Efficient microwave-assisted synthesis of secondary alkylproparglamines by using A3-coupling with primary aliphatic amines

Article abstract of DOI:10.1002/chem.200903143

(Chemical Equation Presented) Three-component coupling reaction: An efficient, microwave-assisted, Cu^Icatalysed A³-coupling reaction with primary aliphatic amines that gives access to secondary propargylamines is described (see schem

Full text of DOI:10.1002/chem.200903143

COMMUNICATION
DOI: 10.1002/chem.200903143
Efficient Microwave-Assisted Synthesis of Secondary Alkylpropargylamines
by Using A3-Coupling with Primary Aliphatic Amines
Jitender B. Bariwal, Denis S. Ermolatꢀev, and Erik V. Van der Eycken*[a]
Multicomponent reactions (MCRs) have attracted much
attention in the framework of combinatorial chemistry
owing to their synthetic efficiency, intrinsic atom economy,
high selectivity and procedural simplicity. These reactions
constitute a valuable approach for the creation of large li-
braries of structurally related, drug-like compounds, thereby
enabling rapid lead identification and optimisation in drug
discovery. They represent environmentally friendly process-
es by reducing the number of steps, energy consumption and
waste production.[1]
The three-component coupling of an aldehyde, an alkyne
and an amine, commonly called an A3-coupling, is an MCR
that has received much attention in recent years.[2] The re-
sulting propargylamines are synthetically versatile key inter-
mediates[3a,b] for the preparation of biologically active com-
pounds and drugs.[3c–e] Classical methods for the synthesis of
propargylamines use strong bases, such as butyllithium, or-
ganomagnesium reagents or lithium diisopropylamide
(LDA), exploiting the relatively high acidity of the terminal
acetylene to form alkynyl metal compounds. The stoichio-
metric quantities of the reagents required, as well as their
high sensitivity to moisture, render these processes fairly un-
attractive.[4]
pounds[15] have all been used to run this reaction under ho-
mogeneous conditions. Moreover, AuI, AgI and CuI in ionic
liquids and supported AuIII, AgI, CuI and CuCl were success-
fully used to catalyse A3-coupling reactions under heteroge-
neous conditions with preservation of the transition-metal
catalyst.[16] Additionally, the enantioselective addition of ter-
minal alkynes to imines provides access to optically active
propargylamines. A variety of chiral ligands have been used
for this reaction. High asymmetric induction has been re-
ported by applying 1-(2-diACTHNUTRGNENGpU henylACHTUNGTERNpNUGN hosphino-1-naphthyl)iso-
quinoline (QUINAP) ligands.[17] In addition to these ligands,
metal complexes of chiral amino acids,[18] chiral alcohols,[19]
chiral binaphthylamines[20] and 2,6-bis(2-oxazolinyl)pyridine
(PyBOX) ligand[21] have been used successfully.
Despite huge advancements, A3-coupling reactions have
mainly been optimised for reactions involving anilines and
secondary amines, which result in the formation of N-aryl-
propargylamines or tertiary propargylamines. Primary
amines are considered to be difficult substrates for A3-cou-
pling reactions; this limits access to secondary propargyla-
mines.[22] Nevertheless, secondary alkylpropargylamines are
potent synthetic intermediates that have mainly been ex-
plored for the synthesis of pyrrolidin,[23a] 5-alkylideneselena-
zolin-2-ones,[23b] pyrroles,[23c] quinolines[23d] and oxazolidinon-
es.[23e] The synthesis of secondary alkylpropargylamines by
using A3-coupling reactions is scarcely reported in the litera-
ture[8c,23c,24–26] and, to the best of our knowledge, no system-
atic study has ever been described. Herein, we present an
optimised protocol for the synthesis of secondary alkylpro-
pargylamines by using a microwave-assisted A3-coupling re-
action.
During recent years, substantial progress has been made
in A3-coupling reactions. Several transition-metal catalysts
À
have been exploited that activate the C H bond of the ter-
minal alkyne. AgI salts,[5] AuI/AuIII salts,[6] AuIII–salen
(salen=N,N’-bis(salicylidene)ethylenediamine) complexes,[7]
CuI salts,[8] IrI complexes,[9] Hg2Cl2,[10] Cu/RuII bimetallic sys-
[14]
tems,[11] InCl3,[12] ZnCl2,[13] FeCl3
and nano CuO com-
In an optimisation study, benzylamine (1{1}) was used as a
primary amine in combination with phenylacetylene (2{1})
and isobutyraldehyde (3{1}) (Table 1). As stated in the liter-
ature, the initial reagent ratio was selected as 1.3 equivalents
of amine, 1.0 equivalent of aldehyde and 1.6 equivalents of
alkyne[8c] with toluene as the solvent.[12,14] Reactions were
carried out in the presence of different copper salts under
microwave irradiation at various ceiling temperatures
(Table 1). Relatively low concentrations of the CuI catalyst
[a] Dr. J. B. Bariwal, Dr. D. S. Ermolatꢀev, Prof. E. V. Van der Eycken
Laboratory for Organic and
Microwave-Assisted Chemistry (LOMAC)
Department of Chemistry, Katholieke Universiteit Leuven
Celestijnenlaan 200F, 3001 Leuven (Belgium)
Fax : (+32)16-32-79-90
E-mail: erik.vandereycken@chem.kuleuven.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903143.
Chem. Eur. J. 2010, 16, 3281 – 3284
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3281

Table 1. Optimisation of the A3-coupling reaction with benzylamine.[a]
Surprisingly, applying these optimised conditions (as in
Table 1, entry 6) to perform the A3-coupling reaction with 4-
methylbenzaldehyde, 3{2}, resulted in a low yield of the cor-
responding propargylamine, 4{2} (Table 1, entry 11). The
lower yield can be attributed to the high reactivity of the re-
sulting secondary propargylamine, which, as indicated by
the mass spectrum of the reaction mixture, further reacts
with aldehyde and acetylene to give a dimeric propargyl-
Entry Catalyst ([mol%])
T [8C]
R
Yield [%][b]
1
2
3
4
5
6
7
8
CuI (5)
CuI (5)
80
100
80
100
120
100
120
100
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
5
18
38
65
57
78
CuI (10)
CuI (10)
CuI (10)
CuI (20)
CuI (20)
CuI (20)
AHCTUNGTRENNUNG
amine.[22] Therefore, modified reagent ratios and alternative
CuI catalysts were evaluated. The reaction was first run with
1.5 equivalents of amine, 1.0 equivalent of aldehyde and
3 equivalents of alkyne. By using 20 mol% CuCl, the prod-
uct, 4{2}, was obtained in a slightly improved yield of 64%
(Table 1, entry 15). Neither an increase of the irradiation
time nor irradiation of the neat reaction mixture improved
the yield (Table 1, entries 12 and 13). However, when
20 mol% of CuBr was used, the desired propargylamine,
4{2}, was obtained in an excellent 85% yield (Table 1,
entry 17). As CuBr is air sensitive under the microwave irra-
diation conditions generally used for the reaction,[27] it is
necessary to perform these reactions in an inert atmosphere.
Next we evaluated the scope of this microwave-assisted
CuBr-catalysed A3-coupling protocol (Table 2). A variety of
primary alkyl- and cycloalkylamines were evaluated
(Table 2, entries 3–12). Good yields were obtained, except in
the case of dodecylamine (Table 2, entry 10). Heterocyclic
and aliphatic acetylenes were also explored as partners in
the A3-coupling reaction, but only yielded the target com-
pounds, 4, in moderate yields due to the formation of un-
identified side products (Table 2, entries 15–17). To expand
the scope of the protocol, a variety of aliphatic aldehydes
were also evaluated. The reactions proceeded smoothly, de-
62
68[c]
57
9
CuI (20) + 4 ꢂ molecular sieves 100
CuI (20)
CuI (20)
CuI (20)
10
11
12
13
14
15
16
17
18
19
20
21
22
100
100
100
100
100
100
100
100
100
100
100
100
100
57[d]
p-tolyl 60
p-tolyl 41[e]
p-tolyl 55[f]
iPr
p-tolyl 64
iPr 68
p-tolyl 85
iPr
iPr
iPr
iPr
iPr
CuI (20)
CuCl (20)
CuCl (20)
CuBr (20)
CuBr (20)
CuOAc (20)
CuOTf (20)
CuACHTUNGTRENNUNG(OTf)2 (20)
InCl3 (20)
FeCl3 (20)
73
34
21
30
–
–
[a] Reaction conditions using isobutyraldehyde: amine (1.3 mmol), iso-
butyraldehyde (1.0 mmol), alkyne (1.6 mmol), CuBr (0.05, 0.1 and
A
ACHTUNGTRENNUNG
0.20 mmol), toluene (1.0 mL), MW, 80W, 25 min; reaction conditions
using 4-methylbenzaldehyde: amine (1.5 mmol), 4-methylbenzaldehyde
(1.0 mmol), alkyne (3.0 mmol), CuBr (0.20 mmol), toluene (1.0 mL),
MW, 80W, 25 min. [b] Isolated yields after column chromatography.
[c] Irradiation was continued for 50 min. [d] The reaction mixture was
conventionally heated for 17 h. [e] Irradiation was continued for 40 min.
[f] The reaction mixture was irradiated without solvent.
livering the corresponding prop
yields (Table 2, entries 18–26).
ACHUTGTNRENaUNG rgylCAHUTNGTRENaNUNG mines in 64–86%
resulted in low yields of the propargylamine 4{1} (Table 1,
entries 1–5). The optimal concentration of this catalyst was
found to be 20 mol% (Table 1, entry 6) yielding the desired
propargylamine, 4{1}, in 78% yield. Other attempts to im-
prove the yield by increasing the reaction temperature
(Table 1, entry 7), increasing the irradiation time (Table 1,
entry 8) or by using molecular sieves (Table 1, entry 9) did
not improve the yield. When the reaction was conducted
under conventional heating for 17 h, the desired propargyl-
A tentative mechanism for the CuBr-catalysed, one-pot,
three-component A3-coupling is proposed in Scheme 1. The
CuBr catalyst reacts with the alkyne to form an alkynylcop-
per(I) complex and release HBr. Microwave irradiation is
necessary to speed up the A3-coupling as well as for the for-
mation of the alkynylcopper and the imine.[8c] The A3-cou-
pling using a primary amine is thought to commence with
the in situ formation of an imine and subsequent attack by
alkynylcopper via transition state A (Scheme 1). After intra-
molecular transfer of the alkyne moiety to the imine, the
copper-complexed product B is formed. Decomplexation
produces the free propargylamine C and regenerates the
CuI catalyst.[24] Secondary propargylamine C is a highly reac-
tive A3-coupling partner and, in the presence of excess alde-
hyde, can easily produce iminium salt D. Subsequent attack
on D by alkynylcopper would give the tertiary propargyl-
ACHTUNGTRENNUNGamine, 4{1}, was obtained in moderate yield together with
multiple unidentified byproducts (Table 1, entry 10). Other
readily available CuI salts, such as CuCl and CuBr, also gave
competitive yields (Table 1, entries 14 and 16, respectively),
whereas CuOAc, CuOTf and CuACHTNUGTRENUNG(OTf)2 gave the desired
product in poor yields (Table 1, entries 18, 19 and 20, respec-
tively). The application of InCl3 did not yield any trace of
the product (Table 1, entry 21).[12] Finally, we tried the re-
cently reported catalyst FeCl3, which is described as being
very efficient in reactions involving secondary amines.[14]
Unfortunately, this catalyst did not work for our reaction
with benzylamine (Table 1, entry 22). The use of more polar
solvents, such as THF or EtOH, resulted in low yields due
to the formation of multiple unidentified byproducts.
AHCTUNGTREGaNNUN mine E (Scheme 1). Because of this unwanted side reac-
tion, all the A3-coupling reactions were performed by using
excess amine and acetylene.
To conclude, we have successfully developed an efficient,
fast and economical one-pot A3-coupling protocol applying
primary aliphatic amines that provides access to secondary
alkylpropargylamines in high yields. The reactions were car-
3282
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3281 – 3284

Synthesis of Secondary Alkylpropargylamines
COMMUNICATION
Table 2. Scope and limitations of the microwave-assisted CuBr-catalysed
A3-coupling reactions.[a]
ried out in the presence of catalytic amounts of CuBr with-
out the use of any ligand under microwave irradiation. The
reactions were also applicable to sterically hindered amines
and aldehydes.
Entry R1
R2
R3
Yield
[%][b]
Experimental Section
1
2
3
4
5
6
7
8
Bn
Bn
Pr
Ph
Ph
Ph
iPr
p-tolyl
iBu
iBu
iBu
iBu
iBu
iBu
iBu
89
85
94
66
73
72
68
60
67
46
83
69
89
62
42
44
41
86
73
65
78
77
83
75
General procedure for the preparation of alkyl-substituted prop
ACHTUNGTRENNUNGargyl-
ACHTUNGTRENNUNG
3-methoxyphenethyl Ph
tBu
cycloheptyl
cyclododecyl
p-methoxybenzyl
iBu
dodecyl
cyclooctyl
copper bromide (0.2 mmol) and toluene (1.0 mL) were added to a micro-
wave vial equipped with a magnetic stirring bar. The mixture was de-
gassed and backfilled with argon. The reaction vessel was sealed and irra-
diated in the cavity of a CEM-Discover microwave reactor for 25 min at
a ceiling temperature of 1008C and a maximum power of 80 W. The re-
sulting reaction mixture was cooled to ambient temperature, diluted with
dichloromethane (2 mL), loaded on a silica gel column and flash filtered
with 10–20% EtOAc in heptane to afford the product as a light yellow
oil. The identity and purity of the products was confirmed by 1H and
13C NMR spectroscopies and high-resolution mass spectrometry (see the
Supporting Information for full details).
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-tolyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
iBu
pentyl
iPr
Bn
p-methoxybenzyl
p-
N
p-FPh
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
p-pentyloxyphenyl p-tolyl
thiophene-3-yl
Bn
cyclopentyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Pr
Bu
Acknowledgements
Support was provided by the Research Fund of the University of Leuven
and by the F.W.O. (Fund for Scientific Research - Flanders (Belgium)).
D.S.E. and J.B.B. are grateful to the University of Leuven for obtaining a
postdoctoral fellowship.
iBu
pentyl
octyl
decyl
cyclopropyl 64
cyclohexyl 85
Keywords: A3-coupling
·
microwave
chemistry
·
[a] Reaction conditions: alkyne 1 (3.0 mmol), aldehyde 2 (1.0 mmol),
amine 3 (1.5 mmol), CuBr (0.20 mmol, 57 mg), toluene (1.0 mL), MW,
80 W, 1008C, 25 min; [b] Isolated yields after column chromatography.
multicomponent reactions · propargylamines · synthetic
methods
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Received: November 16, 2009
Published online: February 16, 2010
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