Palladium-catalyzed synthesis of free-NH indole 2-acetamides and derivatives from ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates

Article abstract of DOI:10.1055/s-0029-1217377

The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates with primary or secondary amines in the presence of Pd₂(dba) ₃, dppf, and carbon monoxide in THF at 80 °C provides ready access to free-NH indole 2-acetamide

Full text of DOI:10.1055/s-0029-1217377

LETTER
1817
Palladium-Catalyzed Synthesis of Free-NH Indole 2-Acetamides and Deriv-
atives from Ethyl 3-(o-Trifluoroacetamidoaryl)-1-propargylic Carbonates
P
alladium-Cat
a
alyze
d
Syn
n
F
ree
d
-NH Indole
r
2-Acetam
o
ides and
D
erivativ
C
es acchi,* Giancarlo Fabrizi, Eleonora Filisti
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 17 March 2009
primary or secondary amines, provides ready access to
Abstract: The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-
free-NH indole 2-acetamides 3 (Scheme 1).
propargylic carbonates with primary or secondary amines in the
presence of Pd2(dba)3, dppf, and carbon monoxide in THF at 80 °C
provides ready access to free-NH indole 2-acetamides. The reaction
OCO2Et
O
R3
R4
can be applied to the synthesis of free-NH indole 2-acetic acid me-
thyl esters.
R2
R1
R1
R3
R4
N
Pd cat.
H
N
CO
NHCOCF3
Key words: palladium, carbonylation, indoles, alkynes, propargyl-
ic esters
– EtOCOCF3
– CO2
R2
N
H
3
1
2
Scheme 1
The indole moiety is prevalent in a vast array of biologi-
cally active natural and unnatural compounds. Conse-
quently, the development of efficient methods to construct
functionalized indole scaffolds is a subject of great inter-
est in drug discovery. Utilization of palladium catalysis
has provided remarkable advances in this area, greatly ex-
panding the generality of the approaches to this class of
compounds both via functionalization of preformed in-
dole rings and via cyclization of suitable precursors.1 In
this context, we became interested in the development of
a new, straightforward palladium-catalyzed approach to
the synthesis of indole 2-acetamides. These indole deriv-
atives exhibit valuable biological activities2 and are useful
synthetic intermediates.3 However, the number of synthe-
ses available for their preparation is quite limited. Tradi-
tional methods rely on the reaction of indole 2-acetic acid
derivatives with amines,3a,4 or on the reaction of anions of
2-alkylindoles with alkylisocyanates.5 In both cases, ac-
cess to the indole 2-acetamides depends on the availability
of preformed indole precursors. Their direct preparation
from acyclic compounds has not been described.
Compounds 1 were usually prepared by a two-step pro-
cess from o-(iodo)trifluoroacetanilides via Sonogashira
cross-coupling with propargylic alcohols, followed by an
esterification step.7
We started our study by examining the conversion of ethyl
3-(o-trifluoroacetamidophenyl)-1-propargyl
(1a) into the indole 2-acetamide 3a. Our optimization
work using Pd2(dba)3 in THF at 80 °C, varying the CO
pressure, ligands, and the concentration of the reagents, is
summarized in Table 1.
carbonate
When the reaction was carried out in the presence of 1,1¢-
bis(diphenylphoshino)ferrocene (dppf) in 5 mL of THF
under 1 atm of CO, the 2-aminomethylindole 4a was iso-
lated in 90% yield and no amide derivative 3a was formed
(Table 1, entry 1). Increasing the CO pressure to 20 atm
led to the isolation of 3a in 64% yield, although 4a was
still obtained in significant yield (Table 1, entry 2). Under
40 atm of CO, the formation of 4a was completely sup-
pressed. Nevertheless, essentially the same yield of 3a
was obtained (Table 1, entry 4). Pleasingly, performing
the reaction under 40 atm of CO in 10 mL of THF allowed
for the isolation of 3a in 83% yield (Table 1, entry 5). We
also examined other bidentate phosphine ligands, but dppf
proved to be superior to all of them, at least with our mod-
el system. No indole product was formed with bis(diphe-
nylphosphino)methane (dppm; Table 1, entry 6), while 3a
was isolated in 56% yield employing 1,3-bis(diphe-
nylphosphino)propane (dppp; Table 1, entry 7). The yield
increased to 61% using 1,4-bis(diphenylphosphino)bu-
tane (dppb; Table 1, entry 8), still lower however than the
yield obtained with dppf.
Recently, we reported on the palladium-catalyzed synthe-
sis of 2-substituted indoles employing ethyl 3-(o-tri-
fluoroacetamidoaryl)-1-propargylic carbonates.6 This
reaction is based on an intramolecular N-cyclization lead-
ing to p-allylic palladium complexes that are converted
into the final products through nucleophilic attack. There-
fore, we decided to examine the use of our indole synthe-
sis for the direct construction of the indole 2-acetamido
structural motif.
Herein, we report that subjecting ethyl 3-(o-trifluoroacet-
amidoaryl)-1-propargylic carbonates 1 to carbon monox-
ide, in the presence of a palladium catalyst and either
The synthetic scope of the reaction was the explored using
Pd2(dba)3, dppf, and 40 atm of CO in 10 mL of THF at
80 °C.8 Nevertheless, other substrates gave similar or bet-
ter results in the presence of dppb (vide infra). Therefore,
SYNLETT 2009, No. 11, pp 1817–1821
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217377; Art ID: G06809ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

1818
S. Cacchi et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
products were formed only in trace amounts, if any.
Deacylated propargylic esters 5 and urea9 derivatives 6
were among the main products characterized (Figure 1).
Apparently, using more hindered primary amines had a
beneficial effect on the reaction outcome by limiting these
side reactions.
OCO2Et
Pd2(dba)3, ligand
CO
NHCOCF3
1a
HN
O
NEt
THF, 80 °C, 24 h
2a
NEt
OCO2Et
R2
R1
N
N
NEt
O
R3
R3
N
H
N
H
NH2
HN
NH
3a
4a
5
6
Figure 1
Entry Ligand
CO (atm) THF (mL) Yield of 3a Yield of 4a
(%)b
(%)b
90
22
9
The isolation of 5 without any evidence of indole forma-
tion is an indirect proof of the crucial role of the trifluoro-
acetamido group in this chemistry.6 Most probably, the
nucleophilicity of the free amino group is too low to per-
form the intramolecular attack on the allenylic/propergyl-
ic palladium complex that is required to construct the
indole ring (vide infra). The acidity of the nitrogen–
hydrogen bond might favor the formation of a stronger,
anionic nucleophile. Furthermore, the trifluoroacetamido
group is readily removed from the indole derivatives un-
der the reaction conditions and/or during work-up, so that
the procedure affords free-NH indoles, avoiding cumber-
some deprotecting protocols.
1
2
3
4
5
6
7
8
dppf
dppf
dppf
dppf
dppf
dppm
dppp
dppb
1
5
–
20
20
40
40
40
40
40
5
64
61
63
83
–
10
5
–
10
10
10
10
–
c
–
56
61
–
–
a Reagents and conditions: 1a (0.3 mmol), 2a (3 equiv), Pd2(dba)3
(0.025 equiv), ligand (0.05 equiv), 80 °C, 24 h.
b Yield of isolated product.
We next briefly investigated an extension of this protocol
to the preparation of indole 2-acetic acid methyl esters 7.10
7a and 7b were isolated in good yields using a large ex-
cess of methanol. Reactions (on a 0.3 mmol scale) were
carried out under the conditions shown in Scheme 2 (add-
ing 1 mL of MeOH to 10 mL of THF). However, when the
preparation of 7c was attempted, the desired indole deriv-
ative was isolated only in 11% yield under these condi-
tions – the main product being the ether 8c (43% yield;
Figure 2). Limiting the excess of methanol to 20 equiva-
lents led to the isolation of 7c in 46% yield.
c 1a was recovered in 77% yield.
it seems advisable that the efficiency of the ligands be
evaluated each time.
As shown by the results listed in Table 2, a variety of ethyl
3-(o-trifluoroacetamidoaryl)-1-propargylic
carbonates
and primary or secondary amines were successfully con-
verted into the corresponding indole 2-acetamides. Sub-
stitution on the aryl fragment and/or the propargylic
carbon was tolerated. Limitations, however, appear to
arise with some primary amines. While the bulky tert-bu-
tylamine and cyclohexylamine gave indoles 3e and 3f in
good yields (Table 2, entries 5 and 6), treatment of 1a
with aniline and benzylamine met with failure. Indole
OMe
N
H
Ph
8c
Figure 2
OCO2Et
O
Pd2(dba)3 (0.02 equiv), dppf (0.05 equiv)
CO (40 atm), MeOH–THF
80 °C, 24 h
R
OMe
N
H
R
NHCOCF3
7a R = H
72%
66%
7b R = Me
7c R = Ph 46%
Scheme 2
Synlett 2009, No. 11, 1817–1821 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Synthesis of Free-NH Indole 2-Acetamides and Derivatives
1819
Table 2 Synthesis of Indole 2-Acetamides 3a
Entry Propargyl carbonate 1
Amine 2
Product 3
Yield of 3 (%)b
O
N
NEt
O
1
3a
3b
83
68
HN
HN
NEt
O
N
H
O
N
2
N
H
O
O
N
N
N
F
3
3c
75
80
HN
HN
N
N
F
N
H
OCO2Et
N
4
3d
N
H
NHCOCF3
OMe
OMe
1a
O
NHt-Bu
5
6
7
NH2t-Bu
3e
3f
75
68
73
N
H
O
NH
H2N
HN
N
H
O
N
3g
N
H
OCO2Et
O
Cl
N
NEt
Cl
8
9
3h
3i
62
75
HN
HN
NEt
N
H
NHCOCF3
1b
OCO2Et
O
MeO2C
N
NEt
MeO2C
NEt
N
H
NHCOCF3
1c
OCO2Et
Ph
O
10
11
3j
3j
50
N
N
NEt
NEt
72c
HN
HN
NEt
NEt
N
H
Ph
NHCOCF3
1d
O
12
13
3k
3k
19
81c
N
H
Synlett 2009, No. 11, 1817–1821 © Thieme Stuttgart · New York

1820
S. Cacchi et al.
LETTER
Table 2 Synthesis of Indole 2-Acetamides 3a (continued)
Entry Propargyl carbonate 1
Amine 2
Product 3
Yield of 3 (%)b
OCO2Et
O
O
HN
N
N
N
N
N
14
3l
81c
N
H
NHCOCF3
1e
HN
N
15
3m 74c
N
H
Cl
Cl
OCO2Et
O
F
N
NEt
F
16
17
3n
3o
54c
HN
NEt
N
NHCOCF3
H
F
F
1f
OCO2Et
O
N
NEt
92c
HN
NEt
N
NHCOCF3
H
1g
a Reagents and conditions: 1 (0.3 mmol), THF (10 mL), 80 °C, CO (40 atm), 2 (3 equiv), Pd2(dba)3 (0.025 equiv), dppf (0.05 equiv), 24 h.
b Yield of isolated product.
c With dppb.
A plausible rationale for this indole synthesis considers
the following basic steps (Scheme 3): (a) initial reaction
OCO2Et
O
1
Nu
of the palladium complex with 1 to give the s-allenyl–
palladium complex 9 that would be in equilibrium with
the p-propargylic palladium intermediate 10; (b) intramo-
lecular nucleophilic attack of the nitrogen on the central
carbon of the allenylic/propargylic palladium complex;
(c) protonation of the resultant carbene 11; (d) reaction of
the p-allylic–palladium complex 12 with carbon monox-
ide (capture of 12 by nitrogen or oxygen nucleophiles
leads to the formation of 4 and 8); (e) intermolecular nu-
cleophilic attack of the nucleophile on the resultant carbo-
nyl-containing intermediate 13 to afford the indole
product and regenerate the active palladium catalyst.
NHCOCF3
N
EtOCOCF3
H
3, 7
CO2
Pd(0)
EtOH
HNu
EtO–
Pd+
Pd+
O
N
Pd+
N
9
10
COCF3
COCF3
N
COCF3
CO
13
In summary, we have reported a new synthesis of indole
2-acetamides that can be a valid alternative to known pro-
cedures based on the functionalization of preformed in-
dole precursors. The reaction was found to be applicable
to the preparation of indole 2-acetic acid methyl esters.
Pd+
Pd+
N
N
COCF3
11
COCF3
12
Nu = NR2, OR
EtO–
EtOH
Acknowledgements
The work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’
supported by the Ministero dell'Università e della Ricerca Scientifi-
ca e Tecnologica and by the University La Sapienza.
Scheme 3
Synlett 2009, No. 11, 1817–1821 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Synthesis of Free-NH Indole 2-Acetamides and Derivatives
1821
the residue was purified by chromatography on neutral
aluminum oxide (Brockmann 1; n-hexane–EtOAc,
90:10→70:30) to afford 3d (87 mg, 80% yield); viscous oil;
IR (KBr): 3296, 3064, 2989, 2929, 2852, 1630 cm–1; 1H
NMR (400 MHz, CDCl3): d = 9.36 (br s, 1 H), 7.59–7.58 (m,
1 H), 7.36–7.34 (m, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.18–
7.12 (m, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.31 (s, 1 H), 3.90
(s, 2 H), 3.84 (s, 3 H), 3.69–3.68 (m, 2 H), 3.58–3.56 (m, 2
H), 3.44 (s, 2 H), 2.43–2.40 (m, 2 H), 2.37–2.35 (m, 2 H); 13C
NMR (100.6 MHz, CDCl3): d = 168.4, 159.0, 136.5, 132.0,
130.4, 129.6, 128.4, 121.6, 120.0, 119.7, 113.8, 111.1,
101.0, 62.1, 55.3, 52.9, 52.5, 46.4, 42.1, 33.3; MS: m/z (%)
= 121 (100) [M – C14H16N3O]+, 85 (50), 78 (44), 56 (52);
Anal. Calcd. for C22H25N3O2: C, 72.70; H, 6.93; Found: C,
72.63; H, 6.91.
References and Notes
(1) For some selected recent reviews, see: (a) Zeni, G.; Larock,
R. C. Chem. Rev. 2004, 104, 2285. (b) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873. (e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875. (f) Ackermann, L. Synlett 2007, 507. (g)Krüger,
K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350,
2153.
(2) (a) Abou-Gharbia, M. A. US 4748247, Chem. Abstr. 1988,
109, 129055. (b) Weber, D.; Berger, C.; Eickelmann, P.;
Antel, J.; Kessler, H. J. Med. Chem. 2003, 46, 1918.
(c) Mjalli, A. M. M.; Andrews, R. C.; Yarragunta, R. R.;
Xie, R.; Ren, T.; Subramanian, G.; Quada, J. C. Jr. WO
20040212 Chem. Abstr. 2004, 141, 225511.
(3) (a) Sundberg, R. J.; Hong, J.; Smith, S. Q.; Sabat, M.
Tetrahedron 1998, 54, 6259. (b) Phillips, A. J.; Uto, Y.;
Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
11656.
(4) Kidwai, M.; Misra, P.; Bhushan, K. R.; Saxena, R. K.; Singh,
M. Monatsh. Chem. 2000, 131, 937.
(9) For some recent selected references on the formation of urea
derivatives via palladium-catalyzed reactions of amines with
carbon monoxide, see: (a) Gabriele, B.; Salerno, G.;
Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69, 4741.
(b) Nishiyama, Y.; Kawamatsu, H.; Sonoda, N. J. Org.
Chem. 2005, 70, 2551.
(10) Typical Procedure for the Preparation of Free-NH
Indole 2-Acetic Acid Methyl Esters (7): A stainless steel
reaction vessel was charged with 1e (99 mg, 0.3 mmol),
Pd2 (dba)3 (6.9 mg, 0.0075 mmol), dppf (8.3 mg, 0.015
mmol), anhydrous THF (10 mL), and MeOH (1 mL). The
reactor was pressured to 40 atm with CO, warmed to 80 °C,
and stirred for 24 h. After cooling and eliminating CO, the
volatile materials were evaporated at reduced pressure and
the residue was purified by chromatography on silica gel (n-
hexane–EtOAc, 80:20) to afford of 7b (40.2 mg, 66% yield);
mp 90–93 °C; IR (KBr): 3356, 2952, 1714, 1458, 1427
cm–1; 1H NMR (400 MHz, CDCl3): d = 8.55 (br s, 1 H), 7.60
(d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0
Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 6.41 (s, 1 H), 4.00 (q,
J = 7.1 Hz, 1 H), 3.77 (s, 3 H), 1.66 (d, J = 7.2 Hz, 3 H);
13C NMR (100.6 MHz, CDCl3): d = 174.1, 136.7, 136.2,
128.2, 121.9, 120.3, 119.9, 110.9, 100.3, 52.5, 39.2, 17.5;
Anal. Calcd. for C12H13NO2: C, 70.92; H, 6.45; Found: C,
70.83; H, 6.47.
(5) Katritzky, A. R.; Akutagawa, K. J. Am. Chem. Soc. 1986,
108, 6808.
(6) (a) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 10,
2083. (b) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Tetrahedron
Lett. 2007, 48, 7721.
(7) Compounds 1b, 1c and 1f were prepared via Sonogashira
cross-coupling of o-iodoanilines with the THP derivative of
propargyl alcohol. The cross-coupling products were treated
with (CF3CO)2O. The resultant trifluoroacetamido
derivatives were deprotected and subjected to ethyl
chlorocarbonate to give the title propargylic esters.
(8) Typical Procedure for the Preparation of Free-NH
Indole 2-Acetamides (3): A stainless steel reaction vessel
was charged with 1a (94.5 mg, 0.3 mmol), Pd2 (dba)3 (6.9
mg, 0.0075 mmol), dppf (8.3 mg, 0.015 mmol), 2d (185.7
mg, 0.9 mmol), and anhydrous THF (10 mL). The reactor
was pressured to 40 atm with CO, warmed to 80 °C, and
stirred for 24 h. After cooling and eliminating CO, the
volatile materials were evaporated at reduced pressure and
Synlett 2009, No. 11, 1817–1821 © Thieme Stuttgart · New York