A simple and eco-friendly method for the aminomethylation of 3-substituted oxindoles via three-component Mannich reaction in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2010.12.060

A simple and eco-friendly method for the aminomethylation of various 3-substituted oxindoles via three-component Mannich reaction in aqueous media has been established. A variety of oxindoles containing a quaternary carbon center, which comprises an amino

Full text of DOI:10.1016/j.tetlet.2010.12.060

Tetrahedron Letters 52 (2011) 903–906
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A simple and eco-friendly method for the aminomethylation of 3-substituted
oxindoles via three-component Mannich reaction in aqueous media
Xiong-Li Liu a,b, Xiao-Mei Zhang a, Wei-Cheng Yuan a,
⇑
a Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate School of 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:
A simple and eco-friendly method for the aminomethylation of various 3-substituted oxindoles via three-
component Mannich reaction in aqueous media has been established. A variety of oxindoles containing a
quaternary carbon center, which comprises an aminomethyl group were obtained smoothly in good
yields (up to 93%) with this method. Particularly valuable features, such as employing cheap and readily
available formalin as a useful aminomethylation C1 unit and using water as a reaction medium, are
embodied in this method.
Received 25 August 2010
Revised 6 December 2010
Accepted 14 December 2010
Available online 21 December 2010
Keywords:
Oxindole
Ó 2010 Elsevier Ltd. All rights reserved.
Mannich reaction
Formalin
Aminomethylation
Water mediated reaction
Oxindoles bearing a quaternary carbon center at the C3 position
are ubiquitous in nature and utilized as building blocks for alkaloid
synthesis1a,b as well as development of potential therapeutic
agents.1c In particular, oxindoles containing a hydroxymethyl or
aminomethyl group at the C3 position are very attractive and
valuable synthetic targets. Due to the ease of transforming
hydroxymethyl and aminomethyl group to other functionalities,
hydroxymethylation or aminomethylation oxindoles can act as po-
tential intermediates for further elaboration. Actually, the addition
reaction of prochiral 3-substituted oxindoles to formaldehyde or
formaldehyde-derived imines provides a beneficial route to access
oxindole derivatives containing a quaternary carbon center, which
comprises a hydroxymethyl or aminomethyl group (Scheme 1).
Although many transformations using 3-substituted oxindoles as
nucleophiles (donor) reacting with various electrophiles (acceptor)
have been developed,2–4 to the best of our knowledge, the exam-
ples that can directly deliver oxindoles bearing a hydroxymethyl
or aminomethyl group at the C3 position with formaldehyde or
formaldehyde-derived imines as electrophiles are still scarce. Very
recently, we developed one method for the hydroxymethylation of
3-substituted oxindoles with paraformaldehyde as C1 source and
chiral bifunctional thiourea-tertiary amine as catalysts.4b Inspired
by the success of hydroxymethylation of 3-substituted oxindoles,4b
we hope to continue pursuing aminomethylation approach to ac-
cess a series of oxindoles bearing an aminomethyl group at the
C3 position via Mannich reaction.5
The Mannich reaction,6 in which an enol or enolate attacks an
imine or an iminium ion, is a powerful tool for introducing amino-
alkyl fragments into organic molecules. Because formaldehyde
does not form stable imines, in an attempt to avoid this issue, we
chose to examine the three-component reaction of 3-substituted
oxindoles, amine, and formaldehyde (Scheme 1, (2)). We envi-
sioned that the iminium ion, generated in situ from formaldehyde
and amine, was attacked by the C3-position of oxindoles to form
the corresponding aminomethylation products. On the other hand,
organic reaction in water has recently attracted great interest in
organic synthesis due to its cost, safety, and environmental con-
cern.7 Herein, as continuation of our studies on the synthesis of
oxindole-derivatives,4,8 we report the first three-component
Mannich reaction of 3-substituted oxindoles, formalin, and various
secondary amines in aqueous media for the aminomethylation of
3-substituted oxindoles, particularly with formaldehyde-derived
iminium ion generated in situ as electrophile.
R2
R2
OH
O
O
hydroxymethylation
O
O
(1)
(2)
+
H
H
H
H
N
R1
N
R1
R
R2
R2
N
O
R
R'
N
R'
aminomethylation
+
+
O
N
R1
H
N
R1
⇑
Corresponding author. Fax: +86 28 85232228.
E-mail address: yuanwc@cioc.ac.cn (W.-C. Yuan).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.060

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X.-L. Liu et al. / Tetrahedron Letters 52 (2011) 903–906
We initially investigated the three-component Mannich reac-
tion of oxindole 1a (0.3 mmol), dibutylamine (2a) (0.9 mmol),
and paraformaldehyde (0.9 mmol) in various solvents (6.0 mL) at
35 °C (Table 1, entries 1–8). It was found that ethyl acetate (EtOAc)
was superior to other examined solvents like chlorinated solvents,
toluene, xylene, CH3CN, and THF in view of the yield (Table 1, entry
4 vs entries 1–3 and 5–8). However, with further consideration on
the development of environment-friendly chemistry, we tried to
conduct Mannich reaction in water. To our delight, with further
studies by adding sodium dodecyl sulfate (SDS) as additive or
increasing reaction temperature, the desired product 4a could be
obtained smoothly in 85% yield in a shortened reaction time
(3 h) (Table 1, entry 11). Afterward, the paraformaldehyde was re-
placed with more widely available formalin as C1 source for ami-
nomethylation reaction,9,10 we were pleased to find that 4a could
be obtained in 85% yield in 3 h (Table 1, entry 12). Finally, it was
noted that a slightly higher yield of 4a could be obtained with
2.0 equiv of 2a and 4.0 equiv of formalin (based on the pure form-
aldehyde) at 90 °C (Table 1, entry 13).9,10
Next, the scope of the three-component Mannich reaction of
various 3-substituted oxindoles with dibutylamine (2a) and forma-
lin (3) was investigated (Table 2). Firstly, the 3-benzyl-oxindoles
1b and 1c were able to deliver the corresponding products 4b in
88% yield and 4c in 73% yield, respectively (Table 2, entries 1 and
2). Substrate 1d could be converted to the desired aminomethyla-
tion product in 3 h,11 but the aminomethylation product was
decomposed to the starting material 1d during the purification
via flash chromatography (SiO2) (Table 2, entry 3). We presumed
that there was a retro-Mannich process occurring during the
course of purification for this case. Afterward, N-benzyl-oxindoles
1e–g were also investigated; we found that their corresponding
aminomethylation products were able to be obtained in good
Table 1
The optimization studies on the aminomethylation of oxindole 1aa
C4H9
C4H9
Bn
Bn
N
O
O
O
+ C4H9
C4H9
+
N
H
N
Bn
N
H
H
Bn
4a
3
2a
1a
Entry
Solvent
3
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
(ClCH2)2
CH2Cl2
CHCl3
EtOAc
Toluene
Xylene
CH3CN
THF
Water
Water
Water
Water
Water
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
(CH2O)n
Formalin
Formalin
35
35
35
35
35
35
35
35
35
35
70
70
90
24
24
24
24
24
24
12
24
24
24
3
46
45
36
90
41
23
84
38
30
43c
85c
85c
87c,d
3
3
a
Unless otherwise specified, the reactions were carried out in solvent 6.0 mL
with 0.3 mmol 1a, 3.0 equiv 2a and 3.0 equiv 3 at the specified temperature.
b
Isolated yield after chromatographic purification.
Using 10 mol % sodium dodecyl sulfate (SDS) as additive.
The reaction was carried out in solvent 6.0 mL with 0.3 mmol 1a, 2.0 equiv 2a
c
d
and 4.0 equiv formalin in the presence of 10 mol % SDS at 90 °C.
Table 2
Three-component reaction for the aminomethylation of various 3-substituted oxindolesa,b
C4H9
R2
R2
N
O
R3
SDS (10 mol %)
as additive
R3
C4H9
O
C4H9
C4H9
+
formalin
+
N
H
N
R1
Water (6.0 mL)
90 oC
N
R1
3
1b-r
2a
4b-r
Entry
1
Time (h)
4/Yieldc (%)
Bn
1
2
3
R1 = Me (1b)
R1 = MOM (1c)
3
5
3
4b/88
4c/73
R
1 = Boc (1d)
4d/—d
O
O
N
R1
R2
4
5
6
R2 = CH(CH3)2 (1e)
R2 = C2H5 (1f)
5
5
5
4e/81
4f/80
4g/82
R
2 = 4-MeOC4H4 (1g)
N
Bn
7
8
R2 = 4-MeOPhCH2 (1h)
R2 = 4-MePhCH2 (1i)
3
3
4h/86
4i/82
4j/90
4k/88
4l/78
4m/88
4n/85
4o/75
4p/72
R2
9
10
11
12
13
14
15
R
R
R
R
R
R
R
2 = 3-MePhCH2 (1j)
2 = 4-BrPhCH2 (1k)
2 = 3-BrPhCH2 (1l)
2 = 4-ClPhCH2 (1m)
2 = 4-MeOC6H4 (1n)
2 = 2-thienylmethyl (1o)
2 = 1-naphthylmethyl (1p)
3
3
3
3
5
4
5
O
N
Me
Bn
16
17
R3 = Me (1q)
R3 = Br (1r)
3
3
4q/81
4r/93
R3
O
N
Me
a
Unless otherwise specified, the reactions were carried out in 6.0 mL water with 0.3 mmol 1, 2.0 equiv 2a and 4.0 equiv formalin (based on the pure formaldehyde) in the
presence of 10 mol % SDS at 90 °C.
b
In these reactions, only trace amount hydroxymethylation product was observed.
Isolated yield after chromatographic purification.
The corresponding aminomethylation product 4d was decomposed to the starting material 1d during the purification via flash chromatography.
c
d

X.-L. Liu et al. / Tetrahedron Letters 52 (2011) 903–906
905
yields, regardless of alkyl or aryl group connected with the C3 po-
sition of oxindole scaffold (Table 2, entries 4–6). Subsequently, var-
ious 3-substituted N-methyl-oxindoles with different substitution
patterns on the phenyl ring of benzyl group were also examined
and good yields were obtained in these cases (Table 2, entries 7–
12). Oxindole incorporating a 2-thienylmethyl group at the C3 po-
sition was also a viable substrate (Table 2, entry 14). Substrate
bearing a bulky 1-naphtylmethyl group also gave smoothly its
product in 72% yield (Table 2, entry 15). Using 3-aryloxindole 1n
as a substrate, the Mannich reaction also proceeded smoothly
and afforded the product in 85% yield (Table 2, entry 13). In addi-
tion, N-methyl-3-benzyl-oxindoles bearing an electron-donating
or electron-withdrawing group at the C5 position also could en-
gage in the process efficiently (Table 2, entries 16 and 17).
the course and leading to their corresponding aminomethylation
and hydroxymethylation products, respectively. However, when
the amount of dimethylamine was increased up to 4.0 equiv from
2.0 equiv to oxindole, the same reaction gave 4s in 74% yield and 5
in 20% yield (Table 3, entry 2). Subsequently, various other second-
ary amine 2c–j were, respectively, employed for the reaction with
1b and formalin (3) with substrates ratio 1:4:4 (1b/2/3) (Table 3,
entries 3–10). We found that, except that 2e, 2f, and 2j gave
hydroxymethylation product 5 as the major product (Table 3, en-
tries 5, 6 and 10), the other substrates mainly provided the desired
aminomethylation products. In addition, when primary amine 2k
and 2l were employed, only trace amount of aminomethylation
products were found but hydroxymethylation product 5 could be
obtained in poor yields (Table 3, entries 11 and 12).12
Furthermore, the amine component of the three-component
reaction was surveyed. Under the optimal reaction conditions,
when dimethylamine (2b) was used as an amine partner, it was
observed that the desired aminomethylation product 4s was ob-
tained in 56% yield, while the hydroxymethylation product 5 was
also obtained in 38% yield (Table 3, entry 1). It is likely that there
were three-component Mannich reaction and the aldol reaction
of oxindole to formaldehyde proceeding simultaneously during
A postulated mechanism for the formation of aminomethyla-
tion and hydroxymethylation products is illustrated in Scheme 2.
3-Substituted oxindoles as nucleophiles attack the methylene
iminium ion, generated by the condensation of secondary amines
2 and formaldehyde 3, leading to the corresponding Mannich prod-
ucts 4. On the other hand, possibly 3-substituted oxindoles attack
formaldehyde component via aldol addition process, thereby yield-
ing the hydroxymethylation product 5. The Mannich reaction is
Table 3
Three-component reaction for the aminomethylation of 3-substituted oxindoles 1b with various aminesa
Bn
R
R'
Bn
Bn
OH
O
N
O
SDS (10 mol %)
R
R'
as additive
O
+
+ formalin
N
+
N
Me
Water (6.0 mL)
90 oC
H
N
Me
N
Me
1b
4s-x
2b-l
3
5
Entry
2
Time (h)
4/Yieldb (%)
5/Yieldb (%)
N
H
1c,d
2
3
3
3
3
4s/56
38
20
23
18
(2b)
(2b)
N
H
4s/74
N
3
4t/72
H
(2c)
(2e)
N
H
4
4u/75
(2d)
(2f)
5
6
7
5
5
3
Trace
Trace
4v/85
64
68
12
N
H
N
H
N
H
(2g)
8
5
4w/87
11
N
H
O
(2h)
(2i)
9
5
5
4x/52
43
75
N
H
Ph
N
H
Ph
10
Trace
(2j)
Ph
NH2
11
12
3
3
Trace
Trace
42
35
(2k)
Ph NH2
(2l)
a
Unless otherwise specified, the reactions were carried out in 6.0 mL water with 0.3 mmol 1b, 4.0 equiv 2 and 4.0 equiv formalin (based on the pure formaldehyde) in the
presence of 10 mol % SDS at 90 °C.
b
Isolated yield after chromatographic purification.
The solution of dimethylamine in water (40%) was used.
The reaction was performed 6.0 mL water with 0.3 mmol 1b, 2.0 equiv 2b and 4.0 equiv formalin in the presence of 10 mol % SDS at 90 °C.
c
d

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X.-L. Liu et al. / Tetrahedron Letters 52 (2011) 903–906
O
R
R'
-OH
R
N
+
H
H
H
2
3
R'
O
N
R
R2
O
R2
N
R'
H
R2
H
H
iminium ion
3
O
H
N
R1
N
R1
OH
N
R1
OH
1
R
R2
OH
O
R2
N
R'
O
N
N
R1
R1
5
4
Scheme 2. Proposed reaction pathway for the aminomethylation of 3-substituted oxindoles.
N. V.; Sahin, A. H.; Chang, W.; Fettinger, J. C.; Franz, A. K. Angew. Chem., Int. Ed.
2010, 49, 744–747; (i) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548–
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presumably of great priority compared to the aldol reaction in the
reaction system, therefore, the aminomethylation products were
observed as major products in most cases. In contrast, in the case
of using some bulky structure amines or primary amines as sub-
strates (Table 3, entries 5 and 6 and 10–12), maybe the preferential
reaction is aldol reaction, thus affording the hydroxymethylation
product as the major product.
In conclusion, we have developed a simple and eco-friendly ap-
proach for the aminomethylation of various 3-substituted oxin-
doles with the three-component Mannich reaction of 3-
substituted oxindoles, secondary amines, and formalin. This trans-
formation can furnish a variety of oxindoles bearing a quaternary
carbon center at the C3 position in good yields with 10% SDS as
additive in water. Particularly valuable features of this method in-
clude employing cheap and easily available formalin as useful ami-
3. For selected examples about organocatalyzed reactions, see: (a) Hills, I. D.; Fu,
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nomethylation C1 unit, using water as
a reaction medium.
Meanwhile, we also observed hydroxymethylation product as a
major product in some examples, while using bulky structure sec-
ondary amines or primary amines as substrates. Further studies to-
ward the development of more efficient protocol for the
preparation of structurally diverse oxindoles are ongoing in our
laboratory.
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 20802074).
4. Our recent research about using oxindoles as nucleophiles, (a) Liao, Y.-H.; Liu,
X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896–
2899; (b) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. J.
Org. Chem. 2010, 75, 4872–4875, to our delight, this article has been selected by
the Editorial Board of SYNFACTS for its important insights, see: Synfacts 2010, 9,
1065.
Supplementary data
5. The first stereoselective Mannich reaction of 3-substituted oxindoles with
imines was reported by Chen et al., see Ref. 3h.
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Supplementary data associated with this article can be found, in
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9. Formalin we used in this work, is an aqueous solution of formaldehyde and
contains 37% formaldehyde by volume.
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10. The amount of formalin used in the reaction is based on the pure
formaldehyde.
11. The compound 4d was confirmed by 1H NMR spectroscopy of the crude
reaction mixture and TLC analysis.
12. The trace amount of aminomethylation products (<10% yield) were monitored
by TLC.