Tunable hydride transfer in the redox amination of indoline with aldehyde: An attractive intramolecular hydrogen-bond effect

Article abstract of DOI:10.1002/chem.201001896

Hydride hijacked by "hydrogen"! N-Alkylindoles and N-alkylindolines were obtained in the redox amination of indoline with aldehyde, which was tuned by a hydrogen-bond effect. Salicylaldehyde gave the indoline-type product via intermolecular hydride transfer, while other aromatic aldehydes gave the indole-type product via intramolecular hydride transfer. Copyright

Full text of DOI:10.1002/chem.201001896

DOI: 10.1002/chem.201001896
Tunable Hydride Transfer in the Redox Amination of Indoline with
Aldehyde: An Attractive Intramolecular Hydrogen-Bond Effect
Hui Mao,[a] Runsheng Xu,[a] Jieping Wan,[a, b] Zhengyang Jiang,[a] Cuirong Sun,*[a] and
Yuanjiang Pan*[a]
Analogous to atom economy[1] and step economy,[2] redox
economy has received considerable attention in modern or-
ganic synthesis, especially in the total synthesis of natural
products since it was proposed by Baran in 2008.[3] Through
using the inherent reducing power of hydrogen to reduce
other functional groups, redox isomerizations can reduce the
additional steps of oxidation or reduction.[3b] Moreover, se-
À
lective C H bond functionalization has been accomplished
via intramolecular hydride transfer in the process of redox
isomerization.[4] Recently, redox amination has become a
[5]
À
very powerful tool in C N bond formation. Our group has
been interested in this field. Herein, we report a Brønsted
acid-catalyzed intermolecular redox amination of indoline 1
with aldehyde 2, which involves intramolecular hydride
transfer and gives N-substituted product 3 [Eq. (1)]. N-Al-
kylindoles are prevalent in numerous biologically active nat-
ural products and pharmaceutical compounds[6] and this
firstly presented manipulation is unprecedented among
those established protocols.[7] Additionally, a novel type of
Scheme 1. A proposed hypothesis for the formation of N-benzylindole
3a.
amination involving intermolecular hydride transfer is also
studied when salicylaldehyde is employed, which is switched
by intramolecular hydrogen bond and leads to N-alkylindo-
lines [Eq.(2)].
the final product 3a is formed from B by deprotonation.
The aromatization is considered to be the original motif of
this redox process, which distinguishes indoline from some
other cyclic secondary amine, such as tetrahydroquinoline
and morpholine.
To investigate the feasibility of this redox process, we ini-
tially tested the reaction of benzaldehyde (1 equiv) with in-
doline (2 equiv) in the presence of AcOH (0.2 equiv) at
1108C using toluene as reaction medium. Just as expected,
the reaction gave N-benzylindole with 40% yield (Table 1,
entry 1). Inspired by these results, we further investigated
this transformation under different conditions. Various
Brønsted and Lewis acids were evaluated as catalysts in this
reaction (Table 1, entries 2–7). Generally, Brønsted acids
catalyzed this reaction more efficiently than Lewis acids,
and benzoic acid was found to be the best among those
tested. Next, we began to study the solvent effect, and tolu-
Our original hypothesis for the formation of N-benzylin-
dole 3a involves the condensation of indoline 1 with benzal-
dehyde 2a in the presence of an acid (Scheme 1). The re-
sulting iminium ion A is supposed to undergo intramolecu-
lar hydride transfer to furnish intermediate B. Ultimately,
[a] H. Mao, R. Xu, Dr. J. Wan, Z. Jiang, Prof. Dr. C. Sun,
Prof. Dr. Y. Pan
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P. R. China)
Fax : (+86)571-87951629
E-mail: cheyjpan@zju.edu.cn
[b] Dr. J. Wan
College of Chemistry and Chemical Engineering
Jiangxi Normal University, Nanchang 330022 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001896.
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Chem. Eur. J. 2010, 16, 13352 – 13355

COMMUNICATION
Table 2. Representative intermolecular redox amination.[a]
ene turned out to be the best medium compared with
DMSO, DMF and 1,4-dioxane (Table 1, entries 8–10). Fur-
ther optimization was focused on reaction temperature, and
the best result was achieved at 1258C (Table 1, entries 11–
13). Remarkably, addition of 4 ꢁ MS led to higher yields
(Table 1, entry 14). The use of 2 equiv indoline was essential
to allow full conversion of aldehyde and provide high yield.
Entry
Aldehyde 2
Product 3
Yield [%][b]
Table 1. Optimization of intermolecular redox amination.[a]
1
2
3
4
5
6
7
8
R=H
3a
3b
3c
3d
3e
3 f
3g
3h
3i
76
R=o-OMe
R=o-OMOM
R=p-F
R=o-F
R=p-Cl
69[c]
68[c]
79
81
77
78
75
77
80
80
82
Entry
Catalyst
Solvent
T [8C]
Yield [%][b]
R=o-Cl
R=p-Br
R=o-Br
R=p-CF3
R=p-NO2
R=m-NO2
R=o-NO2
1
2
3
4
5
6
7
8
AcOH
TFA
p-TsOH
PhCOOH
FeCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
1,4-dioxane
toluene
toluene
toluene
toluene
110
110
110
110
110
110
110
110
110
110
115
125
130
125
40
41
45
60
trace
20
trace
58
48
45
9
10
11
12
13
3j
3k
3l
3m
85
TMSCl
CoCl2
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
14
3n
3o
73
70
9
10
11
12
13
14
65
70
67
76[c]
15
[a] Benzaldehyde (0.5 mmol), indoline (1.0 mmol) and catalyst in 2 mL of
solvent under nitrogen atmosphere for 18 h. [b] Yield of isolated product
based on benzaldehyde. [c] 4 ꢁ MS (20 mg) was added.
16
17
X=O
X=S
3p
3q
86
84
Under the established protocol, we next examined the
scope of this redox amination with a variety of different al-
dehydes. As shown in Table 2, various aldehydes bearing
electron-donating or -withdrawing groups on the aromatic
ring were treated with indoline to smoothly afford corre-
sponding N-alkylindoles in moderate to good yields
(Table 2, entries 1–13). Generally, the aldehyde substrates
having electron-donating groups demanded longer time and
got lower yields (Table 2, entries 2–3). 1-Naphthaldehyde
and 9-anthraldehyde were also found to react with indoline
to give desired products in good yields (Table 2, entries 14–
15). Furthermore, heteroaromatic aldehydes turned out to
be excellent partners for the redox amination (Table 2, en-
tries 16–18). While aromatic aldehydes having electron-do-
nating groups at para-position or aliphatic aldehydes were
employed, this redox process failed to give desired product.
Unexpectedly, when salicylaldehyde was employed in the
standard condition, instead of our desired product, the reac-
tion afforded N-alkylindoline 5a, of which the structure was
fully characterized by mass spectrometry and NMR spec-
troscopy. Encouraged by the novel amination, we subse-
quently examined the scope of the reaction, and typical re-
sults were summarized in Table 3.[8] To our delight, the reac-
tions proceeded smoothly to give N-alkylindolines in 73–
82% yields (Table 3, entries 1–4). In addition to indoline,
18
3r
80
[a] Aldehyde (0.5 mmol), indoline (1.0 mmol), PhCOOH (0.1 mmol) and
4 ꢁ MS (20 mg) in 2 mL toluene under nitrogen atmosphere for 18 h.
[b] Yield of isolated product based on aldehyde. [c] 30 h.
the 2-methylindoline also showed good reactivity, albeit
with longer time and lower yields (Table 2, entries 5–7).
In view of our original hypothesis, the indoline-type prod-
uct implies that this novel amination may involve intermo-
lecular hydride transfer. In the reaction system, obviously,
there are only two potential candidates, that is, salicylalde-
hyde[9] and indoline that can provide the external hydride.
Scheme 2. Isotopic labeling reaction.
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C. Sun, Y. Pan et al.
Table 3. Novel amination of indoline with salicylaldehyde.[a]
Entry
Salicylaldehyde 4
Product 5
Yield [%][b]
1
2
3
4
R=H
R=5-NO2
R=5-Cl
5a
5b
5c
5d
82
78
75
73
R=3,5-dibromo
Scheme 4. Proposed mechanism for this novel amination.
salicylaldehyde to afford addition product C, which subse-
quently transforms into intermediate D in the presence of
an acid. Due to the effect of intramolecular hydrogen bond
(N–H···O) in D, the intramolecular hydride transfer is inhib-
ited. After intermolecular hydride transfer from another
molecular indoline to D, the final product 5a is obtained.
Meanwhile, the intermediate iminium ion E, generated from
indoline, transforms into indole by deprotonation.
5[c]
6[c]
7[c]
R=H
R=5-Cl
R=3,5-dibromo
5e
5 f
5g
77
72
70
[a] Salicylaldehyde (0.5 mmol), indoline (1.25 mmol), PhCOOH
(0.1 mmol) and 4 ꢁ MS (20 mg) in 2 mL toluene under nitrogen atmos-
phere for 18 h. [b] Yield of isolated product based on benzaldehyde.
[c] 2-Methylindoline (1.25 mmol) was added instead of indoline, 30 h.
Although g-hydroxy indole 3s couldn’t be obtained direct-
ly from the reaction of indoline with salicylaldehyde, two
potential methods for its preparation had been achieved in
Scheme 5. Compound 3c, readily prepared from indoline,
was converted to 3s by deprotection in a straightforward
To investigate whether the hydride came from another mo-
lecular salicylaldehyde, an isotopic labeling reaction was car-
ried out between indoline and [D1]salicylaldehyde
(Scheme 2), which was prepared by reduction of salicylic
acid with LiAlD4 and subsequent oxidation with PDC.[10] As
shown in Scheme 1, the reaction gave [D]-5a with 78% iso-
lated yield while no [D2]5a was determined (see Supporting
Information for the full determination of [D]-5a). Accord-
ing to the result from the deuterium labeling experiment,
the external hydride is believed to come from another mo-
lecular indoline, which is also supported by the isolation of
same amount of byproduct indole.[11]
fashion. And treatment of 5a with PhI
ACHTUNGRTEN(NUNG OAc)2 in dioxane
also produced 3s in good yield.[13]
On the other hand, as shown in Scheme 3, when the hy-
Scheme 5. Synthesis of g-hydroxy indole 3s.
In summary, we have developed a Brønsted acid-catalyzed
redox amination of indoline with aldehyde for the synthesis
of N-alkylindoles and N-alkylindolines, in which an attrac-
tive intramolecular hydrogen bond effect was observed.
Through this efficient and economic protocol, a series of N-
alkylindoles were prepared from readily available aldehydes.
Furthermore, by employing salicylaldehyde in the reaction,
a novel type of amination involving intermolecular hydride
transfer is also demonstrated to synthesize N-alkylindolines.
We anticipate that this unique amination may stimulate sub-
Scheme 3. Effect of substituent groups at the ortho-position.
droxyl group of salicylaldehyde is protected by Me or
MOMO, the product becomes indole-type, indicating that
the hydroxyl group at ortho-position has an important
impact on the reaction process.[12]
Based on these results, we propose a mechanism for this
novel amination in Scheme 4. Initially, the indoline attacks
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Redox Amination of Indoline with Aldehyde
COMMUNICATION
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formation.
Representative procedure (3a): To
a
solution of benzaldehyde
(0.5 mmol), indoline (1.0 mmol) in toluene (2 mL) was added PhCOOH
(0.1 mmol) and 4 ꢁ MS (20 mg) under nitrogen atmosphere. The mixture
was stirred at room temperature for 0.1 h and then heated at 1258C for
another 18 h. After the completion of the reaction, the solvent was
evaporated off and the crude mixture was purified by flash column chro-
matography to give the product 3a in 76% yield.
Acknowledgements
We thank the National Natural Science Foundation of China (No.
21025207) and 20975092 for the financial support.
[9] The aldehyde also can be a potential candidate to supply the hy-
dride in some reactions, such as Cannizzaro reaction. For details,
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mowatari, S. Nagumo, N. Kawahara, H. Suemune, J. Org. Chem.
2004, 69, 1144.
Keywords: hydride transfer · hydrogen bonds · indoles ·
redox amination · redox chemistry
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[11] See Table S1 in the Supporting Information.
[12] For another example about the effect of the hydroxyl group at
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Received: July 6, 2010
Published online: November 4, 2010
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