Mannich Reaction of Indole with Cyclic Imines in Water

Article abstract of DOI:10.1016/j.tetlet.2017.12.069

An efficient MsOH promoted direct Mannich reaction of indoles with α-nonsubstituted aliphatic cyclic imines has been developed. The reactions were performed in water and the obtained piperidin-2-yl-indoles act as a useful precursor for the synthesis of various alkaloid-like derivatives.

Full text of DOI:10.1016/j.tetlet.2017.12.069

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Mannich Reaction of Indole with Cyclic Imines in Water
Liang-Hui Xie, Jie Cheng, Zi-Wei Luo, Gui Lu
PII:
S0040-4039(17)31600-3
https://doi.org/10.1016/j.tetlet.2017.12.069
TETL 49571
DOI:
Reference:
Tetrahedron Letters
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29 October 2017
18 December 2017
23 December 2017
Please cite this article as: Xie, L-H., Cheng, J., Luo, Z-W., Lu, G., Mannich Reaction of Indole with Cyclic Imines
in Water, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.069
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Mannich Reaction of Indole with Cyclic Imines in Water
Liang-Hui Xie, Jie Cheng, Zi-Wei Luo, Gui Lu∗
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient MsOH promoted direct Mannich reaction of indoles with α-nonsubstituted aliphatic
cyclic imines has been developed. The reactions were performed in water and the obtained
piperidin-2-yl-indoles act as a useful precursor for the synthesis of various alkaloid-like
derivatives.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Mannich reaction
Brønsted acids
Aliphatic cyclic imines
Water
Indole
The Mannich reaction is an important reaction for the direct
construction of new C–C and C–N bonds. Its endproducts,
Mannich bases have attracted more and more attention of
chemists due to their specific biological activities, such as
aliphatic cyclic imines. In their catalytic system, moisture-
sensitive catalyst was used, and cyclic imines were limited to α-
polyfluoroalkylated (CF3- and C2F5-substituted) cyclic imines,
while non-fluorinated cyclic imines that containing a phenyl or
butyl moiety didn’t work at all in the same reaction. Later,
Monaco and co-workers reported the Mannich reaction of
ketones with aliphatic cyclic imines,23 albeit the reaction time
was extremely long and the yield was quite low. In this sense,
low reactivity is a huge challenge for the direct Mannich reaction
of aliphatic cyclic imines. Herein, we are devoted to exploring
the reactions between α-nonsubstituted aliphatic cyclic imines
and indole under the appropriate conditions, our aim is to provide
a general synthetic methodology for these saturated nitrogen
heterocycles.
antiviral,1
acetycholinesterase
inhibitory,2
antioxidant,3
antiproliferative.4 What’s more, Mannich bases are also key
precursors to access amino alcohols, peptides, lactams and
optically active amino acids.5-6
On the other hand, saturated nitrogen heterocycles are also
important structural elements that exist in many bioactive
compounds.7 In recent years, more than half of the FDA
approved small-molecule drugs contain nitrogen heterocycles.8
We noticed that the less studied aliphatic cyclic imines might act
as starting point to simplify the preparation of various alkaloid-
like saturated nitrogen heterocycles. For example, the Mannich
reaction of cyclic imines with indole derivatives might provide a
direct way to piperidinyl-substituted indoles, whose core
structure was present in many bioactive compounds (Figure 1).9-
12
This new methodology might also be used for the easy
synthesis of some important drugs as BCX4430 and Veliparib
(Figure 2).
The indole moiety is a privileged structural motif in many
biologically active and medicinally valuable molecules,13 such as
anticancer drugs,14 anti-inflammatory agents,15 antibacterials,16
and anti-HIV drugs.17 Although Mannich reaction of indole with
aromatic cyclic imines has already been reported,18-20 aliphatic
cyclic imines were rarely used owing to their low activities and
stabilities.21 In 1954, van Tamelen and co-workers reported the
direct synthesis of β-(2-piperidy)-indoles by aliphatic cyclic
imines with low yields (40-55%).22 Recently, Shevchenko and
co-workers described the Mannich reaction of indole with
———
Figure 1. Bioactive compounds containing piperidinyl-
substituted indoles
∗ Corresponding author. Tel.: 86-20-39943048, fax: 86-20-39943048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu)

2
Tetrahedron
yield of 3a dropped sharply in THF (Table 2, entry 2). Carrying
out the reaction in CH2Cl2 or CHCl3 could afford 3a with
moderate yield (Table 2, entries 3-4). When the reaction was run
in DCE, MeCN and MeOH, lower yields of the target products
were obtained (Table 2, entries 5, 6, 8). The best result was
observed in H2O/MeOH (2:1) in comparison with other organic
solvents (Table 2, entry 9). In view of the differences of yield
among THF, H2O/THF (2:1), MeOH and H2O/MeOH (2:1), we
also tried H2O as a sole solvent, and obtained satisfactory yield
(Table 2, entry 10). We assumed that MsOH in water might be
benificial for the protonation of imine 1a.
Figure 2. Drugs containing saturated nitrogen heterocycles
Cyclic imine 1a and indole 2a were chosen as representative
substrates in our initial survey of reaction conditions. In the
absence of any activator, no reaction was observed (Table 1,
entry 1). So our efforts were concentrated on the looking for a
proper activator for this transformation. We first tried different
Brønsted acids, and found that MsOH was the best acid (Table 1,
entry 2), other Brønsted acids such as CF3COOH, CH3COOH,
CF3SO3H, PhCOOH, H3PO4, HCl, H2SO4 and Amberlyst 15
resulted in lower yields for the target product. This reaction
didn’t take place when L-proline was employed. We also tried
several Lewis acids, but only obtained poor yields when using
Cu(OTf)2 or ZnF2 (Table 1, entries 13-14). We speculated that
the proper acidity of MsOH might be essential for this
transformation, for both stronger acids (CF3COOH, CF3SO3H)
and weaker acids (CH3COOH, PhCOOH) exhibited inferior
catalytic activities.
Table 2
Screening of solvents, additives and temperatures for the reaction
of indole with cyclic iminea
T
(°C)
40
40
40
40
40
40
40
40
40
40
60
80
40
40
40
40
40
40
40
25
60
80
Yieldb
(%)
80
8
Entry
Solvent
Additive
y =
1
2
H2O/THF=2:1
THF
-
-
3
CH2Cl2
CHCl3
DCE
-
51
55
10
7
4
-
5
-
Table 1
Screening of acids for the reaction of indole with cyclic iminea
6
MeCN
toluene
MeOH
H2O/MeOH=2:1
H2O
-
-
7
nd
25
85
75
75
52
83
79
76
81
77
76
80
27
84
84
8
9
-
-
10
11c
12d
13
14
15
16
17
18
19
20e
21c
22d
-
H2O
H2O
-
-
H2O
H2O
TBAI
TBAB
SDS
PEG-400
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
30
30
30
30
10
20
50
30
30
30
H2O
H2O
Entry
Acid
x =
Yieldb (%)
H2O
H2O
H2O
H2O
1
2
-
MsOH
-
nd
80
72
32
8
100
100
100
100
100
100
100
100
100
100
100
100
100
80
3
TsOH•H2O
CF3COOH
CH3COOH
CF3SO3H
PhCOOH
L-proline
H3PO4
4
H2O
H2O
5
6
5
a Reaction conditions: imine 1a (0.4 mmol), indole 2a (0.33 mmol), MsOH
(0.33 mmol), solvent 5 mL.
7
7
8
9
nd
16
53
46
9
b Determined by GC-MS analysis.
c Reaction time was 18 h.
10
11
12
13
14
15
16
17
18
HCl
H2SO4
d Reaction time was 12 h.
e Reaction time was 60 h.
Amberlyst 15
Cu(OTf)2
ZnF2
TBAI=tetrabutylammonium iodide, TBAB=tetrabutylammonium bromide,
SDS=sodium dodecyl sulfate, PEG-400=poly(ethylene glycol)-400.
9
47
15
79
79
78
MsOH
MsOH
As we all know, the use of organic solvents in organic
synthesis is an incessant source of worry, since it gives rise to
toxicity, hazard, pollution issues, etc. On the contrary, water
offers many advantages because it is a cheap, readily available,
non-toxic and non-flammable solvent.24 Therefore we chose
water as optimal solvent, and several common surfactants were
used as additives to improve the solubility of indole in water.
When 30 mol% of TBAI was used, the yield of 3a was even
higher than that in pure H2O (Table 2, entries 13-16). 30 mol%
was also proved to be the optimum amount of TBAI. Decreasing
or increasing the amount of TBAI resulted in lower yield (Table
2, entries 17-19).
120
150
200
MsOH
MsOH
a Reaction conditions: imine 1a (0.4 mmol), indole 2a (0.33 mmol), solvent
(5 mL) at 40 °C for 36 h.
b Determined by GC-MS analysis.
The reaction was then run with different molar ratios of
MsOH (80 mol%, 100 mol%, 120 mol%, 150 mol%, and 200
mol%, respectively). The optimum loading of MsOH was 100
mol% (Table 1, entry 2). The yield didn’t improve when the
loading of acid was higher than 100 mol% (Table 1, entries 16-
18), while a decrease of MsOH to 80 mol% resulted in a
significant drop in yield (Table 1, entry 15).
Finally, the reaction temperature was also investigated. The
yield of 3a dropped sharply due to a poor conversion when the
reaction was run at 25 oC (Table 2, entry 20). Higher
temperatures (40 oC, 60 oC and 80 oC) afforded comparable yields
Next we performed the reaction in different solvents. As we
know, good yield was obtained in H2O/THF (2:1), whereas the

Table 3
Reaction of various cyclic imines with indole derivativesa
decreased obviously. We speculated that TBAI could restrain
side reaction effectively (Table 2, entries 12 vs 22).
With the optimal conditions in hand (Table 2 entry 19), we
then extended the scope of the reaction to different combinations
of cyclic imines and indole derivatives (Table 3). Firstly, we
examined various indole derivatives in the reaction with cyclic
imine 1a, in most cases the corresponding Mannich adducts can
be obtained in good yields except these indole substrates with
halogenic substituent in C-5 position. Longer reaction time and
higher reaction temperature are beneficial for this transformation.
The yields of 3g (5-fluoroindole substrate) and 3h (5-
chloroindole) reached 57% and 43%, respectively in 30 h, the
yield of 3h can be further improved to 53% at high temperature
R1
NH
R1
MsOH (100 mol%)
TBAI (30 mol%)
R2
R2
N
R3
H2O, 60 oC, 18 h
N
R3
N
1a-1d
2
3a-x
Me
NH
N
H
o
NH
N
H
N
N
NH
NH
(80 C). 5-Bromoindole seems more inert in this reaction, only
37% yield of 3i was isolated after 60 h.
H
H
Me
The cyclic imine 1b with methyl substituent gave results
comparable to 1a, and the corresponding products were highly
trans-selective. This stereochemistry was confirmed by NOESY
experiments, and it is easy to conclude that 3m is trans-adduct
owing to NOESY correlation of “Me-H1”, “Me-H5a” and “H1-
H5a” (Figure 3). For the reaction of N-methyl protected indole
substrate, cyclic imine 1b was more active than 1a (Table 3,
entries 12 vs 17). The isoquinoline-derived cyclic imine 1c and
five-membered cyclic imine 1d also proceeded well in this
reaction, affording products 3r-x in good yields.
Me
3d
3a
3b
3c
68%
74%
77%
78%
N
N
N
N
NH
NH
NH
NH
H
H
H
H
MeO
3f
HO
3e
F
Cl
c
b
68%
78%
3h
3g
53%
57%
N
N
NH
NH
H
N
N
H
H
Me
N
NH
H
Me
Br
Me
d
3j
3k
3l
75%
77%
55%
3i
37%
Me
Me
Me
Me
N
H
NH
N
H
N
H
N
H
NH
NH
Me
NH
OMe
MeO
e
g
h
f
3m
3o
78%
75%
3p
3n
75%
72%
Me
NH
NH
NH
N
H
Me
N
Me
MeO
NH
NH
NH
i
3r
3s
3t
78%
77%
75%
3q
75%
Me
NH
NH
NH
NH
N
H
Me
Figure 3. NOESY correlation for 1,3-trans adduct 3m
F
NH
NH
NH
In conclusion, a green and efficient Mannich reaction of
indoles with cyclic imines has been developed. A variety of
piperidin-2-yl-indoles were obtained in good yields. The
advantage of our presented methodology is the realization of
Mannich reaction of indole with more generic α-nonsubstituted
aliphatic cyclic imines and the utilization of water as solvent. In
view of the potential applications of these piperidin-2-yl-indoles,
their asymmetric synthetic methodologies are being performed in
our laboratory.
Me
3u
3v
3w
3x
57%
79%
79%
71%
a
Reaction conditions: imine 1 (0.4 mmol), indole 2 (0.33 mmol), MsOH
(0.33 mmol), TBAI (0.1 mmol), H2O 5 mL. Isolated yield.
b Reaction time was 30 h.
c Run at 80 °C for 30 h.
d Run at 80 °C for 60 h.
The ratio of 1,3-trans/1,3-cis = 17:1, which was determined by 1H NMR
e
spectroscopic analysis.
f 1,3-trans/1,3-cis = 12:1.
g 1,3-trans/1,3-cis = 17:1.
h 1,3-trans/1,3-cis = 17:1.
Acknowledgments
i
1,3-trans/1,3-cis = 14:1.
This work was financially supported by the National Science
and Technology Major Project of the Ministry of Science and
Technology of China (2017ZX09305010), Guangdong Province
(84%) along with significantly shorter reaction time (Table 2,
entries 13, 21-22, 36 h, 18 h and 12 h respectively). Interestingly,
when we run the reaction at 80 oC without TBAI, the yield

4
Tetrahedron
12. Yu, C.-Y.; Hu, X.-G. CN Patent 101693708, 2008.
13. Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev., 2014, 114,
7108-7149.
Natural Science Foundation (No. 2015A030313184), Science
and Technology Program of Guangzhou (No. 201607010118).
14. Sherer, C.; Snape, T. J. Eur. J. Med. Chem., 2015, 97, 552-560.
15. Kaila, N.; Huang, A.; Moretto, A.; Follows, B.; Janz, K.; Lowe,
M.; Thomason, J.; Mansour, T. S.; Hubeau, C.; Page, K.; Morgan,
P.; Fish, S.; Xu, X.; Williams, C.; Saiah, E. J. Med. Chem., 2012,
55, 5088-5109.
References and notes
1. Roman, G. Eur. J. Med. Chem., 2015, 89, 743-816.
2. Liu, H.-R.; Huang, X.-Q.; Lou, D.-H.; Liu, X.-J.; Liu, W.-K.;
Wang, Q.-A. Bioorg. Med. Chem. Lett., 2014, 24, 4749-4753.
3. Buravlev, E. V.; Shevchenko, O. G.; Kutchin, A. V. Bioorg. Med.
Chem. Lett., 2015, 25, 826-829.
16. Lee, J. H.; Wood, T. K.; Lee, J. Trends Microbiol., 2015, 23, 707-
718.
17. Wang, J.; Li, Y.; Yang, Y.; Zhang, J.; Du, J.; Zhang, S.; Yang, L.
RSC Adv., 2015, 5, 78278-78298.
4. Aeluri, R.; Alla, M.; Polepalli, S.; Jain, N. Eur. J. Med. Chem.,
2015, 100, 18-23.
5. Sahoo, S.; Joseph, T.; Halligudi, S. B. J. Mol. Catal. A: Chem.,
2006, 244, 179-182.
18. Wang, Y.-Q.; Wei, Z.-S.; Zhu, C.-Q.; Ren, Y.-Y.; Wu, C.-R.
Tetrahedron 2016, 72, 4643-4654.
19. Rueping, M.; Raja, S.; Núnez, A. Adv. Synth. Catal., 2011, 353,
563-568.
6. Muller, R.; Goesmann, H.; Waldmann, H. Angew. Chem., Int. Ed.,
1999, 38, 184-187.
7. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett., 2000, 2, 3679-3681.
8. Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem., 2014,
57, 10257-10274.
9. Rowley, M.; Hallett, D. J.; Goodacre, S.; Moyes, C.; Crawforth,
J.; Sparey, T. J.; Patel, S.; Marwood, R.; Patel, S.; Thomas, S.;
Hitzel, L.; O’Connor, D.; Szeto, N.; Castro, J. L.; Hutson, P. H.;
MacLeod, A. M. J. Med. Chem., 2001, 44, 1603-1614.
10. Rebecca, A. J.; Kudzovi, A. A.; Matthew, G. K.; Stuart, G. G.;
Andrew, H. S.; Lynn, S. D. International Patent 66126, 2005.
11. Matthias, N.; Olivier, R. US Patent 32976, 2008.
20. Wu, L.; Liu, R.-R.; Zhang, G.-Q.; Wang, D.-J.; Wu, H.; Gao, J.-
R.; Jia, Y.-X. Adv. Synth. Catal., 2015, 357, 709-713.
21. Shevchenko, N. E.; Shmatova, O. I.; Balenkova, E. S.;
Röschenthaler, G. V.; Nenajdenko, V. G. Eur. J. Org. Chem.,
2013, 2237-2245.
22. Van Tamelen, E. E.; Knapp, G. G.; J. Am. Chem. Soc., 1954, 77,
1860-1862.
23. Monaco, M.-R.; Renzi, P.; Schietroma, D. M. S.; Bella, M. Org.
Lett., 2011, 13, 4546-4549.
24. Simon, M. O.; Li, C.-J. Chem. Soc. Rev., 2012, 41, 1415-1427.

5
● Brønsted acid catalyzed direct Mannich reaction of indoles
with α-nonsubstituted aliphatic cyclic imines have been
developed.
● Water serves as a green solvent.
● Various piperidin-2-yl-indole precursors were obtained in
good yields.

6
Tetrahedron
Graphical Abstract
Leave this area blank for abstract info.
Mannich Reaction of Indole with Cyclic
Imines in Water
Liang-Hui Xie, Jie Cheng, Zi-Wei Luo, Gui Lu