Palladium-catalyzed synthesis of 2-amino ketones from propargylic carbonates and secondary amines

Article abstract of DOI:10.1039/c2ob25670c

A novel palladium-catalyzed approach to 2-amino ketones from arylpropargylic carbonates bearing neutral, electron-rich, and electron-poor aromatic rings and cyclic secondary amines containing useful functional groups such as cyano, chloro, and bromo subst

Full text of DOI:10.1039/c2ob25670c

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COMMUNICATION
Palladium-catalyzed synthesis of 2-amino ketones from propargylic
carbonates and secondary amines†
Sandro Cacchi,*a Giancarlo Fabrizi,a Eleonora Filisti,a Antonella Goggiamani,a Antonia Iazzettia and
Loredana Mauroneb
Received 4th April 2012, Accepted 10th May 2012
DOI: 10.1039/c2ob25670c
and the substitution of the
propargylic–O bond (Scheme 1).
On the basis of our previous studies showing that 2-amino-
Cpropargylic–N bond for the
A novel palladium-catalyzed approach to 2-amino ketones
from arylpropargylic carbonates bearing neutral, electron-
rich, and electron-poor aromatic rings and cyclic secondary
amines containing useful functional groups such as cyano,
chloro, and bromo substituents has been developed.
C
methyl indoles 5 could be prepared from 3-(o-trifluoroacetami-
dophenyl)-1-propargylic carbonates 4 and amines through a
process involving sequential intramolecular/intermolecular C–N
bond forming steps (Scheme 2),13 we hypothesized that a similar
reaction, omitting the trifluoroacetamido group bound to the aro-
matic ring, might provide access to 2-amino ketones via sequen-
tial intermolecular C–N bond forming steps, leading to enamine
intermediates A, and hydrolysis (Scheme 3).
The 2-amino ketone structural motif is present in a number of
biologically active compounds such as mersingines A and B1
and a small family of linear peptides including the antitumor
agent eponemycin.2 Endogenous 2-amino ketones show pro-
oxidant properties.3 2-Amino ketones have also been studied as
candidates for the reactivation of mutant p534 and are used for
the preparation of cosmetic compositions for the treatment of
skin wrinkles.5 Furthermore, they are useful synthetic inter-
mediates.6 Despite their importance, however, direct syntheses of
2-amino ketones are rather limited. Current general synthetic
approaches are based on the α-amination of ketones7 and enolsi-
lanes8 (in some cases taking advantage of copper catalysis8b,d),
on the osmium-catalyzed ketamination of alkenes,9 on the con-
version of the carboxylic group of amino acids into a ketonic
group,10 and on the formation of carbon–carbon bonds between
carbonyl and amino-containing fragments.11 Recently, 2-amino
ketones have been prepared via reaction of N-sulfonyl-1,2,3-tria-
zoles with water in the presence of a rhodium catalyst.12 Palla-
dium catalysis has been rarely applied in this area. To the best
of our knowledge, it has been used only in the preparation
of 2-amino ketones from α-sulfonamidoorganostannanes and
benzoyl chloride.11b
We set out to use the reaction of 1 equiv. of 1a (Ar = R1 = Ph)
with 3 equiv. of morpholine as a probe for evaluating the feasi-
bility of the reaction. First attempts, however, met with failure.
Under the same conditions employed for the synthesis of 2-ami-
nomethyl indoles13 a smooth palladium-catalyzed decarboxyla-
tion–propargylation14,15 of 1a took place and the ether 6a was
formed in almost quantitative yield (Scheme 4a).
Using Pd2(dba)3 as the Pd(0) source and a variety of phos-
phine ligands such as dppp, dppe, and [2,4,6-(MeO)3C6H2]3P in
THF at 80 °C for 24 h led to the recovery of the starting
Herein we report on a new palladium-catalyzed approach to
2-amino ketones 3 from readily available propargylic carbonates
1 and secondary amines 2 that involves a formal anti-
Markovnikov addition of water to the carbon–carbon triple bond
Scheme 1 Palladium-catalyzed synthesis of 2-amino ketones from pro-
pargylic carbonates and secondary amines.
aDipartimento di Chimica e Tecnologie del Farmaco, Sapienza,
Università di Roma, P.le A. Moro 5, 00185 Rome, Italy.
E-mail: sandro.cacchi@uniroma1.it; Fax: +39 (06) 4991-2789;
Tel: +39 (06) 4991-2795
bDipartimento A.B.A.C., Università degli Studi della Tuscia e Consorzio
Universitario “La Chimica per l’Ambiente”, Via S. Camillo De Lellis,
01100 Viterbo, Italy
†Electronic supplementary information (ESI) available: A complete
description of experimental details and product characterization. See
DOI: 10.1039/c2ob25670c
Scheme 2 Synthesis of indoles from 3-(o-trifluoroacetamidophenyl)-1-
propargylic carbonates.
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Scheme 3 Our working hypothesis.
Scheme 5 Proposed reaction mechanism for the palladium-catalyzed
formation of ketocarbamates 7 from propargylic carbonates 1 and
amines.
towards morpholine in the absence of palladium (the starting
material was recovered in 90% yield after 3 h at 80 °C in THF)
supports the view that the conversion of the carbonate fragment
into the carbamate fragment occurs after the formation of a palla-
dium complex. Experimental evidence for the intermediacy of E
was obtained by NMR analysis of the crude reaction mixture
before work-up.
Steric effects due to the substituents of D or D′ might account
for the preferential intramolecular nucleophilic attack of the less
hindered carbamate fragment at one of the allylic termini with
respect to the intermolecular nucleophilic attack of the more
sterically demanding morpholine.
Therefore, we decided to investigate the reactivity of the
unsubstituted proparylic carbonate 1b (Ar = Ph; R1 = H). Pleas-
ingly, its reaction with morpholine in the presence of Pd2(dba)3
and dppf in THF at 80 °C afforded the desired 2-aminoketone 3a
in 76% isolated yield after 3 h.
Using these conditions, we next explored the scope and gener-
ality of the process. As shown in Table 1, clean formation of
2-amino ketones was observed with a variety of propargylic car-
bonates bearing neutral, electron-rich, and electron-poor aromatic
rings and cyclic secondary amines containing useful functional
groups such as cyano, chloro, and bromo substituents. An accep-
table yield was also obtained with the unprotected piperazine
(Table 1, entry 8). The piperazine nucleus, a privileged substruc-
ture,19 is of particular interest. Some limitations of our method
were observed with acyclic secondary amines. For example, the
reaction of 1b with dibutylamine or diethylamine failed to give
Scheme 4 The reaction of 1a with morpholine in the presence of
Pd(PPh3)4 and Pd2(dba)3/dppf.
carbonate in almost quantitative yield. No evidence of the
desired product was also obtained switching to the Pd2(dba)3/
dppf combination. The reaction produced instead the ketocarba-
mate 7a in 76% yield (Scheme 4b). Using MeCN as solvent
gave 7a in a slightly lower yield whereas only degradation pro-
ducts were formed in toluene and DMSO.
A possible rationale for the formation of 7a is outlined in
Scheme 5. The initial reaction of Pd(0) with 1a affords the σ-
allenylic palladium complex B, which would be in equilibrium
with the π-propargylic palladium intermediate C.16 The nucleo-
philic attack of morpholine at the central carbon of the allenylic/
propargylic palladium complex B/C17,18 (path a), followed by a
protonation step gives the allylic palladium carbonate complex
D. This complex is subsequently converted into the allylic carba-
mate palladium complex D′ via displacement of the ethoxy
group by morpholine. Alternatively (path b), morpholine can
displace the ethoxy group of B/C to give B′/C′ that is converted
into D′ via nucleophilic attack of another molecule of morpho-
line at the central carbon of the allenylic/propargylic palladium
complex and protonation. Subsequently, the intramolecular
nucleophilic attack of the carbamate oxygen at one of the allylic
carbons of D′‡ and the hydrolysis of the resultant enamine inter-
mediate E generates the ketocarbamate 7a. The inertness of 1a
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Table 1 Synthesis of 2-amino ketones 3 from propargylic carbonates 1
and amines 2a
Yield %b
Propargylic
Entry ester 1 Ar
Amine 2
T (h)
3
7
1
2
3
4
Ph
3
76 (a)
—
1.5
2
46 (b)
75 (c)
60 (d)
30
7
Scheme 6 Proposed reaction mechanism for the palladium-catalyzed
synthesis of 2-amino ketones 3.
1
—
5
6
2
74 (e)
49 (f)
—
18
20
7
5.5
0.5
4.5
2
92 (g)
57 (h)
57 (i)
—
—
—
—
—
—
—
6
8
9
4-MeOC6H4
10
11
12
13
14
15
16
66 (j)
73 (k)
58 (l)
88 (m)
84 (n)
92 (o)
65 (p)
4
4-MeCOC6H4
4-EtO2CC6H4
7
3
1
Scheme 7 Palladium-catalyzed reaction of the allylic carbamate 8 with
and without piperazine.
1.5
1.5
—
—
3-MeC6H4
substituted terminus of the π-allylic palladium complex F fol-
lowed by the hydrolysis of the resultant enamine intermediate A
(Scheme 6, path a). The presence of the latter was detected by
NMR analysis of the crude reaction mixture before work-up.
The formation of 3 from F′, however, cannot be ruled out.
The isolation of ketocarbamate by-products 7 in some of the
reactions of unsubstituted propargylic esters with amines
(Table 1, entries 2, 3, 6 and 14) might indicate its involvement
as a common intermediate for the formation both of 3 and of 7
(Scheme 6, path b). Support for this view is provided by the
results obtained by treating the allylic carbamate 8 (expected to
react with Pd(0) to form the allylic intermediate G that could be
taken as model of F′) with piperidine (Scheme 7, a). Under
a Reactions were carried out on a 0.35 mmol scale at 80 °C in THF
(2 mL), under a nitrogen atmosphere, using 1 equiv. of 1, 3 equiv. of 2,
0.025 equiv. of Pd2(dba)3, and 0.05 equiv. of dppf. b Yields are given for
isolated products.
the desired products and the starting propargylic carbonate was
recovered in 73% and almost quantitative yield, respectively.
As for the mechanism of formation of 2-amino ketones 3,
they are most probably generated through the intermolecular
nucleophilic attack of the nitrogen nucleophile at the less
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excellent yield.
The alternative formation of A from F′ via intramolecular
nucleophilic attack of the nitrogen of the carbamate fragment at
the less substituted allylic terminus seems unlikely in view of
the known behavior of related allylpalladium carbamate inter-
mediates in the presence of nitrogen nucleophiles20 and of the
reaction of 8 with piperidine that we carried out. Only in the
absence of an external nucleophile the intramolecular nucleophi-
lic attack of morpholine takes place affording 9 in high yield
(Scheme 7, b).
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Conclusions
In summary, we have developed a novel palladium-catalyzed
approach to 2-amino ketones from arylpropargylic carbonates
unsubstituted at the propargylic carbon, bearing neutral, elec-
tron-rich and electron-poor aromatic rings, and cyclic secondary
amines containing useful functional groups such as cyano,
chloro, and bromo substituents. Our procedure is simple, uses
readily available starting materials and may represent a useful
tool for the synthesis of this class of compounds. With aryl-
propargylic carbonates containing aryl substituents at the pro-
pargylic carbon the reaction affords α-ketocarbamates in high
yield.
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Acknowledgements
We gratefully acknowledge MURST and the University “La
Sapienza”, Rome, for financial support.
Notes and references
‡Electronic effects of the substituents on the aromatic rings bound to the
propargylic system exert a strong influence on the regiochemistry of the
reaction. In the presence of electron-withdrawing 4-ethoxycarbonyl and
3-trifluoromethyl groups the benzylic position of the phenyl ring is more
electrophilic, whereas the electron-donating 4-methoxy group favors the
nucleophilic attack at the benzylic position of the substituted aromatic
ring. Minor differences in the electronic properties of the two aromatic
rings leads to the formation of an approximately equimolar regioisomeric
mixture.
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