Light promoted aqueous phase amine synthesis via three-component coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.07.060

By applying a simple TiO₂-(NH₄)₂S ₂O₈ system and promoted by UV light, the three-component reactions of cyclic ether, aniline and aldehyde can be progressed efficiently. 29 substituted amines with different structures were synthesized with up to 97% isolated yields. Isotope effect study revealed that the rate-determining step might be the nucleophilic addition step but not radical generation.

Full text of DOI:10.1016/j.tetlet.2013.07.060

Tetrahedron Letters 54 (2013) 5217–5219
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Light promoted aqueous phase amine synthesis via three-component
coupling reactions
Lina Zhang a,b, Youquan Deng a, Feng Shi a,
⇑
a Center for Green Chemistry and Catalysis, Lanzhou Institute of Chemical Physics, CAS, Lanzhou 730000, China
b University of the Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2013
Revised 3 July 2013
Accepted 11 July 2013
Available online 17 July 2013
By applying a simple TiO2–(NH4)2S2O8 system and promoted by UV light, the three-component reactions
of cyclic ether, aniline and aldehyde can be progressed efficiently. 29 substituted amines with different
structures were synthesized with up to 97% isolated yields. Isotope effect study revealed that the rate-
determining step might be the nucleophilic addition step but not radical generation.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amine
Imine
Heterogeneous catalysis
Light
The selective C–H bond functionalization is one of the funda-
mental problems in chemistry.1 Due to the stability of C–H bond,
especially the unactivated sp3 C–H bond, the pre-functionalization
is necessary in order to realize the selective transformation reac-
tions, which results in low atomic efficiency and serious environ-
ment pollution. The development of a new catalyst to realize the
selective transformation of C–H bond under mild reaction condi-
tions will undoubtedly be interesting in the synthesis of many
functional substrates. The application of transition metal catalyst
is an efficient method to carry out the C–H bond activation.1 Nor-
mally, the transition metal can react with C–H bond to produce
C–M bond and it can be selectively transformed into desired prod-
uct. In the last years, a variety of catalytic C–H bond activation
processes have been developed with excellent performance.
Except the catalytic activation of C–H bond via the formation of
C–M bond, the C–H bond activation through the formation of rad-
ical is also an attractive route.2 Since 1980s the radical chemistry
based synthetic methods have been studied extensively, which is
strictly related to the development of new radical precursors.
Therefore, the discovery of a specific radical initiator for a specific
reaction is one of the major tasks for researchers in order to find a
valuable synthetic method. In the last decades, many radical
initiators such as azo compounds or peroxides,3 samarium iodide,4
triethylborane,5 hexabutylditin,6 indium7 and dimanganese deca-
carbonyl8 have been reported and many good results were
obtained. Recently, great progresses have been achieved in the
catalytic addition of RX,7,9 HCONH2,10 olefins11 and Mitsunobu’s
reagent12 to imines. Besides the reactions discussed above, the
selective addition of cyclic ethers to C@N bond is one of the chal-
lenging reactions in this field. About this transformation,13–17 good
results were obtained under ionizing radiation13 or in the presence
of large excess of Me2Zn,2a,15 TiCl3/PhN2+16 or ROOH/PhN2+2b,c,17 as
radical initiator. Undoubtedly, the usage of large excess of radical
initiators is one of the big disadvantages of the radical based syn-
thetic method. It makes the reaction complicated and difficult for
the treatment of the reaction. Meanwhile, the generality of the
methodology is usually limited and the selectivities to the desired
products are not good enough. It would be an ideal choice if a
clean, economic and general method can be developed for this
transformation. Herein, we would like to present our new results
about the light promoted activation of cyclic ether and its applica-
tion in the three-component coupling reactions with aldehydes
and anilines. The reaction was initiated with TiO2–(NH4)2S2O8
and promoted by UV-light.
The catalytic performance of this system was first explored using
the reaction of p-toluidine, benzaldehyde and 1,4-dioxane as model
reaction, Table 1. Clearly, the combination of TiO2 and UV is essen-
tial to gain the selective transformation of the three-component
reaction. The desired product 3a was not detectable in the absence
of TiO2, entry 1. The three-component reaction can progress well if a
suitable amount of TiO2 was added and the selectivity to 3a in-
creased to 66%, entry 2. The addition of water as co-solvent is indis-
pensible to realize the transformation. Almost no nucleophilic
addition product of 1,4-dioxane was observed under water free con-
dition, entry 3. As a radical initiator is extensively used, the applying
⇑
Corresponding author.
E-mail address: fshi@licp.cas.cn (F. Shi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.060

5218
L. Zhang et al. / Tetrahedron Letters 54 (2013) 5217–5219
Table 1
Reaction condition optimizationa
O
O
O
HN
O
O
O
HN
O
HN
O
HN
O
HN
O
O
NH2
CHO
O
O
HN
O
+
+
OCH3
OCH3
(3e) 74% (48:52)
(3a) 86% (46:54)
(3c) 89% (50:50)
(3b) 87% (42:58)
(3d) 72% (46:54)
1a
3a
2a
OCH3
OCH3
OCH3
Entry
Initiator
Additive
Sel.b (%)
O
O
O
O
1
2
—
—
—
—
0
66
HN
O
HN
O
O
HN
O
HN
O
TiO2
TiO2
TiO2
—
TiO2
TiO2
TiO2
TiO2
TiO2
HN
O
3c
4
3
(NH4)2S2O8
(NH4)2S2O8
FeSO4
NaHSO3
Na2SO3
97 (86d)
OCH3
5
6
7
8
9
10
0
OCH3
(3i) 80% (47:53)
62
72
6
18
98
(3f) 88% (47:53)
(3g) 85% (46:54)
(3h) 71% (45:55)
(3j) 46% (48:52)
Cl
Cl
Br
Cl
Br
Na2S2O3
(NH4)2S2O8 + NaHSO3
O
O
O
O
O
HN
O
HN
O
HN
O
HN
O
HN
O
a
0.2 mmol amine, 0.3 mmol aldehyde, 2.5 mL 1,4-dioxane, 2.5 mL H2O,
0.25 mmol TiO2 (P25), 6 mg additive, argon, UV, (365 nm LED), rt, 9 h.
b
Selectivity based on the peak area of GC-FID without modification. The dr ratios
OCH3
(3m) 90% (47:53)
of the reactions were ꢀ45:55. The conversions of all the reactions were ꢀ100% and
(3n) 97% (47:53)
(3o) 70% (45:55)
(3k) 81% (48:52)
(3l) 74% (44:56)
the major byproducts were imines.
c
Br
Without addition of H2O.
d
Br
O
Isolated yield.
Br
O
O
HN
O
HN
O
HN
O
of (NH4)2S2O8 as co-catalyst can promote the reaction significantly.
The selectivity of 3a was 97% and (E)-N-benzylidene-4-toluidine
was observed as byproduct. Meanwhile, the isolated yield of 3a
was 86%, entries 4 and 5. Moreover, other sulfate and sulfide inor-
ganic salts as co-catalysts were also studied but no better result
was obtained, entries 6–9. It is noteworthy, as a classical combina-
tion for radical generating, the co-addition of (NH4)2S2O8 and
NaHSO3 was tested, too, and a similar result as (NH4)2S2O8 itself
as co-catalyst was observed, entry 10. Thus, according to the above
results, it can be concluded that the applying of TiO2 is indispensible
for the three-component reaction. Meanwhile, (NH4)2S2O8 as co-
catalyst can promote the reaction.
Next, the generality of this system was explored, (Scheme 1).
Initially, aniline and benzaldehyde as starting materials were tried
and 3c as the major product was obtained with 89% yields. Similar
yield, that is 87%, to the desired product 3b was obtained if the
p-MeO group was incorporated into benzaldehyde. p-Toluidine
also exhibited nice reactivity and 72–86% yields to 3d and 3e were
obtained in the reactions with benzaldehyde, p-Me benzaldehyde
or p-methoxybenzaldehyde and 1,4-dioxane. The use of m-substi-
tuted starting materials does not affect the reactivity significantly.
For example, 88% and 85% isolated yields of 3f and 3g were
obtained if m-toluidine was used and reacted with benzaldehyde
and p-methoxybenzaldehyde. When p-methoxyaniline was
employed to react with benzaldehyde and p-methoxybenzalde-
hyde, 71–80% yields to the 3h and 3i can be achieved. However,
the yield to 3j was only 46%. The incorporation of halide substitu-
ents into the nucleophilic addition reaction should be interesting
because the presence of active C–X bonds is helpful to extend their
applications in the synthesis of other compounds. Here, a series of
chloro and bromo functionalized aniline derivatives as starting
materials were tested. To our delight, they can react with benzal-
dehyde and 1,4-dioxane smoothly and 3k–3r can be synthesized
with up to 97% isolated yields. It should be mentioned that the
dr ratios in all the products were close to 45:55. When o-toluidine
was used as starting material, the selectivity to the aim product
was 74% determined by GC-FID. However, we still do not get the
pure products now.
OCH3
(3p) 84% (45:55)
OCH3
(3q) 83% (45:55)
(3r) 85% (48:52)
Scheme 1. Three-component reaction of 1,4-dioxane with aniline and benzalde-
hyde derivatives. 0.2 mmol amine, 0.3 mmol aldehyde, 2.5 mL 1,4-dioxane, 2.5 mL
H2O, 0.25 mmol TiO2 (P25), 6 mg (NH4)2S2O8, UV (365 nm LED), argon, rt, 20 h.
Isolated yields. Diastereomer ratios are given in parenthesis.
tives, (Table 2). Similar as the three-component reactions using
1,4-dioxane, aniline and benzaldehyde derivatives with different
substituting groups can be used as the starting materials and the
yields to products 4a–4j were 65–93%, entries 1–10. The dr ratios
of products using 1,3-dioxolane as nucleophile were all close to
15:85.
Except the syntheses of compounds 3 and 4 discussed above,
THF can be used as nucleophile for the three-component reaction
and the yield to 5a was 58%. It should be mentioned that the dr
ratio of 5a was 47:53. If o-toluidine was used as starting material,
the reaction can also be carried out and the selectivity to the aimed
product was 59% determined by GC-FID.
Following, the isotope effect study was employed to explore the
mechanism of the reaction, (Scheme 2). Clearly, there are four
steps involved in the nucleophilic addition of THF to imine. It is
the reaction of benzaldehyde and p-toluidine to form imine (step
1), radical generation (step 2), nucleophilic addition of radical to
imine (step 3) and formation of amine product (step 4), respec-
tively. Among the four steps, step 1 and step 4 should not be the
rate determining steps because relatively a large amount of imine
and amine was observed during the reaction. In addition, the ratio
of (5a + d1À5a):(d7-5a + d8À5a) was 1.30:1. This number is close to
1 and it suggests that step 2, that is the generation of THF radical, is
not the rate-determining step, and we suppose that step 3 might
be the rate-determining step but it cannot be confirmed at this
stage. Moreover, the ratio of d7-5a to d8-5a is 6.15:1. That means
the major deuterated product is d7-5a, which shows remarkable
proton exchange in the presence of water as solvent.
This system is also very efficient in the three-component reac-
tions of 1,3-dioxolane with different aniline and aldehyde deriva-
In summary, a simple and efficient method for the three-com-
ponent reactions of aldehyde, amine and cyclic ethers was devel-

L. Zhang et al. / Tetrahedron Letters 54 (2013) 5217–5219
5219
Table 2
tope effect study revealed that the rate-determining step might be
the nucleophilic addition of radical to imine but not radical
generation.
Three-component reaction of 1,3-dioxolane with aniline and benzaldehyde deriva-
tivesa
R1
Acknowledgments
O
NH2
CHO
O
O
HN
R2
R1
R2
O
+
+
This work was financially supported by the National Natural
Science Foundation of China (21073208) and the Chinese Academy
of Sciences.
1a-e
2a-c
4a-j
Entry
R1
R2
Isolated yields (%) (a)
Supplementary data
1
2
3
4
5
6
7
8
9
10
H (1a)
H (1a)
H (2a)
p-MeO (2b)
H (2a)
p-MeO (2b)
H (2a)
p-Me (2c)
p-MeO (2b)
p-MeO (2b)
p-MeO (2b)
p-Me (2c)
87%(dr = 14:86) (4a)
84%(dr = 14:86) (4b)
78%(dr = 14:86) (4c)
93%(dr = 14:86) (4d)
71%(dr = 15:85) (4e)
78%(dr = 14:86) (4f)
65%(dr = 11:89) (4g)
75%(dr = 15:85) (4h)
73%(dr = 19:81) (4i)
75%(dr = 19:81) (4j)
m-Me (1b)
m-Me (1b)
p-MeO (1c)
p-MeO (1c)
p-MeO (1c)
p-Cl (1d)
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.060.
References and notes
m-Br (1e)
m-Br (1e)
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a
0.2 mmol amine, 0.3 mmol aldehyde, 2.5 mL 1,3-dioxolane, 2.5 mL H2O,
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CHO
NH2
+
step 1
O
O
d8
[cat]
[cat]
step 2
[cat-H]
step 2
[cat-D]
N
+
O
O
d7
+
step 3
step 3
O
N
O
d7
N
[cat-H]
[cat-D]
O
[cat-D]
[cat-H]
step 4
step 4
+
O
O
O
d7
d7
+
N
D
N
H
N
H
N
D
5a: m/z = 267
d1-5a: m/z = 268
d7-5a: m/z = 274
d8-5a: m/z = 275
5a : d1-5a : d7-5a : d8-5a = Peak267 : Peak268 : Peak274 : Peak275
= 7.89( 1.36) : 1.39( 0.21) : 6.15( 0.33) : 1
K
IE = (5a+d1-5a) : (d7-5a+d8-5a) = 1.30
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Yamada, K.-I.; Umeki, H.; Maekawa, M.; Yamamoto, Y.; Akindele, T.; Nakano,
M.; Tomioka, K. Tetrahedron 2008, 64, 7258–7265.
Scheme 2. Isotope competition reactions of THF and d8-THF.
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5986–5994.
oped applying a simple UV promoted TiO2–(NH4)2S2O8 system.
Various benzaldehydes, anilines and cyclic ethers can be trans-
formed into the amine products with up to 97% isolated yields. Iso-