Highly efficient oxidation of amines to imines by singlet oxygen and its application in ugi-type reactions

Article abstract of DOI:10.1021/ol9018166

A variety of secondary benzylic amines were oxidized to imines in 90% to >99% yields by singlet oxygen generated from oxygen and a porphyrin photosensitizer. On the basis of these reactions, a protocol was developed for oxidative Ugi-type reactions with singlet oxygen as the oxidant. This protocol has been used to synthesize C1- and N-functionalized benzylic amines in up to 96% yields.

Full text of DOI:10.1021/ol9018166

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4568-4571
Highly Efficient Oxidation of Amines to
Imines by Singlet Oxygen and Its
Application in Ugi-Type Reactions
Gaoxi Jiang,† Jian Chen,† Jie-Sheng Huang,‡ and Chi-Ming Che*,†,‡
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of
Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road,
Shanghai 200032, China, and Department of Chemistry and Open Laboratory of
Chemical Biology of the Institute of Molecular Techology for Drug DiscoVery and
Synthesis, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong, China
cmche@hku.hk
Received August 6, 2009
ABSTRACT
A variety of secondary benzylic amines were oxidized to imines in 90% to >99% yields by singlet oxygen generated from oxygen and a
porphyrin photosensitizer. On the basis of these reactions, a protocol was developed for oxidative Ugi-type reactions with singlet oxygen as
the oxidant. This protocol has been used to synthesize C1- and N-functionalized benzylic amines in up to 96% yields.
Selective oxidation of amines is important in organic
synthesis owing to the immense applications of the oxidation
products such as imines in the synthesis of biologically active
nitrogen containing organic compounds.1 Significant efforts
have been made to develop mild and practical oxidation
reactions for the synthesis of imines from secondary amines;
notable examples include stoichiometric oxidation with
N-tert-butylphenylsulfinimidoyl chloride2 or 2-iodoxybenzoic
acid (IBX),3 metal-catalyzed oxidation with tBuOOH, PhIO,
N-methylmorpholine N-oxide, 2,6-dimethoxybenzoquinone,
or K2S2O8,4 iridium-catalyzed dehydrogenation,5 along with
ruthenium-,6 cobalt-,7 copper-,8 palladium-,9 and gold-
catalyzed10 aerobic oxidation.
Our studies on oxidation of secondary amines to imines
with singlet oxygen (1O2) were prompted by the recent surge
of interest to develop practical aerobic oxidation reactions11
and the well-documented use of singlet oxygen as an
(3) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192.
(4) (a) Murahashi, S.-I.; Naota, T.; Taki, H. J. Chem. Soc., Chem.
Commun. 1985, 613. (b) Mu¨ller, P.; Gilabert, D. M. Tetrahedron 1988, 44,
7171. (c) Porta, F.; Crotti, C.; Cenini, S.; Palmisano, G. J. Mol. Catal. 1989,
50, 333. (d) Yamazaki, S. Chem. Lett. 1992, 823. (e) Goti, A.; Romani, M.
† Shanghai Institute of Organic Chemistry.
‡ The University of Hong Kong.
´
(1) (a) Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443.
(b) Murahashi, S.-I.; Imada, Y. In Transition Metals for Organic Synthesis,
2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
2004; Vol. 2, p. 497.
Tetrahedron Lett. 1994, 35, 6567. (f) Ell, A. H.; Samec, J. S. M.; Brasse,
C.; Ba¨ckvall, J.-E. Chem. Commun. 2002, 1144. (g) Choi, H.; Doyle, M. P.
Chem. Commun. 2007, 745.
(5) (a) Gu, X.-Q.; Chen, W.; Morales-Morales, D.; Jensen, C. M. J.
Mol. Catal. A: Chem. 2002, 189, 119. (b) Yamaguchi, R.; Ikeda, C.;
Takahashi, Y.; Fujita, K.-i. J. Am. Chem. Soc. 2009, 131, 8410.
(2) Mukaiyama, T.; Kawana, A.; Fukuda, Y.; Matsuo, J.-i. Chem. Lett.
2001, 390.
10.1021/ol9018166 CCC: $40.75
Published on Web 09/21/2009
 2009 American Chemical Society

important tool in organic synthesis.12 In literature, singlet
oxygen has been extensively used for organic transformations
including the ene reaction, cycloaddition, and heteroatom
oxidation.12 Reaction of singlet oxygen with amines has
received considerable attention,12f including recent examples
of oxidation of tertiary amines such as PhCH2NMe2 and
ArCH2N(R)CH2Ar′ to aldehydes or N-dealkylation prod-
ucts.13 However, reports on the singlet oxygen oxidation of
secondary amines to imines are sparse; an example is the
dehydrogenation of an N-neopentyl allylic amine by singlet
oxygen with meso-tetraphenylporphyrin (H2TPP) as a pho-
tosensitizer.14
We aim to find a clean oxidation of secondary amines to
imines with singlet oxygen and directly use the in situ formed
imine products for further functionalization. In this regard,
our attention was attracted by the recent work of Zhu and
co-workers on the development of an oxidative Ugi-type
reaction,15 a key step of which is the oxidation of secondary
benzylic amine to imine by IBX, followed by reaction of
the imine with isocyanide and carboxylic acid. Given the
immense applications of Ugi-type multicomponent reactions
in organic synthesis,16 a challenging study of interest is to
perform the oxidative Ugi-type reaction with green oxidants
such as singlet oxygen. Herein we report singlet oxygen
oxidation of a variety of benzylic amines to imines with
practical interest and the development of an oxidative Ugi-
type reaction featuring the oxidation of secondary amines
with singlet oxygen.
dichlorophenyl)porphyrin) under light irradiation using a
300-W tungsten filament lamp. The reaction gave imine
2a in >99% NMR yield within 8 h (Table 1, entry 1).
Table 1. Oxidation of 1a to 2a with Various Photosensitizersa
entry
sensitizer (mol %)
t (h)
yield (%)
>99
trace
trace
no reaction
>99
1
[RuII(TDCPP)(CO)] (1.0)
[RuII(TDCPP)(CO)] (1.0)
[RuII(TDCPP)(CO)] (1.0)
8
8
8
2b
3c
4
8
5
6
7
[RuII(TDCPP)(CO)] (0.01)
H2TPP (0.01)
H2TDCPP (0.01)
methylene blue (0.01)
H2TPP (0.1)
71
71
71
71
14
>99
>99
8
10
9d
98e
a Reaction conditions: 1a (10 mg), CH2Cl2 (1.0 mL), rt; yields were
determined by 1H NMR except for entry 9. b Under N2 instead of O2.
c Without light source. d Reaction conditions: 1a (200 mg), CH2Cl2 (2 mL),
4 Å MS (500 mg). e Yield of isolated product.
Control experiments (Table 1, entries 2-4) revealed that
oxygen, light source, and the sensitizer are all required
for this reaction. Lowering the loading of [RuII(TDCPP)-
(CO)] to 0.01 mol % lengthened the reaction time to 71 h
(Table 1, entry 5); under the same conditions, similar
results were obtained by using H2TPP or H2TDCPP as
the sensitizer (Table 1, entries 6 and 7), but only 10%
yield of 2a was formed when the sensitizer was methylene
blue (Table 1, entry 8). The oxidation of 1a to 2a was
insensitive to solvent, as similar product yields were found
for the reactions conducted in CH2Cl2, CH3CN, CS2, THF,
and ethyl acetate (EA). When the reaction was scaled up
from 10 mg to 200 mg of 1a, a complex mixture of
products was found. Interestingly, in the presence of 4 Å
MS (500 mg), the 200 mg-scale reaction for 14 h with
H2TPP (0.1 mol %) as sensitizer resulted in the isolation
of 2a in 98% yield (Table 1, entry 9) by removal of the
solvent after filtration; the imine product was subsequently
used for Ugi-type reactions without further purification
(see below), and no adverse effect was observed.
Initially, we treated dibenzylamine 1a (10 mg) with
oxygen in the presence of 1.0 mol % of sensitizer
[RuII(TDCPP)(CO)] (H2TDCPP ) meso-tetrakis(2,6-
(6) (a) Bailey, A. J.; James, B. R. Chem. Commun. 1996, 2343. (b)
Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480. (c)
´
Samec, J. S. M.; Ell, A. H.; Ba¨ckvall, J. E. Chem.sEur. J. 2005, 11, 2327.
(d) Murahashi, S.-I.; Okano, Y.; Sato, H.; Nakae, T.; Komiya, N. Synlett
2007, 1675.
(7) Nishinaga, A.; Yamazaki, S.; Matsuura, T. Tetrahedron Lett. 1988,
29, 4115.
(8) (a) Shimizu, M.; Orita, H.; Hayakawa, T.; Suzuki, K.; Takehira, K.
Heterocycles 1995, 41, 773. (b) Minakata, S.; Ohshima, Y.; Takemiya, A.;
Ryu, I.; Komatsu, M.; Ohshiro, Y. Chem. Lett. 1997, 311. (c) Maeda, Y.;
Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76, 2399.
(9) Wang, J.-R.; Fu, Y.; Zhang, B.-B.; Cui, X.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2006, 47, 8293.
(10) (a) Zhu, B.; Angelici, R. J. Chem. Commun. 2007, 2157. (b) Zhu,
B.; Lazar, M.; Trewyn, B. G.; Angelici, R. J. J. Catal. 2008, 260, 1. (c)
Grirrane, A.; Corma, A.; Garcia, H. J. Catal. 2009, 264, 138. (d)
Aschwanden, L.; Panella, B.; Rossbach, P.; Keller, B.; Baiker, A. Chem-
CatChem. 2009, 1, 111, and references cited therein. (e) So, M.-H.; Liu,
Y.; Ho, C.-M.; Che, C.-M. Chem.-Asian J. In press.
With H2TPP (0.1 mol %) as sensitizer and in the
presence of 4 Å MS, secondary amines 1b-l were
oxidized by singlet oxygen to afford imines 2b-l in 90%
to >99% yields (Table 2). These light-induced amine
oxidations by singlet oxygen were remarkably clean, as
the imine products were not contaminated by N-oxide or
nitrone. The oxidation is regioselective, occurring at the
less substituted position for the unsymmetric dibenzy-
lamines 1d,e (Table 2, entries 3 and 4). In the oxidation
(11) For recent reviews, see: (a) Punniyamurthy, T.; Velusamy, S.; Iqbal,
J. Chem. ReV. 2005, 105, 2329. (b) Stahl, S. S. Science 2005, 309, 1824.
(c) Frei, H. Science 2006, 313, 309. (d) Que, L., Jr.; Tolman, W. B. Nature
2008, 455, 333.
(12) For reviews, see: (a) Ohloff, G. Pure Appl. Chem. 1975, 43, 481.
(b) Wasserman, H. H.; Ives, J. L. Tetrahedron 1981, 37, 1825. (c) Prein,
M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996, 35, 477. (d) Wahlen, J.;
De Vos, D. E.; Jacobs, P. A.; Alsters, P. L. AdV. Synth. Catal. 2004, 346,
152. (e) Clennan, E. L.; Pace, A. Tetrahedron 2005, 61, 6665. (f) Iesce,
M. R.; Cermola, F.; Rubino, M. Curr. Org. Chem. 2007, 11, 1053. (g)
Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008,
41, 1001. (h) Hoffmann, N. Chem. ReV. 2008, 108, 1052.
(13) (a) Baciocchi, E.; Giacco, T. D.; Lapi, A. Org. Lett. 2004, 6, 4791.
(b) Baciocchi, E.; Giacco, T. D.; Lapi, A. Org. Lett. 2006, 8, 1783. (c)
Baciocchi, E.; Giacco, T. D.; Lanzalunga, O.; Lapi, A. J. Org. Chem. 2007,
72, 9582.
(16) For reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3169. (b) Do¨mling, A. Curr. Opin. Chem. Biol. 2000, 4, 318. (c)
Ugi, I. Pure Appl. Chem. 2001, 73, 187. (d) Tempest, P. A. Curr. Opin.
Drug DiscoVery DeV. 2005, 8, 776. (e) Akritopoulou-Zanze, I. Curr. Opin.
Chem. Biol. 2008, 12, 324.
(14) Matsumoto, M.; Kitano, Y.; Kobayashi, H.; Ikawa, H. Tetrahedron
Lett. 1996, 37, 8191.
(15) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775.
Org. Lett., Vol. 11, No. 20, 2009
4569

Table 2. Oxidation of 1b-l to 2b-l with Singlet Oxygena
Table 3. Oxidation of Unsymmetric Dibenzylamines 1m,n with
Singlet Oxygena
product ratiob
entry
R
substrate
A
B
C
D
yield (%)c
1
Br
Br
OMe
OMe
1m
1m
1n
1.0 2.0 1.7 1.0
1.0 0.8 1.7 1.2
1.0 1.1 0.7 0.9
1.0 1.6 0.7 1.0
94
99
99
99
2d
3
4d
1n
a Reaction conditions: 1m or 1n (1.0 mmol), H2TPP (0.1 mol %), EA
(2 mL), 4 Å MS (500 mg), O2 (1 atm), rt, 14 h. b Determined by 1H NMR.
c Yield of isolated product. d Data from ref 3b.
Encouraged by the almost quantitative yields of 2a,l readily
obtained from gram-scale oxidation of 1a,l with singlet oxygen,
we started to explore the feasibility of applying such reaction
to the oxidative Ugi-type reaction. In the work by Zhu and co-
workers, reaction of 1l, isocyanide, and carboxylic acid in the
presence of IBX gave Ugi products in 50-99% yields.15 From
oxidation of 1l (134 mg, 1.0 mmol) with singlet oxygen,
followed by removal of the solvent and direct addition of tBuNC
a Reaction conditions: 1 (1.0 mmol), H2TPP (0.1 mol %), EA (2.0 mL),
4 Å MS (500 mg), O2 (1 atm), 300 W tungsten lamp, rt. b Yield of isolated
product.
Table 4. Ugi-Type Reaction by Using 1l as Starting Material
with Singlet Oxygen as Oxidanta
of N-isopropylbenzylamine (1f), a selective formation of
N-benzylidene rather than N-isopropylidene moiety was
observed (Table 2, entry 5). 1,2,3,4-Tetrahydroisoquino-
line (1l) was oxidized to 2l in 97% yield (Table 2, entry
11); the latter is an important precursor for the synthesis
of isoquinoline alkaloids.
We also examined the oxidation of unsymmetric diben-
zylamines 1m,n; the results are depicted in Table 3 (entries
1 and 3). In each case, a mixture of four products were
detected, with both the total yield (94-99%) and product
ratio being comparable to those reported by Nicolaou and
co-workers for the oxidation of the same substrates by IBX
(Table 3, entries 2 and 4).3b This suggests involvement of
an imine hydrolysis/cross-condensation mechanism in the
amine oxidation by singlet oxygen, similar to that by IBX.3b
The singlet oxygen oxidation of secondary benzylic amines
to imines can be scaled up to gram-scale without appreciable
decrease in product yields. Treatment of 1a (4.0 g, 20.3
mmol) in EA (10 mL) with H2TPP (0.1 mol %) and 4 Å
MS (10 g) at room temperature under oxygen with light
irradiation for 14 h afforded 2a in 97% yield. Under the same
conditions, 2l was prepared in 97% yield from the oxidation
of 1l (2.24 g, 16.8 mmol).
a Reaction conditions for the Ugi-type reaction: R1NC (0.77 mmol),
R2COOH or R3OH (1.0 mmol), MeOH (5 mL), 60 °C, 46 h. b Yield of
isolated product.
4570
Org. Lett., Vol. 11, No. 20, 2009

and carboxylic acid PhCHdCHCOOH or PhCOOH, we
obtained Ugi products 3a or 3b in 89% or 82% yield,
respectively (Table 4, entries 1 and 2).
by X-ray crystallographic studies (Table S1 in the Supporting
Information and Figure 1).
El Ka¨ım, Grimaud, and co-worker developed a new type
of Ugi reaction using nitrophenol instead of acid.17 We found
that the singlet oxygen oxidation of 1l to 2l can be applied
to this type of Ugi reaction as well, affording Ugi products
4a and 4b in 41% and 62% yields, respectively, upon
t
addition of isocyanide BuNC or BnNC and o-nitrophenol
(Table 4, entries 3 and 4).
For the oxidative Ugi-type reaction based on the IBX
oxidation of 1a to 2a, the corresponding Ugi product was
obtained in 32% yield.15 Remarkably, upon oxidation of 1a
(197 mg, 1.0 mmol) by singlet oxygen, treatment of the in
situ formed 2a with isocyanide and carboxylic acid or
nitrophenol afforded the Ugi products 5 and 6a,b in 72-96%
yields (Table 5). The structure of 6a has been determined
Figure 1. ORTEP drawing for 6a.
Table 5. Ugi-Type Reaction by Using 1a as Starting Material
with Singlet Oxygen as Oxidanta
In summary, we have demonstrated a clean oxidation of
various secondary benzylic amines to imines by singlet
oxygen under mild conditions. Such amine oxidation can be
performed on gram-scale with almost quantitative yield. We
have also developed oxidative Ugi-type reactions featuring
reaction of isocyanide and carboxylic acid/nitrophenol with
the imines formed in situ from oxidation of secondary amines
by singlet oxygen.
Acknowledgment. This work was supported by The
University of Hong Kong (University Development Fund),
the University Grants Council of HKSAR (the Area of
Excellence Scheme: AoE 10/01P), the Hong Kong Research
Grants Council (HKU7009/06P and CityU 2/06C), and the
CAS-Croucher Funding Scheme for Joint Laboratory. We
thank Prof. Kuiling Ding (SIOC) for his useful discussion.
G.J. and J.C. thank the Croucher Foundation of Hong Kong
for a postgraduate studentship.
Supporting Information Available: Experimental pro-
1
cedures, compound characterization data, Table S1, and H
NMR and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reaction conditions for the Ugi-type reaction: R1NC (0.77 mmol),
R2COOH or R3OH (1.0 mmol), MeOH (5 mL), 60 °C, 42 h. b Yield of
isolated product.
OL9018166
(17) El Ka¨ım, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
44, 7961.
Org. Lett., Vol. 11, No. 20, 2009
4571