N719 dye-sensitized organophotocatalysis: Enantioselective tandem michael addition/oxyamination of aldehydes

Article abstract of DOI:10.1021/ol3011858

A remarkably efficient photosensitizer, N719 dye, was used in asymmetric tandem Michael addition/oxyamination of aldehydes, rendering α,β-substituted aldehydes in good yields with excellent levels of enantioselectivity and diastereoselectivity. This is the first report of a multiorganocatalytic reaction involving iminium catalysis and photoinduced singly occupied molecular orbital (SOMO) catalysis. This reaction is expected to expand the scope of tandem organocatalytic reactions.

Full text of DOI:10.1021/ol3011858

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3272–3275
N719 Dye-Sensitized Organophotocatalysis:
Enantioselective Tandem Michael
Addition/Oxyamination of Aldehydes
Hyo-Sang Yoon, Xuan-Huong Ho, Jiyeon Jang, Hwa-Jung Lee, Seung-Joo Kim, and
Hye-Young Jang*
Energy Systems Research, Ajou University, Suwon, 443-749, South Korea
hyjang2@ajou.ac.kr
Received May 1, 2012
ABSTRACT
A remarkably efficient photosensitizer, N719 dye, was used in asymmetric tandem Michael addition/oxyamination of aldehydes, rendering
R,β-substituted aldehydes in good yields with excellent levels of enantioselectivity and diastereoselectivity. This is the first report of a
multiorganocatalytic reaction involving iminium catalysis and photoinduced singly occupied molecular orbital (SOMO) catalysis. This reaction is
expected to expand the scope of tandem organocatalytic reactions.
Rapid and significant advances in organocatalysis have
provided relatively simple, efficient, and environmentally
benign methods of forming highly complex organic mole-
cules with excellent stereoselectivity, resulting in numerous
applications of organocatalytic reactions to natural prod-
uct synthesis and in the pharmaceutical industries.1 In
recent years, organophotocatalytic reactions combining
enamine-mediated organocatalysis and a photoredox re-
action have been reported to broaden the scope of con-
ventional enamine-mediated organocatalytic reactions.2À4
In the presence of photoredox complexes (Ru and Ir
complexes, TiO2, and organic dyes), intermediates gener-
ated in the enamine-mediated organocatalytic reaction
€
(1) For recent organocatalysis reviews, see: (a) Berkessel, A.; Groger,
H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim: 2005. (b) Lelais,
G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. (c) Marigo,
M.; Jørgensen, K. A. Chem. Commun. 2006, 2001–2011. (d) Marion, N.;
(3) For review articles on photoredox organocatalysis, see: (a)
Renaud, P.; Leong, P. Science 2008, 322, 55–56. (b) Melchiorre, P.
Angew. Chem., Int. Ed. 2009, 48, 1360–1363. (c) Zeitler, K. Angew.
ꢀ
Gonzalez, D.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000.
€
ꢀ
(e) List, B. Chem. Rev. 2007, 107, 5413–5415. (f) Erkkila, A.; Majander,
Chem., Int. Ed. 2009, 48, 9785–9789. (d) Teply, F. Collect. Czech. Chem.
I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. (g) Mukherjee, S.;
Yang, J. W.; Hoffmannm, S.; List, B. Chem. Rev. 2007, 107, 5471–5569.
(h) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656–5682. (i)
Ye, L.-W.; Zhou, I.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140–1152. (j)
Commun. 2011, 76, 859–917. (e) Narayanam, J. M. R.; Stephenson,
C. R. J. Chem. Soc. Rev. 2011, 40, 102–113. (f) Ravelli, D.; Fagnoni, M.
ChemCatChem 2012, 4, 169–171.
(4) For selected articles regarding enamine catalysis under photo-
oxidation conditions, see: (a) Nicewicz, D. A.; MacMillan, D. W. C.
Science 2008, 322, 77–80. (b) Nagib, D. A.; Scott, M. E.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2009, 131, 10875–10877. (c) Koike, T.;
ꢀ
Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev. 2009, 38, 632–653.
(2) For selected articles on photoredox organic reactions, see: (a)
Ischay, M. A.; Anzovino, M. E.; Yoon, T. P. J. Am. Chem. Soc. 2008,
130, 12886–12887. (b) Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131,
€
Akita, M. Chem. Lett. 2009, 38, 166–167. (d) Neumann, M.; Fuldner, S.;
ꢀ
ꢀ
€
14604–14605. (c) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2010, 132, 1464–1465. (d) Tucker, J. W.;
Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C. R. J. Org. Lett.
Konig, B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50, 951–954. (e) Ho,
X.-H.; Kang, M.-J.; Kim, S.-J.; Park, E. D.; Jang, H.-Y. Catal. Sci.
Technol. 2011, 1, 923–926. (f) Rueping, M.; Vila, C.; Koenigs, R. M.;
Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47, 2360–2362. (g)
€
2010, 12, 368–371. (e) Prasad, D.; Konig, B. Org. Lett. 2011, 13, 3852–
€
Cherevatskaya, M.; Neumann, M.; Fuldner, S.; Harlander, C.;
3855. (f) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, M.-J.; Rong, J.; Chen., J.-
R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171–7175. (g)
Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47,
8679–8681. (h) Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun.
2011, 47, 9615–9617.
€
€
Kummel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.; Konig, B. Angew.
Chem., Int. Ed. 2012, 51, 4062–4066. (h) Rueping, M.; Zoller, J.; Fabry,
D. C.; Poscharny, K.; Koenigs, R. M.; Weirich, T. E.; Mayer, J. Chem.;
Eur. J. 2012, 18, 3478–3481.
r
10.1021/ol3011858
Published on Web 06/08/2012
2012 American Chemical Society

undergo single-electron oxidation/reduction, which in-
ducesradical processesfornovel chemicalbondformation.
Compared to previously reported enamine radical pro-
cesses involving a large excess of chemical oxidants,5 photo-
redox-catalyzed reactions require relatively small catalytic
loadings of photoredox compounds (5À0.5 mol %) under
light irradiation. Although enamine reactions with photo-
redox materials have shown advantages over chemical-
oxidant-mediated reactions, there are issues to be addressed
with regard to current organophotocatalytic reactions.
First, the loadings of expensive photoredox materials need
to be reduced by increasing the photocatalytic activity.
Second, enamine-mediated organophotocatalytic reactions
are confined to single-step reactions such as R-alkylation
of carbonyl compounds via photoredox cleavage of CÀX
(X = Br and I) and R-oxyamination of carbonyl com-
pounds in the presence of TEMPO radicals.4 Photoinduced
multiorganocatalytic one-pot reactions for installing several
stereogenic centers have not yet been reported.
With the aim of developing green organocatalytic pro-
cesses, our research group has tried to establish environ-
mentally friendly oxidation protocols in enamine-mediated
organocatalytic reactions; we have reported R-oxyamina-
tion of aldehydes under galvanostatic conditions and TiO2-
photocatalytic conditions and R-alkylation of aldehydes
under galvanostatic conditions.4e,6 In our research on the
development of green organocatalytic reactions, we have
found that TiO2-bound N719-catalyzed organophotoreac-
tions induce highly enantio- and diastereoselective tandem
iminium/SOMO (singly occupied molecular orbital) reac-
tions to afford R,β-substituted aldehydes under cost-
effective, nontoxic, and visible light-induced photocatalytic
conditions. Ru(II) complexes (e.g., N719) attached to
TiO2 supports have been used in dye-sensitized solar cell
(DSSC) devices and in water photolysis7 but have not been
used in asymmetric organic reactions.4h,8,9 In addition to the
first use of a DSSC dye in an asymmetric organocatalytic
reaction, a new type of tandem organocatalytic reaction (an
iminium/SOMO combination) is achieved in this work.
Although numerous combinations of iminium, enamine,
Brønstedacid,Brønstedbase, carbene, and transition-metal
catalysts have been reported for use in multiple catalytic
reactions, there has been no example of a tandem iminium
catalysis/photoinduced SOMO process.10 The optimiza-
tion results are listed in Table 1. To obtain a tandem
iminium-SOMO reaction, Michael additions of malonates
to R,β-unsaturated aldehydes followed by R-oxyamination
of the resulting β-substituted aldehydes in one pot were
attempted under visible light. A mixture of 1a (0.25 mmol),
diethyl malonate (0.75 mmol), and TEMPO (0.5 mmol) in
CH3CN (0.4 M) was subjected to organophotocatalytic
conditions using (S)-2-[diphenyl(trimethylsilyloxy)methyl]-
pyrrolidine (20 mol %) and N719/TiO2 (25 mg) under
visible light from 8 W cool white fluorescent tubes. The
loading of N719 on TiO2 (25 mg) was determined by UV
spectroscopy and was 0.04 mol % of the Ru(II) complex
with respect to 1a.11 Since the addition of acid additives
promotes iminium ion formation from 1a and a chiral amine
catalyst,12 10 mol % of benzoic acid was added, providing
the desired product 1b in 46% yield with a diastereomeric
excess (de) higher than 95% and an enantiomeric excess (ee)
of 96% (entry 1). The enantiomerically enriched 1b can be
converted to biologically active chiral lactones or chiral
lactams after chemical modifications, including cyclization,
for further applications.12e The relative stereochemistry was
confirmed by NMR analysis of the lactone compound
derived from 1b.13 By increasing the amount of benzoic acid
to 30 mol %, the yield of 1b was increased to 70%, while
maintaining a similar stereoselectivity (entry 2). Next, acetic
acid, 2-bromobenzoic acid, p-toluene sulfonic acid (TsOH),
adamantane carboxylic acid, perchloric acid, and NaOAc
base additives were tested (entries 3À8). Among the acid and
base additives, adamantane carboxylic acid gave the highest
(5) (a) Beeson, T. D.; Mastrachhio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582–585. (b) Jang, H.-Y.; Hong,
J.-B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004–7005. (c)
Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 395–405. (d)
Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398–399. (e)
Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 11332–11334. (f) Amatore, M.; Beeson, T. D.; Brown, S. P.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121–5124. (g)
Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2010, 132, 10012–10014. (h) Akagawa, K.;
Fujiwara, T.; Sakamoto, S.; Kudo, K. Org. Lett. 2010, 12, 1804–1807. (i)
Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Chem. Commun.
2010, 46, 8040–8042. (j) Kano, T.; Mii, H.; Maruoka, K. Angew. Chem.,
Int. Ed. 2010, 49, 6638–6641. (k) Van Humbeck, J. F.; Simonovich, S. P.;
Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
10012–10014. (l) Beel, R.; Kobialka, S.; Schmidt, M. L.; Engeser, M.
Chem. Commun. 2011, 47, 3293–3295. (m) Simonovich, S. P.; Van
Humbeck, J. F.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 58–61.
(6) (a) Bui, N.-N.; Ho, X.-H.; Mho, S.-i.; Jang, H.-Y. Eur. J. Org.
Chem. 2009, 5309–5312. (b) Ho, X.-H.; Mho, S.-i.; Kang, H.; Jang,
H.-Y. Eur. J. Org. Chem. 2010, 4436–4441.
(9) Mitkina, T.; Stanglmair, C.; Setzer, W.; Gruber, M.; Kisch, H.;
€
Konig, B. Org. Biomol. Chem. 2012, 10, 3556–3561.
(10) For review articles of tandem organocatalytic reaction, see: (a)
Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745–2755. (b) Zhou, J.
Chem.;Asian. J. 2010, 5, 422–434. (c) Zhong, C.; Shi, X. Eur. J. Org.
Chem. 2010, 2999–3025.
(11) The experimental details for the determination of the amount of
Ru(II) species are provided in the Supporting Information.
(12) For selected articles regarding malonate addition to R,β-unsa-
turated carbonyl compounds via iminium catalysis, see: (a) Yamaguchi,
M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int. Ed. 1993, 32, 1176–
1178. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520–3530. (c) Holland, N.; Aburel, P. S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 661–665. (d) Knudsen, K. R.; Mitchell, C. E. T.;
Ley, S. V. Chem. Commun. 2006, 66–68. (e) Brandau, S.; Landa, A.;
ꢀ
Franzen, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006,
(7) For review articles regarding DSSC dyes and their applications,
€
blood, W. J.; Lee, W.-H. A.; Meada, K.; Mallouk, R. E. Acc. Chem. Res.
2009, 42, 1966–1973. (c) Hagfeldt, A.; Boschloo, G.; Sun, L.; Kloo, L.;
Pettersson, H. Chem. Rev. 2010, 110, 6595–6663.
(8) For visible light-induced dye-sensitized TiO2 photocatalytic oxi-
dation, see: (a) Zhang, M.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem.,
Int. Ed. 2008, 47, 9730–9733. (b) Jeena, V.; Robinson, R. S. Chem.
Commun. 2012, 48, 299–301. (c) 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, 784–788.
45, 4305–4309. (f) Wang, Y.; Pengfei, L.; Liang, X.; Ye, J. Adv. Synth.
Catal. 2008, 350, 1383–1389. (g) Maltsev, O. V.; Kucherenko, A. S.;
see: (a) Gratzel, M. Acc. Chem. Res. 2009, 42, 1788–1798. (b) Young-
ꢀ
Zlotin, S. G. Eur. J. Org. Chem. 2009, 5134–5137. (h) Companyo, X.;
ꢀ
Hejnova, M.; Kamlar, M.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron
Lett. 2009, 50, 5021–5024. (i) Fleischer, I.; Pfaltz, A. Chem.;Eur. J.
2010, 16, 95–99. (j) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2,
42–53.
(13) The trans relationship between C2 and C3 was reported in ref
10e. By measuring the coupling constants of protons at C3 and C4, the
relationship between C3 and C4 was determined. Detailed information
and NMR spectra are provided in the Supporting Information.
Org. Lett., Vol. 14, No. 13, 2012
3273

yield (80%) and stereoselectivity (99% ee and >95% de)
(entry 6). N719/TiO2 was recycled and gave 1b in 63% (first
recycling) and 37% (second recycling) yields using the condi-
tions of entry 6. In the absence of light, the addition of diethyl
malonate to 1a occurs without formation of 1b (entry 9).
combination is responsible for the low yield of 1c, because
the yield of 1c is higher without photocatalysts. Then, 1c
was converted to 1b in 91% yield with greater than 95% de
and 97% ee. On the basis of these experiments, the
enantioselectivity of the β-position was clearly determined
at the first step (iminium catalysis). In the case of the
R-position, cooperative enantiocontrol by the chiral cata-
lyst and the chiral substrate 1c directs remarkably high
stereoselectivity during the second photoinduced SOMO
catalysis.14
Table 1. Optimization of Tandem Michael Addition/Oxyami-
nation of 1a
Scheme 2. Stepwise Reactions under Organophotoreaction
Conditions
a Experiment performed in the dark; the 1,4-addition product was
observed without forming 1b.
After optimization of the reaction using N719/TiO2 photo-
catalysts, N719-catalyzed reactions were carried out in the
absence of TiO2 (Scheme 1). With 0.05 mol % N719, 1b was
formed in 62% yield. The reaction with only TiO2 gave 1b in
11% yield. TiO2 may therefore function as a cooperative
second photocatalyst.4h Ru(bpy)3Cl2 (0.05 mol %) was used
in a reaction; no product was obtained. With an increased
amount of Ru(bpy)3Cl2 (0.5 mol %), 1b was isolated in 32%
yield. A catalyst loading of 0.05 mol % was too low to give the
desired photoredox product. The excellent catalytic activity of
N719/TiO2 may stem from both the ligand effect of the Ru
complex and combining N719 with the TiO2 photocatalyst.
Accordingly, N719 on TiO2 was chosen for the rest of the
experiments.
Using the optimized conditions listed in Table 1, a series
of R,β-unsaturated aldehydes were tested with dimethyl
malonate and diethyl malonate (Table 2). The reaction of
dimethyl malonate, TEMPO, and 1a afforded product 2b
in 30% yield with >95% de and 90% ee (entry 2).
Compared with diethyl malonate, the addition of dimethyl
malonate gave a reduced yield and selectivity. Next, a
range of aromatic R,β-unsaturated aldehydes were
checked. Aldehydes possessing electron-rich groups were
transformed to the desired products in good yields with
excellent stereoselectivities (entries 3À5). Nitro-substi-
tuted cinnamaldehyde 6a participated in the reaction to
provide 6b in a slightly lower yield of 53% with 99% ee and
>95% de (entry 6). The halogen-substituted aldehydes 7a
and 8a were smoothly converted to 7b and 8b in 67% and
62% yields (98% ee and 99% ee), respectively. Heteroaro-
matic aldehyde 9a also coupled with diethyl malonate
and TEMPO, giving a good yield (69%) with a selectivity
of >95% de and 98% ee (entry 9).
Scheme 1. Tandem Iminium/SOMO Reaction with Assorted
Photocatalysts
A proposed catalytic cycle for the tandem Michael
addition/oxyamination is shown in Scheme 3. As proposed
in the iminium catalysis mechanism of β-addition
of malonates to R,β-unsaturated aldehydes,12 imi-
nium intermediate I is generated from the secondary
amine catalyst and 1a and reacts with malonates to pro-
vide enamine intermediate II. At this stage, intermediate
II undergoes either hydrolysis to form β-substituted
After optimization of the reaction conditions, stepwise
reactions were conducted (Scheme 2). Compound 1a was
exposed to iminium catalysis conditions to afford 1c in
34% yield with 97% ee. The photocatalyst and visible light
(14) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2005, 127, 15051–15053.
3274
Org. Lett., Vol. 14, No. 13, 2012

Scheme 3. Mechanism for Tandem Michael Addition/Oxyami-
nation
Table 2. Examples of Tandem Michael Addition/Oxyamination
is assumed to be oxidized by oxygen in the air or TEMPO in
the solution.4f,6a Subsequent addition of TEMPO to III and
hydrolysis afford the desired product 1b. The organocatalyst
is regenerated during the catalytic reaction, and the photo-
catalyst is also re-excited by visible light irradiation.
In conclusion, we have presented a highly efficient
multicatalytic system for tandem Michael addition/oxya-
mination of aldehydes under organophotocatalytic condi-
tions. By using a chiral amine organocatalyst along with
N719/TiO2 under visible light, asymmetric iminium cata-
lysis was combined with photoinduced SOMO catalysis.
This methodology offers cost-effective, environmentally
benign, and step-economic reaction conditions for produ-
cing a variety of R,β-substituted aldehydes in good yields
with excellent levels of enantio- and diastereoselectivities.
Acknowledgment. This study was supported by the
Korea Research Foundation (Nos. 2011-0030745 and
2011-0005996).
Supporting Information Available. Detailed experimen-
tal procedures and characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) During the anodic scan, the enamine derived from pyrrolidine
and hydrocinnamaldehyde gave an oxidation peak at 0.72 V, and the
oxidation peak of TEMPO was observed at 1.03 V (vs a silver wire
pseudoreference electrode, in CH2Cl2, TBAClO4 electrolyte).
aldehydes or photo-oxidation by the photoexcited Ru(II) dye
to form enamine radical III.4c,e,6a,15,16 The resulting Ru(I) dye
(15) Liu, H.; Feng, W.; Kee, C. W.; Zhao, Y.; Leow, D.; Pan, Y.; Tan,
C.-H. Green Chem. 2010, 12, 953–956.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3275