Synthesis of free NH 2-(aminomethyl)indoles through copper-catalyzed reaction of 3-(ortho-trifluoroacetamidophenyl)-1-propargylic alcohols with amines and palladium/copper- cocatalyzed domino three-component Sonogashira cross-coupling/cyclization/substitu

Article abstract of DOI:10.1002/adsc.201400881

Free NH 2-(aminomethyl)indoles have been prepared via copper-catalyzed cyclization of 3-(ortho-trifluoroacetamidophenyl)-1-propargylic alcohols in the presence of primary or secondary amines. The synthesis has been developed into a simple and very efficie

Full text of DOI:10.1002/adsc.201400881

UPDATES
DOI: 10.1002/adsc.201400881
Synthesis of Free NH 2-(Aminomethyl)indoles through Copper-
Catalyzed Reaction of 3-(ortho-Trifluoroacetamidophenyl)-1-
propargylic Alcohols with Amines and Palladium/Copper-
Cocatalyzed Domino Three-Component Sonogashira
Cross-Coupling/Cyclization/Substitution Reactions
Sandro Cacchi,a Giancarlo Fabrizi,a Antonia Iazzetti,a Carmela Molinaro,a
Rosanna Verdiglione,a and Antonella Goggiamania,*
a
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universitꢀ di Roma, P.le A. Moro 5, 00185 Rome, Italy
Fax : (+39)-06-4991-2780; e-mail: antonella.goggiamani@uniroma1.it
Received: September 8, 2014; Revised: December 19, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400881.
Abstract: Free NH 2-(aminomethyl)indoles have
been prepared via copper-catalyzed cyclization of 3-
(ortho-trifluoroacetamidophenyl)-1-propargylic al-
cohols in the presence of primary or secondary
amines. The synthesis has been developed into
a simple and very efficient domino three-compo-
nent Sonogashira cross-coupling/cyclization/substi-
tution process that, omitting the isolation of 3-
(ortho-trifluoroacetamidophenyl)-1-propargylic al-
cohols, provides access to this class of compounds
by treating 2-iodotrifluoroacetanilides, propargylic
alcohols, and primary or secondary amines with
a copper/palladium catalyst system.
from 2-ethynyl(N-tosyl)anilines, aldehydes, including
formaldehyde, and secondary amines (Scheme 1).[4]
However, some limits exist to the structure of the
indole derivatives that can be prepared: N-protected
indoles are obtained, requiring a further operative
step to generate free NH derivatives. This is impor-
tant from a potential application perspective. In addi-
tion, only secondary amines are employed.
Because of the importance of this class of com-
pounds and our continuing interest in the copper-cata-
lyzed synthesis of indoles,[5] it appeared to us of inter-
est to develop an alternative, more general copper-
based approach to 2-(aminomethyl)indoles. Herein
we present the results of this study.
On the basis of the previous copper-catalyzed cycli-
zation of 2-(alkynyl)trifluoroacetanilides to 2-aryl-
and 2-heteroaryl indoles,[5a] 3-(ortho-trifluoroacetami-
dophenyl)-1-propargylic alcohols 1, readily available
Keywords: 2-(aminomethyl)indoles; copper cataly-
sis; domino reactions; multicomponent processes;
palladium catalysis
through
iodotrifluoro
were initially selected as precursors.
We started our study by examining the conversion
Sonogashira
AHCTUNGTRENNUNG
cross-coupling
of
2-
Because of the economic attractiveness of copper-cat-
alyzed methods (and hence of their potential in large- of 1a and diethylamine into 2a. After an initial screen
scale reactions), in the last 20 years or so a great deal
of attention has been dedicated to the utilization of
copper catalysis in organic synthesis[1] and a variety of
new practical and efficient methods based on copper-
catalyzed reactions have also been developed for the
synthesis of functionalized indoles.[2]
In this context, the construction of the 2-(aminome-
thyl)indole motif, a key structural feature present in
several biologically active compounds,[3] has been per-
formed through a facile and elegant copper-catalyzed
domino three-component coupling/cyclization process
Scheme 1. The synthesis of 2-(aminomethyl)indoles through
a copper-catalyzed domino three-component coupling/cycli-
zation process.
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
system
Solvent Base
Time Yield [%]
[h]
2a[b] 3a[b]
1
2
3
4
5
6
7
8
CuCl2/PPh3
CuI/proline
DMF
DMF
–
–
–
–
–
–
–
–
–
4
8
2.5
6
5
8
1.5
1
50
40
78
74
78
51
86
86
69
97
97[g]
87[j]
–
9[c]
14[d]
10
–
12
–
10
8
20
–
CuI/CHDA[e] DMF
CuI/phen[f]
CuI/PPh3
CuBr
Cu(OAc)
CuI
CuI
CuI
CuI
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN K2CO3 0.75
MeCN K2CO3
MeCN K2CO3 1.5
MeCN K2CO3
9
2
10
11
12
13
14
15
1
–
CuI
6
–
Scheme 2. Proposed reaction mechanism.
[h]
[i]
–
1
CuI
MeCN K3PO4 3.5
MeCN K3PO4 3.5
45
–
20
[h]
[i]
–
–
A possible mechanism of this copper-catalyzed
indole synthesis is outlined in Scheme 2 for the
parent 1a. Initially, formation of the p-alkyne copper
complex A takes place. Then, intramolecular nucleo-
philic attack of the anionic nitrogen across the activat-
ed carbon-carbon triple bond forms the s-indolyl
copper intermediate B (the involvement of an anionic
nucleophile is crucial for the success of the copper-
catalyzed cyclization step[5a]). Substitution of the
amino nucleophile for the hydroxy group, assisted by
the coordination of the oxygen to copper, gives C
(the nucleophilic attack of iodide anion to copper and
protonation of the indole fragment would afford the
2-hydroxymethylindole 3). Subsequently, the nucleo-
philic attack of iodide anion to copper and protona-
tion of the indole fragment regenerates the active
[a]
Unless otherwise stated, reactions were carried out at
808C on a 0.5 mmol scale in 2 mL of solvent using
1 equiv. of 1a, 4 equiv. of Et2NH, 0.04 equiv. of [Cu],
2 equiv. of K2CO3 (when added) and 0.08 (PPh3) or 0.04
(proline, CHDA, phen) equiv of ligand (when added).
Yields are given for isolated products.
[b]
[c]
[d]
[e]
[f]
1a was recovered in 21% yield.
1a was recovered in 14% yield.
CHDA=(Æ)-trans-1,2-cyclohexandiamine.
phen=1,10-phenanthroline.
[g]
[h]
3 equiv. of Et2NH.
Before the reaction with the base, 1a was treated with
a saturated NH4Cl solution and then with Smopexꢂ 110.
1a was recovered in almost quantitative yield.
2 equiv. of Et2NH.
[i]
[j]
of copper catalysts, solvents, and bases, we found that copper catalyst and gives the intermediate D from
the use of 0.04 equiv. of CuI and 3 equiv. of diethyl- which the 2-(aminomethyl)indole derivative 2 is
ACHTUNGTRENNUNG
Having promising results in hand for the model other reaction intermediates, such as B or C, and/or
system, the scope and generality of the reaction was occur during work-up. Wherever this hydrolysis takes
next explored.
place in the framework of Scheme 2, it remains that
As shown in Table 2, the reaction of 1, unsubstitut- the trifluoroacetyl group plays a key role in favoring
ed and bearing alkyl, benzyl, and aryl substituents at the cyclization step and generating the free NH
the propargylic carbon, with a variety of primary and indole derivative.
secondary aliphatic and aromatic amines afforded the
desired products usually in good to excellent yields,[6] posal, we carried out the following experiments: the
even when bulky substituents are close to the nitro- reaction of 3-(para-trifluoroacetamidophenyl)-2-
gen atom (Table 2, entries 6, 8, and 11). propyn-1-ol 4 with morpholine (Scheme 3) and the re-
To provide some experimental support to our pro-
2
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Synthesis of Free NH 2-(Aminomethyl)indoles
Table 2. Copper-catalyzed synthesis of 2-aminomethylindoles 2 from 3-(ortho-trifluoroacetamidophenyl)-1-propargyl alco-
hols 1 and amines.[a]
Entry
1
Amine
Product
2b
Yield [%]
1
2
95
94
1a
2c
3
4
2d
2e
70
60
5
1b
1c
2f
90
6
2g
81
7
8
9
2h
2i
96
74
70
1d
2j
10
11
12
13
2k
2l
2m
96
76
87
87
2n
14
1e
1f
1g
1h
2o
2p
81
15
90
16
17
18
2q
2r
2s
87
91
70
19
2t
71
20
2u
70
21
1i
2v
97
[a]
Reactions were carried out at 808C on a 0.5 mmol scale in 2 mL of MeCN using 1 equiv. of 1, 3 equiv. of amine,
0.04 equiv. of CuI, and 2 equiv. of K2CO3.
Yields are given for isolated products.
[b]
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Scheme 3. Reaction of 3-(4-trifluoroacetamidophenyl)-2-
propyn-1-ol with morpholine.
Scheme 5. Retrosynthetic representation of the assembly of
2-(aminomethyl)indoles 2 from 2-iodotrifluoroacetanilides
6, propargylic alcohols 7, and amines.
Scheme 4. Reaction of 2-hydroxymethylindole with diethyl-
ACHTUNGTRENNUNGamine.
action of the 2-hydroxymethylindole 3a with diethyl-
amine (Scheme 4).
In both cases the starting material was recovered in
ACHTUNGTRENNUNG
almost quantitative yield. The result of the first reac-
tion rules out a mechanism in which a copper-cata-
lyzed propargylic amination[7,8] precedes the cycliza-
tion step.[9] The result of the second reaction rules out
the presence of a 2-hydroxymethylindole in the reac-
tion pathway leading to 2. Taken together, these two
experiments support the view that the substitution of
the amino group for the hydroxy group involves an
indole intermediate in which copper can act as alco-
hol-activating agent,[6,7] possibly the intermediate B.
Scheme 6. Synthesis of a 2-(aminomethyl)indole through
a domino three-component Sonogashira cross coupling/cycli-
zation/substitution process.
To make this approach to 2-(aminomethyl)indoles pleased to find that the reaction of 6a, 7a, and N-eth-
more attractive from a synthetic standpoint, we next ylpiperazine in the presence of K2CO3 and both CuI
explored their formation through a process that and PdCl2(PPh3)2 in DMF (slightly modified Sonoga-
would omit the isolation of 3-(ortho-trifluoroacetami- shira conditions[10]) at 808C for 1.5 h gave 2w in 89%
dophenyl)-1-propargylic alcohols 1. Particularly, we yield (Scheme 6).
decided to investigate the formation of 2 from 2-iodo-
The scope and generality of this multicomponent
trifluoroacetanilides 6, propargylic alcohols 7, and approach[11] to 2-(aminomethyl)indoles was next ex-
amines through a domino three-component cross-cou- plored and the results are summarized in Table 3.
pling/cyclization/substitution process (Scheme 5).
Overall yields are good to excellent, comparable or,
Initial attempts showed that neither copper cata- usually, higher than those observed in the stepwise
lysts nor palladium catalysts provided satisfactory re- process. Neutral (Table 3, entries 1–24), electron-rich
sults. For example, subjecting 2-iodotrifluoroacetani- (Table 3, entries 25–27), and electron-poor (Table 3,
lide 6a (0.5 mmol) to propargylic alcohol 7a entry 28) 2-iodotrifluoracetanilides can be successfully
(1.5 equiv.), N-ethylpiperazine (2 equiv.), and K2CO3 employed as well as propargylic alcohols substituted
(2 equiv.) at 808C in DMF (5 mL) overnight in the at the propargylic carbon (Table 3, entries 12–24 and
presence of [Cu(phen](PPh3)2]NO3 (0.04 equiv.)[5a] led 27) and a variety of primary and secondary aliphatic
to the recovery of the starting anilide in almost quan- amines, including amines with bulky substituents close
titative yield and when the same reaction was per- to the nitrogen atom (Table 3, entry 2). However, aro-
formed in the presence of PdCl2(PPh3)2 (0.05 equiv.) matic amines failed to give the desired indole prod-
the desired indole derivative was isolated only in 20% ucts under standard conditions. For example, when
yield, the starting anilide being recovered in 77% para-toluidine or N-methylaniline were treated with
yield.
7a and 6a, the latter was recovered in almost quanti-
As the formation of 2-(aminomethyl)indoles from tative yield after 24 h. With aromatic amines good re-
preformed cross-coupling precursors can be readily sults were obtained by substituting Pd2(dba)3/[(t-
[12]
performed with copper (present work) or palladium[6] Bu)3PH]BF4
for PdCl2(PPh3)2 in MeCN (Table 3,
catalysts, we thought that the efficiency of the domino entries 11, 17, and 18).
process could be primarily limited by a sluggish cou-
In conclusion, we have shown that free NH 2-(ami-
pling step. After some experimentation, we were nomethyl)indoles can be prepared in high to excellent
4
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Synthesis of Free NH 2-(Aminomethyl)indoles
Table 3. Synthesis of 2-aminomethylindoles 2 from ortho-iodotrifluoroacetanilides 6, propargylic alcohols 7, and amines.[a]
Entry
1
6
7
Amine
Product
Yield [%][b]
6a
7a
2w
89
2
3
2x
2b
68
91
4
5
6
7
8
2y
88
97
94
93
82
2z
2za
2zb
2zc
9
2zd
65
10
11
12
2ze
2e
60
49[c]
6a
7b
2h
84
13
14
15
16
2zf
72
68
78
91
2zg
2zh
2z1
17
18
2m
2n
73[c]
60[c]
19
20
21
22
23
6a
7c
2zj
58
81
96
89
94
2zk
2zl
2zm
2zn
24
25
2o
2f
95
90
6b
6b
7a
7b
26
2zo
70
27
2zp
85
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Table 3. (Continued)
Entry
6
7
Amine
Product
Yield [%][b]
50
28
6c
7a
2zq
[a]
Unless otherwise stated, reactions were carried out at 808C on a 0.5 mmol scale in 5 mL of DMF using 1 equiv. of 6,
1.5 equiv. of 7, 2 equiv. of amine, 0.04 equiv. of CuI, 0.005 equiv. of PdCl2(PPh3)4, and 2 equiv. of K2CO3.
Yields are given for isolated products.
Carried out at 808C on a 0.5 mmol scale in 5 mL of MeCN using 1 equiv. of 6, 1.5 equiv. of 7, 3 equiv. of amine,
0.04 equiv. of CuI, 0.0025 equiv. of Pd2(dba)3, 0.05 equiv. of [(t-Bu)3PH]BF4, and 3 equiv. of K2CO3.
[b]
[c]
dissolved at room temperature with 2.0 mL of anhydrous
DMF under nitrogen. Then, 6a (157.5 mg, 0.5 mmol), N-eth-
ylpiperazine (127 mL, 1.0 mmol), 7a (44 mL, 0.75 mmol),
K2CO3 (138.2 mg, 1 mmol), and 3.0 mL of DMF were
added. The mixture was stirred for 1.5 h at 808C. After this
time, the reaction mixture was cooled to room temperature,
diluted with Et2O, and washed with a saturated NaHCO3 so-
lution. The organic layer was separated, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by chromatography (silica gel, n-hexane/EtOAc/
Et3N 30/70/0.01 v/v/v) to afford 2w; yield: 108 mg (89%).
yields via copper-catalyzed cyclization of 3-(ortho-tri-
fluoroacetamidophenyl)-1-propargylic alcohols and
primary or secondary amines, including amines with
bulky substituents close to the nitrogen atom. The
synthesis has been developed into a simple and effi-
cient multicomponent reaction that, omitting the iso-
lation of 3-(ortho-trifluoroacetamidophenyl)-1-propar-
gylic alcohols, provides access to this class of com-
pounds by treating readily available 2-iodotrifluoro-
ACHTUNGTRENNUNGacetanilides, propargylic alcohols, and primary or sec-
ondary amines with a copper/palladium catalyst
system in good to excellent yields.
Typical Procedure for the Copper/Palladium-Co-
catalyzed Synthesis of 2-(Aminomethyl)indoles (2)
from 2-Iodotrifluoroacetanilides (6), Propargylic
Alcohols (7), and Aromatic Amines; Synthesis of N-
[1-(1H-indol-2-yl)ethyl]-3-methoxyaniline (2m)
Experimental Section
Typical Procedure for the Copper-Catalyzed Cy-
clization of 3-(ortho-Trifluoroacetamidophenyl)-1-
propargylic Alcohols (1) to 2-(Aminomethyl)indoles
(2); Synthesis of 2-[(N,N-Diethylamino)methyl]indole
(2a)
In a 50-mL Carousel Tube Reactor (Radley Discovery Tech-
nology) containing a magnetic stirring bar, CuI (3.8 mg,
0.020 mmol), Pd2(dba)3 (1.1 mg, 0.0012 mmol), and [(t-
Bu)3PH]BF4 (7.2 mg, 0.025 mmol) were dissolved at room
temperature with 2.0 mL of anhydrous MeCN under argon.
Then, 6a (157.5 mg, 0.5 mmol), 3-methoxyaniline (202 mL,
1.5 mmol), 7b (84 mL, 0.750 mmol), K2CO3 (207.3 mg,
1.5 mmol), and 3.0 mL of anhydrous MeCN were added.
The mixture was stirred for 5 h at 808C. After this time, the
reaction mixture was cooled to room temperature, diluted
with Et2O, and washed with a saturated NaHCO3 solution.
The organic layer was separated, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by chromatography (silica gel, n-hexane/EtOAc 70/30 v/
v) to afford 2m; yield: 86.5 mg (73%).
In a 50-mL Carousel Tube Reactor (Radley Discovery Tech-
nology) containing a magnetic stirring bar, CuI (3.8 mg,
0.02 mmol) was dissolved at room temperature with 1.0 mL
of MeCN. Then, 1a (121.6 mg, 0.5 mmol), Et2NH (155 mL,
1.5 mmol), K2CO3 (138.2 mg, 1 mmol), and 1.0 mL of MeCN
were added. The mixture was stirred for 1 h at 808C. After
this time, the reaction mixture was cooled to room tempera-
ture, diluted with Et2O, and washed with a saturated
NaHCO3 solution. The organic layer was separated, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was purified by chromatography (silica gel, n-
hexane/EtOAc/Et3N 30/70/0.01 v/v/v) to afford 2a; yield:
98 mg (97%).
Acknowledgements
Typical Procedure for the Copper/Palladium-Co-
catalyzed Synthesis of 2-(Aminomethyl)indoles (2)
from 2-Iodotrifluoroacetanilides (6), Propargylic
Alcohols (7), and Primary or Secondary Aliphatic
Amines; Synthesis of 2-[(4-Ethylpiperazin-1-yl)-
methyl]indole (2w)
We gratefully acknowledge FIRB and La Sapienza, Universi-
ty of Rome, for their financial support.
References
In a 50-mL Carousel Tube Reactor (Radley Discovery Tech-
nology) containing a magnetic stirring bar, CuI (3.8 mg,
0.02 mmol) and PdCl2(PPh3)2 (1.7 mg, 0.0025 mmol) were
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[6] The copper-catalyzed reaction always afforded yields
significantly higher than those obtained with the palla-
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UPDATES
8 Synthesis of Free NH 2-(Aminomethyl)indoles through
Copper-Catalyzed Reaction of 3-(ortho-
Trifluoroacetamidophenyl)-1-propargylic Alcohols with
Amines and Palladium/Copper-Cocatalyzed Domino Three-
Component Sonogashira Cross-Coupling/Cyclization/
Substitution Reactions
Adv. Synth. Catal. 2015, 357, 1 – 8
Sandro Cacchi, Giancarlo Fabrizi, Antonia Iazzetti,
Carmela Molinaro, Rosanna Verdiglione,
Antonella Goggiamani*
8
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These are not the final page numbers!