Studies of multicomponent Kinugasa reactions in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2009.02.035

Micelle-promoted, copper-catalyzed multicomponent Kinugasa reactions were studied in aqueous media. Reactions were performed in a 'single pot' for a series of in situ generated C,N-diphenylnitrones with Cu(I) phenylacetylide providing β-lactams in yields of 45-85%. Substituents affect the reaction by either accelerating cycloaddition or minimizing side reactions.

Full text of DOI:10.1016/j.tetlet.2009.02.035

Tetrahedron Letters 50 (2009) 1893–1896
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Tetrahedron Letters
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Studies of multicomponent Kinugasa reactions in aqueous media
Craig S. McKay a,b, David C. Kennedy a, John Paul Pezacki a,b,
*
a Steacie Institute for Molecular Sciences, National Research Council, 100 Sussex Drive, Ottawa, Canada K1A 0R6
b Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
Micelle-promoted, copper-catalyzed multicomponent Kinugasa reactions were studied in aqueous
media. Reactions were performed in a ‘single pot’ for a series of in situ generated C,N-diphenylnitrones
with Cu(I) phenylacetylide providing b-lactams in yields of 45–85%. Substituents affect the reaction by
either accelerating cycloaddition or minimizing side reactions.
Received 11 January 2009
Revised 23 January 2009
Accepted 2 February 2009
Available online 10 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Multicomponent reactions enable multiple reactions to be com-
bined in a single procedural step. Multicomponent reactions have
been applied to the construction of a number of complex molecular
structures.1,2 These reactions avoid potentially difficult purification
steps and conserve both solvents and reagents. The use of water as
a solvent has further advantages in that it is economical and en-
ables reactions to be performed on water-soluble biomolecular
substrates.3 Organic reactions in water are often limited in scope
due to poor solubility of the organic compounds. Nevertheless, a
number of heterocyclic compounds including acridines,4 furans,5
indoles,6 pyrazines,7 pyridines,8 pyrimidines,9 and pyrazolines10
have been successfully synthesized in aqueous media. The devel-
opment of new multicomponent reactions in aqueous media to
form complex organic molecules remains an important challenge.
b-Lactams represent one of the best known and extensively
studied class of heterocycles, primarily as a result of their powerful
antibiotic activities.11,12 b-lactams were first synthesized by Stau-
dinger in 1907 via the cycloaddition of ketenes with imines.13
Since then there have been a number of methodologies for the con-
struction of the b-lactam ring.14 A convergent route to b-lactams
was reported by Kinugasa et al. in 1972, whereby C,N-diphenylnit-
rones were reacted with in situ-generated Cu(I) phenylacetylide in
anhydrous pyridine,15 and a generally accepted mechanism of b-
lactam formation has been established.16 Asymmetric variants of
the Kinugasa reaction use chiral ligands for chelation to copper
such as bis(oxazoline)-type ligands,17 Evans’ oxazolidinone li-
gand,18 planar chiral bis(azaferrocene) ligands,19 tris(oxazoline) li-
gands,20 and HETPHOX ligands.21
in situ-generated C,N-diphenylnitrone in aqueous media.23 Also
click conditions for the Kinugasa reaction have been successfully
reported.24 Herein, we report studies of simultaneous micelle and
copper-catalyzed multicomponent Kinugasa reactions in water.
The multicomponent process proceeds by a two-step reaction se-
quence involving the micelle-promoted nitrone formation from
substituted benzaldehydes and N-phenylhydroxyl amine followed
by the in situ 1,3-dipolar cycloaddition and rearrangement reac-
tion with Cu(I) phenylacetylide (Fig. 1).
A key step to establishing optimal reaction conditions for the
multicomponent Kinugasa reaction is the optimization of the
in situ generation of the nitrone. To accomplish this, we employed
similar conditions to those used by Chatterjee et al.22 Dehydrative
nitrone formation from benzaldehyde (1a) (0.4 mmol) and phenyl
hydroxylamine (2) (0.5 mmol) in the presence of SDS micelles
(0.4 mmol) in degassed water at room temperature (rt) proceeded
in 30 min. to form C,N-diphenylnitrone. It was found that sonica-
tion of the reaction mixture for 5 min decreased the time of nitrone
2
2
Previously, Chatterjee et al. reported a convenient ‘single pot’
synthesis of isoxazolines which involved micelle-catalyzed nitrone
formation followed by cycloaddition in aqueous media.22 We have
recently utilized this methodology to functionalize an unnatural
.
4
2
amino acid containing
a cyclic a,b-unsaturated ketone with
* Corresponding author. Tel.: +1 613 993 7253; fax: +1 613 941 8447.
E-mail address: John.Pezacki@nrc.ca (J.P. Pezacki).
Figure 1. Micelle-promoted multicomponent b-lactam synthesis by the Kinugasa
reaction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.035

1894
C. S. McKay et al. / Tetrahedron Letters 50 (2009) 1893–1896
X
formation, presumably by helping to effectively solubilize the re-
agents by the surfactant. This method of nitrone formation com-
plements traditional approaches using organic solvents,18 which
often require anhydrous conditions and/or the use of dehydrating
agents.
We found that cooling the in situ-generated C,N-diphenylnit-
rone to 0 °C led to better yields of b-lactam 4a, Scheme 1. The
cooled solution was then reacted with phenylacetylene
X
L Cu
n
H2O
O
N
N
N
O
H
C
O
CuL
-CuLnOH
n
X
(0.2 mmol), (+)-sodium-L-ascorbate (0.08 mmol), and Cu(SO)4
CHO
H
N
(0.04 mmol) in the dark. The latter reaction also contained an ex-
cess of pyridine (1.6 mmol) and 0.1 M ethanolamine (ETA) buffered
at pH 10. This mixture was allowed to react for 30 min at 0 °C and
was then stirred at room temperature for 10 h. The reaction mix-
ture consisted of essentially three products (Scheme 1), the cis-
and trans-b-lactams (4a) in 46% overall yield and an amide product
(5) in 36% yield, the structure of which was confirmed by X-ray
crystallography. As far as we are aware, amide 5 is not a typical
by-product of the Kinugasa reaction or a common decomposition
product of b-lactams.
O
X
5
Scheme 2.
Table 1
Effect of Cu catalyst loading on the multicomponent Kinugasa reaction in watera
Entry
Cu catalystb (mol %)
Time (h)
% Yieldc
4a (cis/trans)
5
To investigate the origins of the side product 5, we performed a
series of reactions systematically removing each component of the
multicomponent reaction. None of these control reactions led to
the formation of 5. Also, we placed product 4a into solutions con-
taining copper, ascorbate, and SDS, to determine if 5 is a decompo-
sition product of 4a. We did not see any reaction of 4a under these
conditions, therefore side product 5 clearly does not arise from the
decomposition of 4a. Previously, Tang and co-workers20b observed
a different side product in the Kinugasa reaction and proposed a
ketene intermediate for it’s formation.20b Here, we propose that
an analogous ketene is formed and that in water it gives rise to
5, according to the pathway given in Scheme 2.
1
2
3
100
80
20
6
7
10
46 (1.2:1)
46 (1.2:1)
46 (1.2:1)
36
36
36
a
Reaction conditions; [1a]:[2]:[3]:ETA:py = 2:2.4:1:2:8 in degassed SDS/H2O
(0.05 M) in dark from 0 °C to rt under argon.
b
Na-ascorbate:CuSO4 = 2:1.
Determined by HPLC analysis. ETA = 0.1 M ethanolamine buffer at pH 10.
c
HO
SDS
H2O
N
N
H
O
Na-ascorbate reduces Cu(II) to Cu(I) under aqueous conditions,
and allows for the in situ generation of the Cu(I) phenylacetylide.
This intermediate then reacts with the in situ-generated nitrone
in a formal [3+2] cycloaddition forming an isoxazoline intermedi-
ate. Protonation and subsequent rearrangement of the oxaziridine
produce a mixture of cis- and trans-b-lactams. The diastereoselec-
tivity depends on the ease of isomerization at C-3, as shown
previously.16,20,25
Under the conditions used in Table 1, Cu(I) loading did not sig-
nificantly affect the product composition; however, lower Cu load-
ing resulted in longer reaction times. Catalyst loading below
20 mol % caused the reaction to be very sluggish and gave poor
yields of cis- and trans-4a. A proposed catalytic cycle for the cop-
per-catalyzed Kinugasa reaction in water is shown in Figure 2.
In a screen of three nitrogen-containing ligands, it was found
that conducting the reaction with excess pyridine yielded cis-
and trans-4a in 46% yield (Table 2). In contrast, decreasing the
amount of pyridine below 2 equiv resulted in a very slow reaction
and trace amounts of cis- and trans-4a were detected. Presumably,
excess pyridine facilitates regeneration of the active Cu catalyst.
Alternatively, 2,20-bipyridyl was found to be a more efficient li-
gand in the reaction and provided cis- and trans-4a and 5 in yields
of 42% and 29%, respectively, with the addition of only one equiv-
alent. This is likely attributed to stronger Cu(I) binding of this
bidentate ligand in solution. Next, tris[(1-benzyl-1H-1,2,3-triazol-
CuL
n
CHO
-H+
CuL
O
Na-Ascorb.
Ligand
.
n
CuL
CuSO4 5H2O
n
N
H
H
H
O
O
H
H
CuL
O
n
+H+
N
N
H
H
N
Figure 2. Proposed catalytic cycle for Cu(I)-catalyzed Kinugasa reaction in water.
Table 2
Effect of ligand on the micelle-catalyzed Kinugasa reaction in watera
Entry
Ligandc (equiv)
Time (h)
Yieldb (%)
4a (cis/trans)
5
1
2
3
4
5
py (10)
py (8)
9
46 (1.2:1)
46 (1.2:1)
15(1:1)
42 (1.4:1)
31 (1:1)
36
36
18
29
22
10
20
10
24
py (2)
bpy (1)
TBTAd (0.2)
a
Reaction conditions; [1a]:[2]:[3]:Na-ascorbate:CuSO4:ETA = 2:2.4:1:0.4:0.2:2 in
degassed SDS/H2O (0.05 M) in dark from 0 °C to rt under argon.
b
Determined by HPLC analysis.
c
py = pyridine, bpy = 2,20-bipyridyl, TBTA = tris[(1-benzyl-1H-1,2,3-triazol-4-
O
1a
yl)methyl]amine.
d
.
TBTA was dissolved in 0.05 M SDS prior to adding to the reaction.
H
CuSO 5H O
4
2
O
Na-Ascorbate
O
H
N
ligand, base
N
NH
4-yl)methyl]amine (TBTA), a ligand commonly used in azide–al-
kyne cycloadditions,26 was examined. The reaction was slower
and provided 4a and 5 in 31% and 22% yields after an extended
reaction time.
3
SDS/H O
OH
2
0 ºC to r.t.
2
5
4a
Scheme 1.

C. S. McKay et al. / Tetrahedron Letters 50 (2009) 1893–1896
1895
Table 3
Effect of stoichiometry on the multicomponent Kinugasa reaction in aqueous mediaa
Table 5
Multicomponent Kinugasa reaction scope with respect to the
a
-aryl nitrone
substituenta
Entry
1a:3
Base
Yieldb (%)
4a (cis/trans)
1a-i
O
5
.
H
CuSO4 5H2O
O
1
2
3
4
5
6
7
4:1
2:1
2:1
2:1
1:2
1:2
1:2
ETA
ETA
Tris
—
ETA
Tris
—
44 (1.1:1)
46 (1.2:1)
39 (1:1)
40 (2:1)
24 (1:1)
37 (1:1)
33 (1.5:1)
35
36
41
47
24
39
37
Na-Ascorbate
O
X
H
N
N
pyridine, ETA
SDS/H2O
0 ºC to r.t.
NH
3
OH
2
4a-i
5
X
Entry
Substituent (X=)
Time (h)
Yieldb (%)
a
Reaction conditions; Na-ascorbate:CuSO4:base:py = 0.4:0.2:2:8 in degassed
4 (cis/trans)
5
SDS/H2O (0.05 M) in dark from 0 °C to rt under argon.
1
2
3
4
5
6
7
8
9
H, 4a
10
13
8
46 (1.2:1)
45 (1.3:1)
62 (1.2:1)
60 (1.2:1)
73 (1.6:1)
85 (1:1)
67 (1.2:1)
79 (1.3:1)
82 (1.1:1)
36
24
26
15
22
13
18
11
15
b
Determined by HPLC analysis. ETA = ethanolamine buffer (0.1 M pH 10),
p-Me, 4b
p-OMe, 4c
m-OMe, 4d
p-Br, 4e
p-CO2Me, 4f
p-CN, 4g
m-NO2, 4h
p-NO2, 4i
Tris = tris(hydroxymethyl)aminomethane buffer (0.1 M pH 8).
9
18
18
18
18
18
The stoichiometry of 1a:3 was also varied (Table 3). We found
that the yield of 4a was consistently higher when using an excess
of 1a relative to 3. Interestingly, the multicomponent Kinugasa
reaction proceeds when buffered to pH 8 using a 0.1 M Tris buffer,
providing cis- and trans-4a and 5 in 39% and 41% yields. The use of
a buffer maintained a constant pH throughout the course of the
reaction, and it was found that the highest yields of cis- and
trans-4a and 5 were 46% and 36%, respectively, when an ETA solu-
tion buffered to pH 10 was used.
We next examined if the base employed affects the yield and
selectivity of the reaction. As shown in Table 4, two inorganic salts,
primary amines, secondary amines, and a tertiary amine could all
effectively promote the reaction. Compared with primary and ter-
tiary amines, secondary amines afforded the b-lactam products
with better cis-diastereoselectivity. Bulkier amines also favored
the formation of the cis-4a diastereomer. This suggests that the
amine may coordinate to Cu(I).
Next, we examined the generality of the micelle-promoted and
copper-catalyzed multicomponent Kinugasa reaction by applying a
series of substituted benzaldehydes27,28 at the para- and meta-
positions (Table 5). The presence of electron-donating groups
(EDGs) resulted in lower yields of the corresponding cis- and
trans-b-lactams (4b–d) in slightly shorter reaction times relative
to when electron-withdrawing groups (EWGs) were employed (Ta-
ble 5, entries 2–4). The yield of 5 was consistently lower when the
electron-withdrawing groups were present on the benzaldehyde.
There are three competing reactions that affect the product com-
position; formation of b-lactams, formation of 5, and hydrolytic
decomposition of the in situ-generated nitrone. Reactions of nitro-
nes bearing EWGs resulted in a lower yield of 5 and less decompo-
sition (higher overall yield of 4+5) relative to those containing
EDGs. While the reactions take slightly longer to reach completion
using EWGs (Table 5, entries 6–9), the lack of competing pathways
results in increased yields of cis- and trans-b-lactams, 4e–i, respec-
a
Reaction conditions; [1a–i]:[2]:[3]:Na-ascorbate:CuSO4:py:ETA = 2:2.4:1:0.4:
0.2:8:2 in degassed SDS/H2O (50 mM) in dark from 0 °C to rt under argon.
b
Determined by HPLC analysis.
tively. The longer reaction times likely result from a modest substi-
tuent effect on the rate constant for cycloaddition between the
in situ-generated Cu(I) phenylacetylide and the in situ-generated
nitrone. Also, less decomposition over the first 10 h contributes
to the much higher yields for the latter reactions. The ratio of
cis/trans for all substituted b-lactams (4b–i) did not change with
respect to 4a.
In conclusion, we have studied multicomponent Kinugasa reac-
tions for the simultaneous micelle-promoted and Cu(I)-catalyzed
coupling of alkynes with in situ-generated nitrones to form b-lac-
tams. The reaction is tolerant to substituents at the a-aryl position
of the nitrone, and the highest yields of b-lactams were obtained
when electron-withdrawing substituents are employed. This reac-
tion provides a convenient method for the construction of the b-
lactam ring in aqueous media.
Acknowledgments
We thank Don Leek and Malgosia Daroszewska for their assis-
tance with NMR and Mass Spectrometry.
Supplementary data
Detailed experimental procedures, characterization data, and
representative HPLC chromatograms are provided. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.02.035.
Table 4
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Entry
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5
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1
2
3
4
5
6
7
Na2CO3
NaHCO3
DIPA
Cy2NH
Et3N
10
8
38 (1.2:1)
44 (1.1:1)
42 (2.5:1)
31 (2.8:1)
45 (1.6:1)
38 (1:1)
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8:2 in degassed SDS/H2O (50 mM) in dark from 0 °C to rt under argon.
b
Determined by HPLC analysis.

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