Amphiphilic methyleneamino synthon through organic dye catalyzed- decarboxylative aminoalkylation

Article abstract of DOI:10.1039/c3ob41091a

The utilization of a photo-induced synthon generated from N-phenyl glycine by an organic dye and visible light irradiation is disclosed. The intermediate could be coupled with either a radical or a nucleophile in a simple operation to afford several natural product-like compounds.

Full text of DOI:10.1039/c3ob41091a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Amphiphilic methyleneamino synthon through
organic dye catalyzed-decarboxylative
Cite this: Org. Biomol. Chem., 2013, 11,
5922
aminoalkylation†
Li Chen,a Chin Sheng Chao,b Yuanhang Pan,a Sheng Dong,a Yew Chin Teo,a
Jian Wang*a and Choon-Hong Tan*b
Received 25th May 2013,
Accepted 12th July 2013
The utilization of a photo-induced synthon generated from N-phenyl glycine by an organic dye and
visible light irradiation is disclosed. The intermediate could be coupled with either a radical or a nucleo-
phile in a simple operation to afford several natural product-like compounds.
DOI: 10.1039/c3ob41091a
www.rsc.org/obc
The functionalization of α C–H bonds of amines represents an work, we hypothesized that α-amino radical 3 could be
efficient approach towards the preparation of complex obtained through a decarboxylative process, catalyzed by
amines.1 A common system of this methodology is to use the organic dyes in the presence of visible light (Scheme 2b).6
transition metal-catalyzed dehydrogenative coupling using Under such conditions, N-phenyl glycine 1 would undergo SET
stoichiometric oxidants such as tert-butyl hydrogen peroxide reaction forming radical cation 2, and decarboxylation would
(TBHP).2 The study of visible light photoredox catalysis has lead us to α-amino radical 3. Further oxidation of 3 would lead
made much progress recently,3,4 and in particular, photoredox to iminium 4. We aimed to manipulate reaction conditions so
aminoalkylation is shown by various groups to be viable.5 Our that a methyleneamino equivalent could be installed in both
groups have also demonstrated that this reaction can be effec- electrophilic and nucleophilic substrates.
tively photocatalyzed using organic dyes.6 The photoredox
We first investigated the reaction between N-phenyl glycine
process begins with the single electron oxidation of the nitro- and N-phenyl maleimide under visible light irradiation with
gen centre by the excited state of the photocatalyst (Scheme 1). various organic dyes as catalysts. Decarboxylative annulation
The α-amino radical is proposed as an intermediate via product 6aa was obtained with 30% yield when CH3CN was
deprotonation in polar solvents. However, it is difficult to trap used as the solvent and Rose Bengal was the catalyst (Table 1,
the α-amino radical while further oxidation often occurs as the entry 1). The yield was increased dramatically when water was
major pathway to form an iminium ion, which is frequently added as a co-solvent (entry 2). A better result was obtained
trapped with nucleophiles.7 Recently, it was found that oxygen when Fluorescein was used as the catalyst in MeOH (entry 3).
could be used as the switch between these two pathways. In Other organic dyes as well as Ru(bpy)3Cl2 did not give good
the absence of oxygen, α-amino radicals can be formed prefer- yields (entries 4–6). Lowering the Fluorescein loading from
entially and added to electron deficient alkenes.8
5 mol% to 2 mol% did not affect the reaction rate and yield
The photo-decarboxylative radical process was reported (entry 7). The slow-addition of glycine was found to improve
using phenanthrene as a stoichiometric sensitizer in the pres- the reaction yield (entry 8). The slow-addition would possibly
ence of UV light (Scheme 2a).9 The process is initiated through suppress the decomposition of the active intermediate. Both
a single-electron transfer (SET) from the carboxylate ion to light and organic dyes have been proved to be essential for this
generate the cation radical, formed by SET from the singlet reaction. However, the reaction showed low conversion to the
excited-state of phenanthrene to 1,4-dicyanobenzene. The expected product when preformed under oxygen-free con-
α-amino radical generated in this way was shown to attack ditions (entry 9).
electron deficient alkenes effectively. At the beginning of this
With the established conditions, we then evaluated the per-
formance of different N-aryl glycines and maleimides in the
aDepartment of Chemistry, National University of Singapore, 3 Science, Drive 3,
Singapore, 117543, Singapore. E-mail: chmwangj@nus.edu.sg
bSchool of Physical & Mathematical Sciences, Division of Chemistry and Biological
Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 63737,
Singapore. E-mail: choonhong@ntu.edu.sg
†Electronic supplementary information (ESI)
available. See DOI:
Scheme 1 Photo-oxidative strategies of generating nitrogen centre intermedi-
10.1039/c3ob41091a
ates from tertiary amine.
5922 | Org. Biomol. Chem., 2013, 11, 5922–5925
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Decarboxylative annulation between N-aryl glycines 1a–f and male-
imides 5a–ca
Entry
1 [R1]
1 [R2]
5 [R3]
6
Yieldb(%)
1
2
3
4
5
6
7
8
9
1a [H]
1a [H]
1a [H]
1b [4-Me]
1b [4-Me]
1c [2-Me]
1c [2-Me]
1d [H]
1e [4-Me]
1f [4-Cl]
[H]
[H]
[H]
[H]
[H]
[H]
[H]
[Me]
[Me]
[H]
5a [Ph]
5b [Et]
5c [Bn]
5a [Ph]
5b [Et]
5a [Ph]
5b [Et]
5b [Et]
5b [Et]
5b [Et]
6aa
6ab
6ac
6ba
6bb
6ca
6cb
6db
6eb
6fb
89
88
90
95
87
78
89
73
64
51
10
Scheme 2 Photo-oxidative decarboxylative strategies of generating nitrogen
a Reaction was performed using 0.12 mmol of 1, 0.1 mmol of 5 and
centre intermediates.
2 mol% of Fluorescein in 1.0 mL of MeOH. b Isolated yield.
Table 1 Decarboxylative annulation between N-phenyl glycine 1a and N-phenyl-
maleimide 5aa
Scheme 3 Proposed mechanism for Fluorescein-catalyzed decarboxylative
Entry
Catalyst
Solvent
Yieldb (%)
annulation using visible light.
1
2
3
4
Rose Bengal
Rose Bengal
Fluorescein
Methylene Blue
Eosin Y
CH3CN
CH3CN–H2O (4 : 1)
MeOH
MeOH
MeOH
30
73
82
61
42
Similarly, other electron deficient unsaturated systems
could be used to trap this α-amino radical. For example,
methylene succinimide 9 could react with 1a under optimized
conditions to give the spiro-bicyclic amine 10 (Scheme 4a).
Diazo-compound was shown to trap the α-amino radical under
similar conditions (Scheme 4b).
5
6
Ru(bpy)3Cl2
Fluorescein
Fluorescein
Fluorescein
MeOH
MeOH
MeOH
MeOH
46
80
89
<10
7c
8c,d
9e
We further hypothesized that in the absence of electrophilic
substrates, α-amino radical 3 would be further oxidized to
iminium 4 (Scheme 2b). Inspired by our previous research,6a
such iminiums could be excellent acceptors for enamines gen-
erated from proline and ketones, providing α-amino-ketone
products in good yields (Table 3). Both simple ketones
(Table 3, entries 1–7) and cyclohexanone (see ESI†) were suit-
able substrates for this reaction. This electrophilic iminium
a Reaction was performed using 0.12 mmol of 1a and 0.1 mmol of 5a
and 5 mol% catalyst in 0.5 mL of a solvent. b Isolated yield. c 2 mol%
Fluorescein. d Slow addition for 1a (see ESI). e The reaction was carried
out under oxygen-free conditions.
presence of 2 mol% Fluorescein using an 11 W household
bulb (Table 2). Substituents on maleimides had little effect on
the result (entries 1–3). The α-substituted N-aryl glycines were
demonstrated to work well under these conditions, but gave
slightly lower yields (Table 2, entries 8 and 9) as compared to
non-substituted ones (entries 3, 2, 5 and 7). Electron donating
substituents on the phenyl ring did not increase the yield sig-
nificantly while electron withdrawing substituents led to a
decrease in yield (entry 10).
We proposed that after the α-amino radical intermediate 3
formed, N-phenyl maleimide then trapped it to generate inter-
mediate 7. Cyclization onto the aromatic ring led to cyclohexa-
dienyl radical 8, which would undergo re-aromatization via
SET and proton elimination to release the annulation product
6aa (Scheme 3).
Scheme 4 Nucleophilic transformation of N-phenyl glycine 1a.
Org. Biomol. Chem., 2013, 11, 5922–5925 | 5923
This journal is © The Royal Society of Chemistry 2013

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 3 Decarboxylative coupling between N-aryl glycines 1a–g and acetonea
Entry
1 [R1]
1 [R2]
13
Yieldb (%)
1
2
3
4
5
6
7
1a [H]
[H]
[H]
[H]
[H]
[H]
[Me]
[Me]
13a
13b
13c
13d
13e
13f
85
92
76
71
88
70
82
1b [4-Me]
1c [2-Me]
1f [4-Cl]
1g [4-OMe]
1d [H]
Scheme 7 Proposed mechanism for cascade reaction between N-phenyl
glycine 1a and N-tosylimine 18.
1e [4-Me]
13g
a Reaction was performed using 0.12 mmol of 1, 0.036 mmol of
L-proline, and 2 mol% Fluorescein in 1.0 mL of acetone. b Isolated yield.
Scheme 8 Decarboxylative annulation using ambient sunlight.
In order to demonstrate the scalability of this organic dye-
catalyzed visible light induced process, we performed the de-
carboxylative
annulation
under
ambient
sunlight
(Scheme 8).10 With only 0.5 mol% of Fluorescein, 0.5 g of 6aa
in 70% yield was isolated after 6 h.
Scheme 5 Electrophilic transformation of N-phenyl glycine 1a.
In conclusion, we have developed N-phenyl glycine as the
reagent for the methyleneamino synthon in an amphoteric
manner. Through an organic dye-catalyzed decarboxylation-
α-amino-alkylation reaction, both electrophilic and nucleo-
philic substrates can be used as acceptors, leading to a variety
of natural product-like compounds. Application of these
methodologies to synthesis is being carried out at the moment.
intermediate could also undergo further transformation such
as Frediel–Crafts reaction (Scheme 5a). 1-Naphthol was added
to glycine 1a to give aminoalcohol 15 in moderate yield. For
the Frediel–Crafts reaction, graphene oxide (GO) was used as a
reaction additive and Rose Bengal performed better as a photo-
catalyst than Fluorescein.6b Other nucleophiles such as
TMSCN also worked well to give 2-(phenylamino) acetonitrile
17 in excellent yield (Scheme 5b).
When N-tosylimine 18 was utilized as the acceptor, a cyclic Acknowledgements
compound 19 was formed, instead of the Mannich adduct that
This work was supported by ARF grants (R-143-000-461-112),
we expected (Scheme 6). After some investigations, we found
that the Mannich adduct underwent further modifications to
give cyclic diamine 19. A cascade process which contained
both radical and ionic pathways was proposed for its for-
mation (Scheme 7). The α-amino radical 3 was added to the
N-tosylimine 18 to afford a diamine intermediate 21. This
adduct was added to iminium ion 4 to form ammonium inter-
mediate 22. Losing an aniline led to iminium cation 23, which
cyclized to form product 19.
Academic Research Fund Tier 1 (RG 6/12 M4011018.110) and a
scholarship (to L. Chen, Y. Pan and S. Dong) from the National
University of Singapore
Notes and references
1 For selected reviews, see: (a) M. Tobisu and N. Chatani,
Angew. Chem., Int. Ed., 2006, 45, 1683–1684;
(b) P. W. Roesky, Angew. Chem., Int. Ed., 2009, 48, 4892–
4894; (c) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer
and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654–2672;
(d) C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41,
3464–3484.
2 For selected reviews, see: (a) C.-J. Li and Z. Li, Pure Appl.
Chem., 2006, 78, 935–945; (b) Z. Li, D. S. Bohle and C.-J. Li,
Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 8928–8933;
(c) C.-J. Li, Acc. Chem. Res., 2009, 42, 335–344;
Scheme 6 Cascade reaction between N-phenyl glycine 1a and N-tosylimine
18.
5924 | Org. Biomol. Chem., 2013, 11, 5922–5925
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
(d) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew.
Chem., Int. Ed., 2011, 50, 11062–11087.
J. Am. Chem. Soc., 2011, 133, 2056–2059; (d) M. Rueping,
C. Vila, R. M. Koenigs, K. Poscharny and D. C. Fabry, Chem.
Commun., 2011, 47, 2360–2362; (e) A. McNally, C. K. Prier
and D. W. C. MacMillan, Science, 2011, 334, 1114–1117;
(f) J. Xuan, Y. Cheng, J. An, L.-Q. Lu, X.-X. Zhang and
W.-J. Xiao, Chem. Commun., 2011, 47, 8337–8339;
(g) D. A. DiRocco and T. Rovis, J. Am. Chem. Soc., 2012, 134,
8094–8097; (h) M. Rueping, R. M. Koenigs, K. Poscharny,
D. C. Fabry, D. Leonori and C. Vila, Chem.–Eur. J., 2012, 18,
5170–5174; (i) Y. Miyake, Y. Ashida, K. Nakajima and
Y. Nishibayashi, Chem. Commun., 2012, 48, 6966–6968;
( j) L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687–7697;
(k) Q. Liu, Y.-N. Li, H.-H. Zhang, B. Chen, C.-H. Tung and
L.-Z. Wu, Chem.–Eur. J., 2012, 18, 620–627; (l) X. Ju, D. Li,
W. Li, W. Yu and F. Bian, Adv. Synth. Catal., 2012, 354,
3561–3567.
3 For selected reviews, see: (a) K. Zeitler, Angew. Chem., Int.
Ed., 2009, 48, 9785–9789; (b) T. P. Yoon, M. A. Ischay and
J. Du, Nat. Chem., 2010, 2, 527–532; (c) J. M. R. Narayanam
and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102–113;
(d) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51,
6828–6838; (e) Y. Xi, H. Yi and A. Lei, Org. Biomol. Chem.,
2013, 11, 2387–2403; (f) D. Ravelli and M. Fagnoni, Chem-
CatChem, 2012, 4, 169–171; (g) D. Ravelli, M. Fagnoni and
A. Albini, Chem. Soc. Rev., 2013, 42, 97–113.
4 For selected examples, see: (a) H. Liu, W. Feng, C. W. Kee,
Y. Zhao, D. Leow, Y. Pan and C.-H. Tan, Green Chem., 2010,
12, 953–956; (b) A. G. Griesbeck, M. Reckenthäler and
J. Uhlig, Photochem. Photobiol. Sci., 2010, 9, 775–778;
(c) M. Neumann, S. Füldner, B. König and K. Zeilter, Angew.
Chem., Int. Ed., 2011, 50, 951–954; (d) K. Ohkubo,
K. Mizushima, R. Iwata and S. Fukuzumi, Chem. Sci., 2011,
2, 715–722; (e) D. P. Hari, P. Schroll and B. König, J. Am.
Chem. Soc., 2012, 134, 2958–2961; (f) K. Fidaly, C. Ceballos,
A. Falguières, M. S.-I. Veitia, A. Guy and C. Ferroud, Green
Chem., 2012, 14, 1293–1297; (g) T. Koike, Y. Yasu and
M. Akita, Chem. Lett., 2012, 999–1001; (h) W. Fu, W. Guo,
G. Zou and C. Xu, J. Fluorine Chem., 2012, 140, 88–94;
(i) H.-S. Yoon, X.-H. Ho, J. Jang, S.-J. Kim and H.-Y. Jang,
Org. Lett., 2012, 14, 3272–3275; ( j) T. Koike, Y. Yasu and
M. Akita, Chem. Commun., 2012, 48, 5355–5357;
(k) T. Courant and G. Masson, Chem.–Eur. J, 2012, 18, 423–
427.
6 (a) Y. Pan, C. W. Kee, L. Chen and C.-H. Tan, Green Chem.,
2011, 13, 2682–2685; (b) Y. Pan, S. Wang, C. W. Kee,
E. Dubuisson, Y. Yang, K. P. Loh and C.-H. Tan, Green
Chem., 2011, 13, 3341–3344.
7 (a) P. Kohls, D. Jadhav, G. Pandey and O. Reiser, Org. Lett.,
2012, 14, 672–675; (b) Y. Miyake, K. Nakajima and
Y. Nishibayashi, J. Am. Chem. Soc., 2012, 134, 3338–3341.
8 S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran and
M. Rueping, J. Am. Chem. Soc., 2013, 135, 1823–1829.
9 (a) Y. Yoshimi, M. Masuda, T. Mizunashi, K. Nishikawa,
K. Maeda, N. Koshida, T. Itou, T. Morita and M. Hatanaka,
Org. Lett., 2009, 11, 4652–4655; (b) Y. Yoshimi, S. Hayashi,
K. Nishikawa, Y. Haga, K. Maeda, T. Morita, T. Itou,
Y. Okada, N. Ichinose and M. Hatanaka, Molecules, 2010,
15, 2623–2630.
5 (a) A. G. Condie, J. C. Gonzalez-Gomez and
C. R. J. Stephenson, J. Am. Chem. Soc., 2010, 132, 1464–
1465; (b) Y.-Q. Zou, L.-Q. Lu, L. Fu, N.-J. Chang, J. Rong, 10 (a) P. Esser, B. Pohlmann and H.-D. Scharf, Angew. Chem.,
J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2011, 50,
7171–7175; (c) Z. Xie, C. Wang, K. E. DeKrafft and W. Lin,
Int. Ed., 1994, 33, 2009–2023; (b) S. Protti and M. Fagnoni,
Photochem. Photobiol. Sci., 2009, 8, 1499–1516.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 5922–5925 | 5925