An efficient catalytic reductive amination: A facile one-pot access to 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones by using B(C 6 F 5 ) 3 /NaBH 4

Article abstract of DOI:10.1007/s12039-015-0825-y

An efficient combination of B(C₆F₅)₃ and NaBH₄ was developed for direct reductive amination of aldehydes. A wide range of functional groups such as ester, nitro, nitrile, halogen, alkene, heterocycles were tolerated. Also, acid sensitive protecting groups like TBDMS and TBDPS were not affected. In addition, the present methodology was extended for tandem amination-amidation of 3-formyl-indole-2-carboxylic acids with substituted anilines to afford 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-015-0825-y

J. Chem. Sci. Vol. 127, No. 4, April 2015, pp. 711–716. ꢀc Indian Academy of Sciences.
DOI 10.1007/s12039-015-0825-y
An efficient catalytic reductive amination: A facile one-pot access to
1
,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones by using B(C F ) /NaBH
6 5 3 4
∗
ATULYA NAGARSENKAR, SANTOSH KUMAR PRAJAPTI and NAGENDRA BABU BATHINI
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Balanagar,
Hyderabad 500037, India
e-mail: bathini@niperhyd.ac.in
MS received 21 August 2014; revised 13 November 2014; accepted 14 November 2014
Abstract. An efficient combination of B(C6F5)3 and NaBH4 was developed for direct reductive amination
of aldehydes. A wide range of functional groups such as ester, nitro, nitrile, halogen, alkene, heterocycles
were tolerated. Also, acid sensitive protecting groups like TBDMS and TBDPS were not affected. In addition,
the present methodology was extended for tandem amination-amidation of 3-formyl-indole-2-carboxylic acids
with substituted anilines to afford 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones.
Keywords. Reductive amination; Lewis acid; tris(pentafluorophenyl)borane; sodium borohydride; less-toxic;
tandem reaction.
LiBH4,9b NaBH /H PW O ,
9c
NaBH /(GuHCl),
4
9d
1
. Introduction
4
3
12 40
10a
10b,c
10d
NiCl /NaBH , pyridine/borane,
picoline/borane,
2
4
Substituted amines are very important industrial organic
compounds owing to their widespread applications as
bioactives, solvents, textile additives, raw materials for
resins, rubber stabilizers, disinfectants, corrosion inhib-
11a
11b
Et SiH/CF CO H, PMHS/BuSn(OCOR) , PhSiH3/
Bu SnCl , Bu SnH/DMForHMPA, PMHS/TFA,
Zr(BH ) /piperazine, bis(triphenylphosphine)copper(I)
tetrahydroborate, phosphonium borates, etc., have
been employed for direct reductive amination.
On the other hand, in terms of reaction conditions,
functional group tolerance and side reactions, most of
these reagents have one or more drawbacks. Earlier,
3
3
2
3
11c n
11d
12a
2
2
3
12b
4
4
12c
12d
1
itors and in the manufacture of detergents and plastics.
Furthermore, they are used as crucial organic interme-
diates for synthesis of natural products, pharmaceuti-
cals and agrochemicals, and have broad applications in
2
synthetic and combinatorial chemistry (figure 1).
NaBH has been used with various Brønsted acids,
4
The simplest approach for the synthesis of amines in-
volves imine reduction or direct reductive amination of
carbonyl compounds. Metal-catalyzed hydrogenation
and hydride reduction are the two strategies used for
which facilitates Brønsted imine formation for suc-
cessful reductive amination. Brønsted catalysts such
as H SO or p-toluenesulfonic acid are commonly
2
4
used, even though these are corrosive, toxic and dif-
3
a
direct reductive amination of aldehydes with amines.
9c
ficult to separate from the reaction solution. Hence,
Metal-catalyzed hydrogenation has limitations to many
substrates bearing reducible functionalities apart from
imines, such as compounds containing a carbon-carbon
double or triple bond groups and other reducible func-
there is an interest to substitute these acids with
more environment-friendly Lewis acids. Lately, var-
ious research groups are engaged in investigating
the potential efficacy of tris(pentafluorophenyl)borane
3
b
tional groups including nitro, cyano and furyl.
A
[
B(C F ) ] as it is non-conventional, less-toxic, air-sta-
6 5 3
n
4a
n
variety of reagents such as Bu SnH/SiO and Bu
13a,b
3
2
2
ble, water-tolerant and thermally stable Lewis acid.
4
b
n
4c
5a
SnIH or Bu SnClH, diborane/MeOH, NaBH4/
Bronsted acidic ionic liquid, NaBH(OAc) , hydrio-
iridium(III) complex, ammoniaborane/Ti(OiPr) ,
2
Recently, our group reported an efficient protocol invol-
5
b
5c
3
ving the use of B(C F ) as an activator in acylation of
6
5 3
5
d
5e
13a
4
a variety of alcohols, phenols, thiophenols, and amines.
In continuation to our interest in developing novel
synthetic methodologies, herein we report a facile
and rapid approach for reductive amination of aldehy-
des in the presence of sodium borohydride and cat-
alytic amount of B(C F ) at room temperature. Most
6
a
6b
6c
PMHS/Ti(OiPr) ,
PMHS/ZnCl ,
PMHS/AlCl ,
4
2
3
6
d
6e
7a
7b
8a
ZnBH , ZnBH /ZnCl , ZnBH /SiO , Zn/AcOH,
4
4
2
4
2
7
c
7d
NaBH /ZnCl , NaBH /ZrCl , Ti(OiPr) /NaBH ,
4
2
4
4
4
4
8
b
3a
8c
9a
NaBH /H SO , NaBH /Fe(OTf) , NaBH /wet clay,
4
2
4
4
3
4
2
solid acid activated NaBH , TiCl(OiPr) /NaBH(OAc) ,
4
3
3
6
5 3
∗
significantly, B(C
6
F
5
)
3
/NaBH
4
can also be employed
For correspondence
711

712
Atulya Nagarsenkar et al.
Scheme 1. B(C6F5)/NaBH4 mediated synthesis of N-
benzylaniline and 2-phenyl-1,2- dihydropyrrolo[3,4-b]indol-
(4H)-one.
Figure 1. Selected examples of pharmaceutically impor-
tant substituted amines.
3
for efficient one-pot synthesis of substituted 1,2-
dihydropyrrolo[3,4-b]indol-3(4H)-ones (scheme 1).
Molecules comprising this scaffold exhibit potent
13c
biological activities mainly renin-inhibition and CNS
depressant activity (figure 2).1 In 1967, Owellen, et al.,
demonstrated the first method for synthesis of 1,2-
dihydropyrrolo[3,4-b]indol-3(4H)-one skeleton, it was
achieved by refluxing 3-amino-4-(2-aminophenyl)-
3d
14a
1
-cyclohexyl-1H-pyrrol-2(5H)-one in acetic acid.
Later in 1990, Kempf, et al., reported a multi-step
approach to synthesize this scaffold, involving Pd/C
hydrogenation as a crucial step.1 Hence, an efficient
and convenient synthesis of this scaffold is not yet repor-
4b
Figure 2. Bioactive
molecules
comprising
of
ted. To the best of our knowledge, the present protocol 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one scaffold.
is the first demonstration of Lewis acid catalyzed one-pot
synthesis of 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones.
Table 1. Effect of Lewis acid concentration on yields
towards reductive amination of aldehydes.
a
2. Experimental
Yield (%)b
Entry
B(C6F5)3 (mol%)
Time (min)
2
.1 General procedure
1
2
3
4
0.5
1
2
68
90
90
88
75
25
25
25
To a stirred solution of aldehyde/3-formyl-indole-2-
carboxylic acid (1.0 mmol) and amine/aniline (1.0
mmol) in ethanol (4 mL), tris(pentafluorophenyl)borane
3
aReaction conditions: Benzaldehyde (1 mmol), aniline (1
mmol), NaBH (2 mmol) and ethanol (4 mL) as solvent at
(1 mol%) was added. After 15 min, NaBH (2.0 mmol)
4
4
was added at room temperature. On completion of the room temperature.
b
reaction (as monitored by TLC), the reaction mixture
was quenched with water, later extracted with ethyl
acetate. Organic layer was dried under vacuum and col-
umn chromatography was carried out for the purifica-
tion product (Silica gel, n-hexane/ethyl acetate).
Isolated yields.
tris(pentafluorophenyl)borane (1 mol%) was added.
After 15 min, NaBH 3.5 g (2.0 mmol) was added
4
slowly at room temperature. On completion of the
reaction (as monitored by TLC), the reaction mix-
ture was quenched with water, later extracted with
ethyl acetate. Organic layer was dried under vacuum
and column chromatography (Silica gel, n-hexane/ethyl
2.2 Scale-up procedure for the synthesis of N-benzyl
aniline
To a stirred solution of benzaldehyde 5g (1.0 mmol) acetate) was carried out for the purification product
and aniline 4.4g (1.0 mmol) in ethanol (25 mL), (7.6 g, 86%).

A facile one-pot access to 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones
713
Table 2. B(C6F5)3/NaBH4 mediated reductive amination of aldehydes with amines.a
Entryref
14a
R
R1
Yield (%)b
Time (min)
90
86
25
1a
30c
29c
88
75
87
89
35
35
32
24
311d
411d
515a
612b
72
85b
915b
88
82
88
83
25
31
28
22
1
015b
115c
75
90
25
25
1
1
215d
89
25
1
1
1
39c
88
85
87
30
22
25
415e
515f
1
615g
90
30
1
715h
815h
89
88
30
25
1
19
85
25
20
83
28
aReaction conditions: Aldehyde (1 mmol), amine (1 mmol), B(C6F5)3 (1 mol%),
NaBH4 (2 mmol) and ethanol (4 mL) as solvent at room temperature.
b
Isolated yields.
Reaction scaled-up to 5g.
c

714
Atulya Nagarsenkar et al.
Table 3. B(C6F5)3/NaBH4 mediated one-pot synthesis of substituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones.a
Entryref
115i
R (a)
H
R1 (b)
Product (c)
Yield(%)b
86
Time (min)
45
1c
2
3
H
H
2c
3c
83
82
52
38
4
H
4c
80
35
5
6
H
5c
6c
82
85
37
40
Ethyl
7
8
Ethyl
Ethyl
7c
8c
82
81
45
48
9
Ethyl
9c
79
43
1
0
1
Ethyl
10c
11c
83
85
45
38
1
Benzyl
1
2
3
Benzyl
Benzyl
12c
13c
82
81
42
35
1
14
Benzyl
14c
84
40
1
5
6
Benzyl
Benzyl
15c
16c
80
89
42
40
1
aReaction conditions: 3-Formyl-indole-2-carboxylic acid (1 mmol), aniline (1 mmol), B(C6F5)3 (1 mol%), NaBH4 (2 mmol)
and ethanol (4 mL) as solvent at room temperature.
b
Isolated yields.
3
. Results and Discussion
in concentration of catalyst, we kept the same reaction
using different concentration of B(C F ) (table 1).
6
5 3
Present strategy was tested with the help of a model With 0.5 mol% concentration, 68% yield was obtained
study involving direct reductive amination of benzalde- (table 1, entry 1) whereas, 1 and 2 mol% afforded 90%
hyde with aniline using 1 mol% of B(C F ) and yield (table 1, entries 2 and 3). With further increase
6
5 3
2
mmol of NaBH , which proceeded smoothly with in concentration of B(C F ) there was no improvement
4
6 5 3
excellent yield (scheme 1). To study the effect of change in yield and reaction time (table 1, entry 4). Hence, we

A facile one-pot access to 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones
715
moved forward taking into account 1 mol% as optimum Table 4. Comparative study using different Lewis acids
towards synthesis of 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
catalyst concentration for the reaction.
a
ones.
To further examine the generality and scope of
the present protocol, diverse range of aldehydes were
subjected to reductive amination by using sodium
borohydride as reductant and B(C F ) (1 mol%) as a
Yield (%)b
Entry
Lewis acid
Time (min)
1
2
3
4
5
Fe(OTf)3
AlCl3
I2
BF3.OEt2
B(C6F5)3
69
77
36
78
86
60
50
120
60
6
5 3
catalyst (table 2). Reaction with substrate having no
reducible functionalities gave excellent yield (table 2,
entry 1). Substrates bearing potentially reducible func-
tional groups including nitro (table 2, entries 2 and 3),
cyano (table 2, entry 4), cinnamyl (table 2, entry 13)
and ester (table 2, entry 7) afforded the anticipated
products in the absence of detectable reduction side
products. Reaction with substrates having electron
donating group proceeded smoothly with good yields
45
aReaction conditions: 3-Formyl-1H-indole-2-carboxylic acid
1 mmol), aniline (1 mmol), 1 mol% Lewis acid, NaBH4
2 mmol) and ethanol (4 mL) as solvent at room temperature.
(
(
b
Isolated yield.
products. Thus, it can be assumed that electron donat-
ing and electron withdrawing groups have a significant
influence on the reactivity of aniline.
(
table 2, entries 8 and 9). Substrates substituted with
halogens like bromo, chloro and iodo (table 2, entries 5,
and 10) provided good yields. Heterocyclic substrates
6
To include more diversity in substrates, we used
different N-substituted 3-formyl-indole-2-carboxylic
acids. NH proton of these 3-formyl-indole-2-carboxylic
like furan-2-carbaldehyde (table 2, entry 11), 1H-
indole-3-carbaldehyde and tryptamine (table 2, entries
14d
1
2 and 16) reacted smoothly to afford desired prod-
acids were substituted with ethyl
(table 3, entries
ucts in excellent yields. In case of aliphatic alde-
hyde and amine, reaction preceded smoothly giving
commendable yields (table 2, entries 14 and 15).
Substrates bearing acid sensitive protecting groups
like TBDMS and TBDPS afforded products in good
yields without any deprotected side products (table 2,
entries 19 and 20). Substrates containing chiral centres
such as (R)-1-(naphthalen-1-yl)ethanamine and (R)-1-
phenylethanamine (table 2, entries 17 and 18) gave
desired products in 89% and 88% yields, respectively,
without any detrimental effect on chirality.
6
–10) and benzyl (table 3, entries 11–16). Interestingly,
reactions using these substrates proceeded smoothly
and afforded fine yields (79–89%). p-anisidine gave
high yield (table 3, entry 16).
Presumably, B(C F ) activates the carbonyl func-
6
5 3
tionality to afford very reactive electrophile source.
Amine used as substrate reacts with the activated alde-
hyde to provide hemiaminol equivalent followed by
dehydration episode that regenerates the catalyst. In situ
generated imine is further reduced with sodium borohy-
dride affording the secondary amine which later reacts
with activated acid to undergo amidation to afford the
In the light of above findings, we extended the scope
of present protocol in the synthesis of 1,2-dihydropyrrolo
1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one.
[
3,4-b]indol-3(4H)-ones (table 3). To begin with, 3-
We also compared the efficiency of B(C F ) with
6
5 3
formyl-1H-indole-2-carboxylic acid was synthesized
by using reported procedure.1 Under the optimized
reaction conditions, a wide range of substituted amines
were investigated for tandem amination–amidation of
other Lewis acids such as Fe(OTf) , AlCl , I & BF
3
3
2
3
4c
etherate for one-pot synthesis of 1,2-dihydropyrrolo
3,4-b]indol-3(4H)-one (table 4). It was found that
B(C F ) was superior than other Lewis acids in terms
[
6
5 3
3-formyl-1H-indole-2-carboxylic acid to synthesize the
of yield as well as reaction time.
corresponding1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones.
Interestingly, it was observed that only aniline deriva-
tives produced the subsequent 1,2-dihydropyrrolo[3,4-b]
indol-3(4H)-ones in good yields (table 3, entries 1–5).
The present protocol was unfruitful when the reactions
were carried out using benzyl and aliphatic amines.
The reactions with aniline derivatives bearing elec-
tron donating groups like methyl (table 3, entries 4
and 5), isopropyl (table 3, entry 3) proceeded with
good yields. Aniline having chloro substitution (table 3,
entry 2) afforded the desired product in good yield
whereas, anilines substituted with electron withdrawing
groups like nitro and cyano failed to provide the desired
4
. Conclusion
In summary, we have demonstrated a facile and novel
method for reductive amination of aldehydes using
B(C F ) /NaBH as an efficient combination. Addition-
ally, we developed a novel protocol for onepot synthesis
of substituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
ones via Lewis acid catalyzed tandem amination-
amidation method. Striking advantages of present meth-
od are functional group tolerance, environmental benign-
ness, rapid reaction, high yields of desired products, low
6
5 3
4

716
Atulya Nagarsenkar et al.
catalyst loading, less-toxicity of catalyst, and simple
experimental procedure.
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Supporting Information
Spectral data (1H and 13C) are available as part of the
supporting information at www.ias.ac.in/chemsci.
1
Acknowledgements
We thank the Department of Pharmaceuticals (Ministry
of Chemicals and Fertilizers) for providing funds and
also CSIR-Indian Institute of Chemical Technology, 11. (a) Chen B-C, Sundeen J E, Guo P, Bednarz M S
and Zhao R 2001 Tetrahedron Lett. 42 1245; (b)
Lopez R M and Fu G C 1997 Tetrahedron 53 16349;
Hyderabad for providing the facilities.
(
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