Gold-catalyzed direct intermolecular coupling of ketones, secondary amines, and alkynes: A facile and versatile access to propargylic amines containing a quaternary carbon center

Article abstract of DOI:10.1002/adsc.201000914

The first gold-catalyzed direct intermolecular coupling of ketones, secondary amines, and alkynes was achieved under mild and solvent-free conditions. The present methodology provides a promising and versatile tool for the construction of propargylic amines with a newly-formed quaternary carbon center.

Full text of DOI:10.1002/adsc.201000914

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DOI: 10.1002/adsc.201000914
Gold-Catalyzed Direct Intermolecular Coupling of Ketones,
Secondary Amines, and Alkynes: A Facile and Versatile Access
to Propargylic Amines Containing a Quaternary Carbon Center
Ming Cheng,a,b Qiang Zhang,a,b Xiao-Yu Hu,a,b Bo-Gang Li,a Jian-Xin Ji,a,*
and Albert S. C. Chanc
a
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
Fax : (+86)-28-8285-5223; e-mail: jijx@cib.ac.cn
Graduate University of the Chinese Academy of Sciences, Beijing 100049, Peopleꢀs Republic of China
The presidentꢀs office, Hong Kong Baptist University, Kowloon Tong, Hong Kong, Peopleꢀs Republic of China
b
c
Received: December 3, 2010; Revised: February 8, 2011; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000914.
Abstract: The first gold-catalyzed direct intermolec-
ular coupling of ketones, secondary amines, and al-
kynes was achieved under mild and solvent-free
conditions. The present methodology provides a
promising and versatile tool for the construction of
propargylic amines with a newly-formed quaternary
carbon center.
tion of the sensitive imines or enamines and (ii) the
nucleophiles do not need to be preactivated.
Nevertheless, in those direct methodologies, the C=
N electrophiles have been restricted to aldimines gen-
erated in situ. Ketoimines[6] are generally considered
to be less reactive towards nucleophilic additions than
aldimines, owing to the steric hindrance and electron-
ic effects. Therefore, the utilization of ketoimines gen-
erated in situ in the direct alkyne addition reaction
still remains a significant challenge for chemists. Up
to date, only few methods have been developed in
this field and almost all of them suffer from limita-
tions,[7] such as the ketoimine being generated in an
intramolecular manner from a preformed precursor
Keywords: alkynes; gold salts; ketones; propargylic
amines; secondary amines
The addition of carbanions to C=N bonds is an extra- containing a ketone moiety and amine, specific reac-
À
ordinarily useful transformation to access C C and tion conditions, poor substrate scope, low yields, and/
C N bond formation in the construction of nitrogen-
À
containing molecules and complex natural products.[1]
For example, the Mannich reaction, first developed
by Carl Mannich in 1912,[2] has become a highly sig-
nificant method for achieving such conversions. Re-
cently, among the well-developed addition reactions,
direct coupling reactions have experienced an explo-
sive growth, and the nucleophiles for which have
À
been extensively extended to various C H activated
compounds such as carboxylic acid derivatives, nitro-
alkanes, electron-rich aromatic compounds, and ter-
minal alkynes (Scheme 1).[3] Notably, in the above
direct coupling reactions, the A3 (aldehydes, alkynes,
and amines) coupling which uses alkynes as carbon
nucleophile source is exceptionally attractive, and
provides a fresh avenue for the construction of terti-
ary carbon-containing propargylic amines.[4] Com-
pared with the indirect coupling reactions,[5] all such
direct transformations exhibit the following conspicu-
ous advantages: (i) it does not require prior prepara- Scheme 1. Direct and indirect coupling reactions.
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Gold-Catalyzed Direct Intermolecular Coupling of Ketones, Secondary Amines, and Alkynes
AHCTUNGTREGUNiNN mines generated in an intermolecular manner from
ketones and secondary amines for the construction of
quaternary carbon-containing propargylic amines
under neat conditions without any ligand or additive
(Scheme 2).
Propargylic amines represent the core of a series of
biologically active molecules and can serve as versa-
tile building blocks for the synthesis of a variety of ni-
trogenous compounds.[8] Traditionally, these com-
pounds are synthesized by amination of propargylic
halides, propargylic phosphates, and propargylic tri-
Scheme 2. The direct intermolecular coupling of ketones,
secondary amines, and alkynes.
or long reaction times. Recently, Che and co-workers flates, or through nucleophilic attack of lithium acety-
described an Au[P(t-Bu)2(o-biphenyl)]Cl/AgSbF6-co- lides, Grignard reagents on imines or their deriva-
AHCTUNGTRENNUNG
catalyzed addition reaction of phenylacetylene to the tives.[9] Convenient and efficient methods to construct
ketoimine generated in an intramolecular manner propargylic amines, especially quaternary carbon-con-
from N-(4-methoxyphenyl)-5-aminopentan-2-one.[7a] taining propargylic amines, through direct coupling
Van der Eycken et al. reported a microwave-assisted reactions, are of extraordinary attractiveness.[10] The
CuI-catalyzed direct alkyne addition reaction to ke- present methodology provides an effective synthetic
toimines generated in situ from aliphatic ketones and tool for the direct construction of quaternary carbon-
primary amines at high temperatures.[7b] Very recently, containing propargylic amines in a one-pot procedure.
Yus et al. reported a Cu(OH)x-Fe3O4-catalyzed addi-
Initially, the direct coupling reaction of cyclohexa-
tion of phenylacetylene to the ketoimine generated in none (1a), morpholine (2a), and phenylacetylene (3a)
situ from 3-pentanone or acetophenone and piperi- was explored as a test reaction in the presence of vari-
dine with low yield over a long reaction time (7 ous transition metals such as Cu, Zn, In, Ag, and Au
days).[7c] Herein, we report a novel and efficient gold- in CH2Cl2 (Table 1, entries 1–11). Among those cata-
catalyzed direct alkyne addition reaction to keto- lysts examined, AuBr3 exhibited the best catalytic ac-
Table 1. Optimization of the intermolecular coupling of cyclohexanone, morpholine, and phenylacetylene.[a]
Entry
Catalyst
CuBr
Solvent
Time [h]/Temperature [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
THF
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/r.t
50/60
50/60
50/60
50/60
8/60
0
0
0
0
0
0
0
8
16
42
51
15
44
49
19
0
Cu
N
AgNO3
AgOTf
Zn
N
In(OTf)3
U
InBr3
AuCN
AuI
9
10
11
12
13
14
15
16
17
AuCl3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
CH3CN
DMF
neat
89
[a]
Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), 3a (1.5 mmol).
Isolated yields based on 2a.
[b]
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Ming Cheng et al.
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Table 2. Intermolecular coupling of ketones, secondary amines, and alkynes cata-
lyzed by AuBr3.[a,b]
[a]
Reaction conditions: ketones 1 (1.5 mmol), amines 2 (1.0 mmol), alkynes 3
(1.5 mmol).
Isolated yields based on amines 2.
The diastereomeric ratio was determined by HPLC analysis.
Reaction conditions: acetone (5 mmol), morpholine (1.0 mmol), and phenylacety-
[b]
[c]
[d]
lene (1.5 mmol).
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Gold-Catalyzed Direct Intermolecular Coupling of Ketones, Secondary Amines, and Alkynes
tivity and afforded the expected product 4a in moder- sults in the intermediate 6. Intermediate 6 underwent
ate yield (51%, Table 1, entry 11). Further optimiza- intramolecular transfer of the alkyne moiety to afford
tion suggested that solvents had a strong effect on a gold-complexed intermediate 7. Subsequent decom-
this process, and the reactions were obviously re- plexation produced the corresponding propargylic
strained when they were performed in toluene, THF, amine 4 and concomitantly regenerated the gold cata-
CH3CN, or DMF even at 608C (Table 1, entries 12– lyst (Scheme 3).
16). Gratifyingly, the reaction proceeded smoothly in
In conclusion, we have developed an efficient
neat conditions (Table 1, entry 17). In summary, the method for the synthesis of quaternary carbon-con-
direct intermolecular coupling of cyclohexanone, mor- taining propargylic amines through a gold-catalyzed
pholine, and phenylacetylene could be effectively re- direct intermolecular coupling of ketones, secondary
alized employing AuBr3 as catalyst at 608C under amines, and alkynes. Taking into account of the fol-
neat conditions.
lowing conspicuous features, such as the importance
With the optimal reaction conditions in hand, the of products, ready availability of the starting materi-
scope and limitation of this reaction were tested with als, simple experimental procedures, and mild reac-
various combinations of ketones, secondary amines, tion conditions, this catalytic system is expected to
and alkynes. As shown in Table 2, aliphatic ketones provide an excellent opportunity for the synthesis of
including cyclic and acyclic ketones exhibited good re- various nitrogenous molecules containing a quaterna-
activity (4a–h). However, aromatic ketones, such as ry carbon center. Further studies on the scope and ap-
acetophenone, 4-methoxyacetophenone, and 4-nitro- plication of this reaction are underway.
ACHTUNGTRENNUNGacetophenone gave none of the desired products (4t–
v), which might be explained by the difficulty of the
transformation of an aromatic ketone and an amine Experimental Section
to the corresponding enamine 5 or iminium cation in-
termediate 6 (Scheme 3) due to the special stability of General Remarks
conjugated aromatic ketones. With respect to the sec-
All chemicals and solvents were used as received without
ondary amines, cyclic amines reacted efficiently under
the standard conditions (4a, 4k, 4l and 4m), whereas
acyclic amines, such as dibenzylamines and dibutyl-
further purification unless otherwise stated. 1H NMR and
13C NMR spectra were recorded in CDCl3 on a Bruker
Avance 600 spectrometer with TMS as internal standard
1
(600 MHz H, 150 MHz 13C) at room temperature, and the
ACHTUNGTRENNUNGamine, generated the corresponding products in lower
chemical shifts (d) were expressed in ppm and J values were
given in Hz. Mass analyses and HR-MS were obtained on a
Finnigan-LCQDECA mass spectrometer and a Bruker Dalton-
ics Bio-TOF-Q mass spectrometer by the ESI method, re-
spectively. Column chromatography was performed on silica
gel (200–300 mesh).
yields (4i, 4j). Compared with aliphatic alkynes (4r,
4s), aromatic alkynes afforded the target products in
much higher yields, especially those armed with elec-
tron-rich groups (4n, 4o, 4p).
Based on the above observations and previous re-
ports, a tentative mechanism was proposed involving
the complexation of gold, alkyne, and enamine 5 gen-
erated in situ from ketone 1 and amine 2, which re-
Scheme 3. Proposed mechanism for direct intermolecular coupling of ketones, secondary amines, and alkynes.
Adv. Synth. Catal. 2011, 353, 1274 – 1278
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Ming Cheng et al.
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General Procedure for Direct Intermolecular Cou-
pling of Ketones, Secondary Amines, and Alkynes
Ketones (1.5 mmol), amines (1.0 mmol), alkynes (1.5 mmol),
and AuBr3 (0.04 mmol) were added to a dried 25-mL round-
bottomed flask containing a magnetic stirring bar. The reac-
tion mixture was stirred for 8 h at 608C. Then the catalyst
was removed by filtration through silica gel and washed
with EtOAc (10 mL). The filtrate was concentrated under
vacuum and the residue was purified by flash chromatogra-
phy to give the desired products.
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