American Chemical Society

air in visible light. We focused our initial studies on the
oxidative coupling reaction of 1 with nitromethane using
the reaction conditions reported by Stephenson and co-
workers,8 but replacing the tris(bipyridine) ruthenium
complex as the visible light photoredox catalyst by the
organic dye eosin Y (2 mol %). The desired product 3 was
obtained in 80% isolated yield after 8 h of irradiation with
green LED light (Table 1, entry 2). Under these condi-
tions (2 mol % of 2, 530 nm) we also examined other
pronucleophiles, such as dialkyl malonates, malononi-
trile, and dialkyl phosphonates at room temperature
(Table 1, entries 4, 5, 6, and 7). In all cases, we obtained
the desired products in good yields and found that for
efficient conversion both light and catalyst are required
(Table 1, entries 8 and 9).
Table 1. Oxidative Trapping of Iminium Ion with Different
Pronucleophiles
entry
1
conditionsa
yieldb (%)
74
2 (1 mol %), CH3NO2, 12 h;
X = CH2NO2
2
3
4
5
6
7
8
9
2 (2 mol %), CH3NO2, 8 h;
X = CH2NO2
80
80
92c
88c
62
86
78
0
2 (5 mol %), CH3NO2, 8 h;
X = CH2NO2
2 (2 mol %), C7H12O4, 10 h;
X = C7H11O4
Table 2. Oxidative Coupling Reaction of Tetrahydroisoquino-
lines with Nitroalkanesa,c,d
2 (2 mol %), C5H8O4, 10 h;
X = C5H7O4
2 (2 mol %), DMF, 10 h;
X = CN
2 (2 mol %), DMF, 3 h;
X = C4H10O3P
No catalyst, CH3NO2, 180 h;
X = CH2NO2
2 (2 mol %), no light, CH3NO2, 72 h;
X = CH2NO2
entry
R1
Ar
R2 product time (h) yieldb (%)
1
2
3
4
5
6
H
Ph
H
6a
6b
6c
8
10
10
8
80
76
78
74
75
66
a With the exception of entries 6 and 7, in all cases nucleophiles were
used as solvents. b Isolated yields after purification by chromatography.
c Isolated yields after removal of the excess solvent by distillation.
H
H
4-BrC6H4
H
4-MeOC6H4
H
OMe Ph
H
6d
6ec
6fd
H
H
Ph
Ph
Me
Et
12
14
Direct formation of CꢀC and CꢀP bonds by CꢀH
activation is a challenging research area in organic synth-
esis. In the past years many elegant methodologies were
developed,9 but those required transition metal catalysts
and harsh conditions. We reported here the metal-free
visible light photoredox catalysis for CꢀC and CꢀP bond
formation using the organic dye eosin Y to initiate a single
electron transfer process without exclusion of moisture or
a The reaction was performed with 4 (0.25 mmol) and eosin Y
(0.02 equiv) in 1.0 mL of 5. b Isolated yield after purification on SiO2. c
dr = 2:1. d dr = 1.4:1.
Various N-aryl tetrahydroisoquinoline derivatives
were reacted with nitromethane, nitroethane, or 1-nitro-
propane and gave the desired coupling products in good
yields (66ꢀ80%; Table 2). Nitromethane always gave
better results than other nitroalkanes (6a vs 6e and 6f),
and the reaction was insensitive to electronic effects on
the aromatic rings (6a, 6b, and 6c). In the case of
nonactivated amine (Scheme 1), a low yield was obtained
after 96 h of irradiation.
(9) For CꢀC bond reactions, see: (a) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215–1292. (b) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780–1824. (c) Fagnoni, M.; Dondi, D.; Ravelli,
D.; Albini, A. Chem. Rev. 2007, 107, 2725–2756. (d) Hoffmann, N. Pure.
Appl. Chem. 2007, 79, 1949–1958. (e) Klussmann, M.; Sureshkumar, D.
Synthesis 2011, 3, 353–369. (f) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–
344. (g) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006,
17, 590–597. (h) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672–3673.
(i) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 6505–6507.
(j) So, M.-H.; Liu, Y.; Ho, C.-M.; Che, C.-M. Chem.;Asian J. 2009, 4,
1551–1561. (k) Griesbeck, A. G.; Hoffmann, N.; Warzecha, K.-D Acc.
Chem. Res. 2007, 40, 128–140. (l) Hoffmann, N. Chem. Rev. 2008, 108,
1052–1103. (m) Griesbeck, A. G.; Abe, M.; Bondock, S. Acc. Chem.
Scheme 1. Reaction of 1-Phenylpyrrolidine with Nitromethane
€
Res. 2004, 37, 919–928. (n) Zeug, N.; Bucheler, J.; Kisch, H. J. Am.
Chem. Soc. 1985, 107, 1459–1464. (o) For more reactions, see:
Albini, A.; Fragnoni, M. Handbook of Synthetic Photochemistry;
Wiley-VCH: Weinheim, 2010. (p) Mattay, J. Top. Curr. Chem. 156
(Photoinduced Electron Transfer I), 1990. (q) Mattay, J. Top. Curr.
Chem. 168 (Photoinduced Electron Transfer V), 1993. For CꢀP bond
reactions, see: (r) Stradiotto, M.; Fujdala, K. L.; Tilley, T. D. Helv. Chem.
Acta 2001, 84, 2958–2970. (s) Basle, O.; Li, C.-J. Chem. Commun.
2009, 4124–4126. (t) Bidan, G.; Genies, M. Tetrahedron 1981, 37,
2297–2301. (u) Bidan, G.; Genies, M.; Renaud, R. Electrochim. Acta
1981, 26, 275–282. (v) Han, W.; Ofial, A. R. Chem. Commun. 2009,
6023–6025. (w) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun.
2011 (DOI: 10.1039/c1cc12907d).
Dialkyl malonates gave β-diester amines in excellent
yields from the reaction with tetrahydroisoquinoline
derivatives using 2 mol % of eosin Y as the photocatalyst
Org. Lett., Vol. 13, No. 15, 2011
3853

and green light irradiation at 530 nm at room tempera-
ture. Excellent product yields (86ꢀ92%; Table 3) were
obtained when dialkyl malonates were used as solvents.
After the reaction excess dialkyl malonates were distilled
off using Kugelrohr distillation10 yielding the analytically
pure reaction products. These results compare favorably
with literature reported results by Li and co-workers11
and Liang et al.12
Table 4. Oxidative Synthesis of R-Amino Nitrilesa
time
yieldb
(%)
entry
Ar
product
(h)
Table 3. Oxidative Coupling Reaction of Tetrahydroisoquino-
lines with Dialkyl Malonatesa
1
2
3
4
Ph
10a
10b
10c
10d
10
12
10
10
62
56
60
58
4-BrC6H4
4-MeOC6H4
2-MeOC6H4
a The reaction was run with 4 (0.25 mmol), malononitrile (1.5 equiv),
and eosin Y (0.02 equiv) in 1.0 mL DMF. b Isolated yield after purifica-
tion on SiO2.
time
(h)
yieldb
(%)
were reacted with dialkyl phosphonates, and representa-
tive results are listed in Table 5. The desired products were
obtained in good to excellent yields.
entry
Ar
R
product
1
2
3
4
5
6
Ph
Ph
Et
8a
8b
8c
8d
8e
8f
10
10
12
12
14
14
92
88
91
90
89
86
Me
Et
4-MeOC6H4
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
Me
Et
Table 5. Oxidative Synthesis of R-Amino Phosphonatesa
Me
a The reaction was performed with 4 (0.25 mmol) and eosin Y (0.02
equiv) in 1.0 mL of 7. b Isolated yield after distillation of excess solvent.
In addition to nitroalkanes and dialkyl malonates, the
photocatalytic reaction was applied to malononitrile.
Surprisingly, R-amino nitriles were obtained as the sole
products instead of the expected β-dicyano substituted
derivatives when malononitrile was treated with tetrahy-
droisoquinolines in DMF at room temperature (Table 4).
Amino nitriles are synthetically useful intermediates. The
nitrile functionality can be hydrolyzed to give R-amino
acids or can be converted into R-amino aldehydes or
R-amino alcohols. The photocatalytic reaction is an
alternative synthetic route to R-amino nitriles avoiding
toxic cyanides and expensive metals.12,13
The success of CꢀC bond formation by using eosin Y
encouraged us to investigate CꢀP bond reactions. A
variety of methods have been described for the synthesis
of R-amino phosphonates,9rꢀw but those typically require
metal catalysts and expensive reagents. To avoid these
catalysts, we applied our methodology for the synthesis of
R-amino phophonates. Various tetrahydoisoquinolines
time
(h)
yieldb
(%)
entry
Ar
R
product
1
2
3
4
5
6
7
8
Ph
Ph
Et
12a
12b
12c
12d
12e
12f
3
4
2
3
3
3
3
3
86
92
82
88
93
91
91
90
Bn
Et
4-BrC6H4
4-BrC6H4
Bn
Et
4-MeOC6H4
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
Bn
Et
12g
12h
Bn
a The reaction was run with 4 (0.25 mmol), dialkyl phosphonate
(4 equiv), and eosin Y (0.02 equiv) in 1.0 mL of DMF. b Isolated yield
after purification on SiO2.
The mechanism of the eosin Y photocatalysis has not
been investigated in detail at this stage. However, on the
basis of our results using nitroalkanes, dialkyl malonates,
and dialkyl phosphonates as pronucleophiles in the
photoreaction and the litreature reports8,14 the following
mechanism can be suggested (Scheme 2). A single electron
transfer from 4 to the excited state of eosin Y gave an
(10) Diethyl malonate and dimethyl malonates were distilled ap-
proximately at 80 °C and 0.5 mm of Hg.
(11) Li, Z.; Scott Bohle, D.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 8928–8933.
(12) (a) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.;
Liang, Y.-M. J. Org. Chem. 2009, 74, 7464–7469. (b) Shu, X.-Z.; Yang,
Y.-F.; Xia, X.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. Org. Biomol.
Chem. 2010, 8, 4077–4079.
(13) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005–11012. (b) Zhang, Y.; Peng, H.; Cheng, Y.;
Zhu, C. Chem. Commun. 2011, 47, 2354–2356.
(14) (a) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.;
Fabry, D. C. Chem. Commun. 2011, 47, 2360–2362. (b) Pandey, G.;
Kumaraswamy, G.; Yella Reddy, P. Tetrahedron 1992, 48, 8295–8308.
(c) Boess, E. B.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fare’s, C.;
Klussmann, M. J. Am. Chem. Soc. 2011dx.doi.org/10.1021/ja201610C.
3854
Org. Lett., Vol. 13, No. 15, 2011

aminyl cation radical 13, which then lost a hydrogen atom
by a radical anion to generate iminium ion 14.15 Subse-
quently, trapping of 14 with pronucleophiles resulted in
the desired product 15. The formation of R-amino nitriles
may result from cyanide ion addition to the iminium ion
14, whereby cyanide ions may be formed by oxidative
cleavage of the malononitrile CꢀCN bond.11,12a,16
transition metal catalysts can be replaced by the redox
active organic dye eosin Y yielding comparable yields.
Using these organic photocatalysts, the scope of the
reaction was extended to dialkyl malonate, malononitrile,
and dialkyl phosphonates as pronucleophiles. Continu-
ing from these results we successfully replaced other
reagents PhI(IOAc)2 (for cyanation) and CuBr-O2 (for
phosphonation). Due to the similar redox properties of
eosin Y and the previously used Ru(bpy)3 complexes we
propose a similar mechanism of the reaction. However,
alternative mechanistic pathways are equally likely and
ongoing investigations must prove the correct mechan-
istic picture.
Scheme 2. Proposed Reaction Mechanism
Acknowledgment. This work was supported by the
GRK 1626 (Chemical Photocatalysis) of German Science
Foundation (DFG).
Supporting Information Available. Experimental pro-
cedures and spectral characterization of all compounds
are available. This material is available free of charge via
the Internet at http://pubs.acs.org
Iridium- and ruthenium-based photocatalysts mediate
the visible light oxidative coupling of tetrahydroisoquino-
line derivatives with nitroalkanes, as recently disclosed by
Stephenson et al. Our experiments have shown that the
(16) (a) CꢀCN bond cleaved by CuII: Marlin, D. S.; Olmstead,
M. M.; Mascharak, P. K. Angew. Chem., Int. Ed. 2001, 40, 4752–4754.
(b) Kharasch, M. S.; Sosnovsky, G. Tetrahedron 1958, 3, 105–112.
(c) Choudary, B. M.; Reddy, P. N. J. Mol. Catal. 1996, 112, 385–388.
(15) We were able to detect hydrogen peroxide as a byproduct of the
reaction using the starch-iodine test (see Supporting Information). This
experimental result supports that the iminium ion is likely to be an
intermediate.
Org. Lett., Vol. 13, No. 15, 2011
3855