Copper(I)-catalyzed three component reaction of sulfonyl azide, alkyne, and nitrone cycloaddition/rearrangement cascades: A novel one-step synthesis of imidazolidin-4-ones

Article abstract of DOI:10.1021/ol202164x

A novel one-pot azide-alkyne/ketenimine-nitrone cycloaddition sequence that is induced by copper(I) and allows the transformation of sulfonyl azides, alkynes, and nitrones to highly substituted imidazolidin-4-ones is described. The corresponding heterogeneous version utilizing Cu(I)-modified zeolites as recyclable heterogeneous catalysts shows marginally improved yield and diastereoselectivity.

Full text of DOI:10.1021/ol202164x

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5728–5731
Copper(I)-Catalyzed Three Component
Reaction of Sulfonyl Azide, Alkyne, and
Nitrone Cycloaddition/Rearrangement
Cascades: A Novel One-Step Synthesis of
Imidazolidin-4-ones
Kayambu Namitharan and Kasi Pitchumani*
School of Chemistry, Madurai Kamaraj University, Madurai-625021, India
pit12399@yahoo.com
Received August 9, 2011
ABSTRACT
A novel one-pot azideꢀalkyne/ketenimineꢀnitrone cycloaddition sequence that is induced by copper(I) and allows the transformation of sulfonyl
azides, alkynes, and nitrones to highly substituted imidazolidin-4-ones is described. The corresponding heterogeneous version utilizing Cu(I)-
modified zeolites as recyclable heterogeneous catalysts shows marginally improved yield and diastereoselectivity.
In the context of sustainable chemistry, multicomponent
cascade reactions have emerged as powerful strategies that
allow multiple bond-forming events occurring in a single
vessel and, as a consequence, significantly increase re-
source efficiency for the overall process. Such reactions
have not only been sought after for their academic interest
but also for their industrial relevance, owing to their high
atom economy, selectivity, and low levels of byproduct
generation.1 In biological systems, concurrent cascade
processes that integrate a series of individual catalyzed
reactions in a continuous process are the most prevalent
ones. Cascade processes involving one cycloaddition step
are quite common; however, those engaging two or more
cycloaddition reactions are rare,2 especially when transi-
tion metals are involved.3,4 Developing novel cascade
reactions combining two cycloaddition steps that achieve
the formation of multiple CꢀC and/or C-heteroatom
bonds with stereocontrol and in a single operation is a
particularly attractive strategy for the efficient construc-
tion of complex molecular architecture.
N-Sulfonylketenimine, a reactive intermediate derived
from the Cu-catalyzed cycloaddition of sulfonyl azide and
terminal alkyne, has recently been utilized for the synthesis
of N-sulfonylamidines, amides, N-sulfonylazetidin-2-imines,
iminocoumarins, and pyrrolines, tetrahydropyrimidines,
dihydrofurans, indoles, pyrrolidinones, γ-nitroimidates,
indolines, isoquinolines etc.,5ꢀ7 mostly from the groups
of Chang6 and Wang.7 Despite the advances, the search for
unprecedented ketenimine-based multiple cascade reactions
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.
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Arns, S.; Barriault, L. Chem. Commun. 2007, 2211–2221. (c) Tour, B. B.;
Hall, D. G. Chem. Rev. 2009, 109, 4439–4486. (d) Nicolaou, K. C.; Chen,
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Gelder, R.; Scheeren, H. W. Chem. Commun. 1999, 855–856. (b) van
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r
10.1021/ol202164x
Published on Web 10/12/2011
2011 American Chemical Society

continues. In this context, use of nitrones as coupling
partners in [3 þ 2] reactions stands out as a powerful method
for the construction of stereodefined heterocycles.8,9 On
this basis, we became interested in the possibility of using
the above-mentioned N-sulfonylketenimine as a suitable
dipolarophile to react with nitrones, and in doing so create
multiple bonds, rings, and stereocenters in a single trans-
formation. Herein, we report a successful execution of this
idea and describe the CuI-catalyzed azideꢀalkyne [3 þ 2]
and ketenimineꢀnitrone [3 þ 2] cycloaddition cascades
(Scheme 1). Significantly, the cycloaddition sequence en-
ables quick construction of heavily functionalized imida-
zolidin-4-ones in high yields with the generation of two
new chiral centers with good diastereoselectivity under
mild reaction conditions.
melanoma,13 in peptidomimetics,14 as chiral auxiliaries for
the synthesis of amino acids,15 as an important chiral
building block in the total synthesis of natural products,16
and, most recently, as successful organocatalysts for a
variety of asymmetric reactions.17
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
base
TEA
solvent
yield (%)b (syn/anti)c
1
2
3
4
5
6
7
8
9
CuI
DCM
DCM
DCM
DCM
DCM
DCM
THF
78 (28:72)
CuCl
TEA
71 (27:73)
CuIꢀY
Cu/Al-HT
CuIꢀY
CuIꢀY
CuIꢀY
CuIꢀY
CuIꢀY
TEA
85 (24:76)
Scheme 1. Copper(I)-Catalyzed AzideꢀAlkyne/Ketenimineꢀ
Nitrone Cycloaddition Cascades to Imidazolidin-4-ones
TEA
trace
63
DIPEA
pyridine
TEA
48
60
TEA
MeCN
Toluene
52
TEA
49
a Reaction conditions: Sulfonyl azide (1 mmol), alkyne (1 mmol),
nitrone (1 mmol), TEA (1.2 mmol), catalyst (20 mg), solvent (2 mL), rt,
N2, 3 h. b Isolated yield. c Diastereomeric ratio (syn/anti) was determined
by 1H NMR.
In addition, imidazolidin-4-ones, and compounds of similar
structures, constitute a widespread structural motif in natural
products and pharmaceuticals.10 Imidazolidin-4-one deri-
vatives have shown wide range of biological activities,11
such as antimalarial activity,12 antiproliferative activity for
The copper(I)-catalyzed cascade process was standard-
ized with tosyl azide 1a, phenylacetylene 2a, and C-4-
chlorophenyl-N-phenyl nitrone 3a in the presence of CuI
and triethylamine (TEA) under N2 atmosphereindichloro-
methane (DCM). Instead of the anticipated oxadiazolidine
(structure B, Schemes 1 and 4), to our surprise, the rear-
ranged product namely imidazolidin-4-one was obtained in
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Org. Lett., Vol. 13, No. 21, 2011
5729

Table 2. Copper(I)-Y Zeolite Catalyzed Cascade Synthesis of Imidazolidin-4-onesa
entry
R1
R2
R3
yield (%)b
(syn/anti)c
1
4-MeC6H4 (1a)
Ph (2a)
2a
4-ClC6H4 (3a)
85
81
91
79
76
83
85
0
4a (24:76)
4b (14:86)
4c (13:87)
4d (16:84)
4e (26:74)
4f (13:87)
4g (35:65)
2
4-ClC6H4 (1b)
3a
3
4-BrC6H4 (1c)
2a
3a
4
2-naphthyl (1d)
2a
3a
5
Ph (1e)
1a
2a
3a
6
4-MeC6H4 (2b)
3a
7
1a
1-cyclohexenyl (2c)
3a
8
1a
4-n-pentyl C6H4 (2d)
3a
9
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3-Cl, 4-ClC6H3 (3b)
Ph (3c)
82
77
0
4h (15:85)
4i (14:86)
10
11
12
13
14
15
16
17
18
1a
1a
Isovaleraldehyde (3d)
4-MeC6H4 (3e)
4-OMeC6H4 (3f)
4-FC6H4 (3g)
2-FC6H4 (3h)
5-Mefurfuryl (3i)
3-NO2C6H4 (3j)
4-NMe2C6H4 (3k)
1a
88
85
90
92
84
89
73
4j (53:47)
4k (62:38)
4l (18:82)
4m (1:99)
4n (37:63)
4o (17:83)
4p (63:37)
1a
1a
1a
1a
1a
1a
a Reaction conditions: Sulfonyl azide (1 mmol), alkyne (1 mmol), nitrone (1 mmol), TEA (1.2 mmol), CuI-zeolite (20 mg), DCM (3 mL), rt, N2, 3 h.
b Isolated yield. c Diastereomeric ratio (syn/anti) was determined by 1H NMR.
78% yield (syn/anti ratio 28:72) after 3 h (Table 1, entry 1),
while lesser yield of product was obtained in the case of
CuCl (entry 2). However, our interest in heterogeneous
catalysis18 on the use of zeolites as solid supports/catalysts,
a well-known approach to increase reactivity and selectiv-
ity, prompted us touse Cu(I)-modified zeolites, whichwere
prepared according to a reported solid-state exchange
procedure19 and were characterized by powder XRD,
XPS, EDX and HR-TEM (see Supporting Information).
This cascade reaction proceeds quite efficiently with CuI-
modified zeolites with higher yields and selectivity. In
comparison with DIPEA and pyridine, TEA generally
gave better yields. Besides DCM, other solvents such as
MeCN, THF and toluene were also used and no significant
improvement was observed (entries 5ꢀ9). The structure
and stereochemistry of the product was unambiguously
confirmed by single crystal X-ray analysis (see Supporting
Information), which are in accordance with the 1H NMR,
and 13C NM R spectra. Thus, the optimal conditions for
this copper-catalyzed cascade process are use of CuI-
modified zeolite as a catalyst and TEA as base in DCM
under N2 atmosphere for 3 h (entry 3).
and base and solvent screening, the reaction is also success-
fully extended to different combinations of azides, alkynes
and nitrones. As depicted in Table 2, this reaction works
very well for a wide range of substrates with good yields
and selectivity. Among the various sulfonyl azides, elec-
tron-withdrawing groups (ꢀCl) as well as electron-donat-
ing groups (ꢀCH3) provided high yields. Phenylacetylene
(3a) was highly reactive, usually giving high yields of
adducts depending on the coreacting azide and nitrone
(entries 1ꢀ6, and 14). p-Tolylacetylene and 1-ethynylc-
yclohexene were as effective as phenylacetylene (3a), giving
the expected adducts in high yields. Among the nitrones,
aryl- and heteroaryl aldehyde derived nitrones (entries 9,
10 and 12ꢀ18) are generally well tolerated in the cascade
reactions. An interesting correlation between electronic
effects of substituents in the aryl ring of nitrone and
diastereoselectivity is noticed. In the case of electron-with-
drawing groups, the anti isomer was obtained as the major
product (entries 1ꢀ7, 9, 10, 14, 15, and 17). In fact, with
2-fluorobenzaldehyde derived nitrone, the anti isomer was
formed almost exclusively (see Supporting Information). In
contrast, the yield of the syn isomer is significantly en-
hanced with electron donating groups (entries 13 and 18).
While the present method has been shown to be effective for
the synthesis of imidazolidin-4-ones from nitrones that bear
an N-phenyl group, it was also of interest to study the reac-
tivity of N-alkyl-substituted nitrone 5 (Scheme 2). Accord-
ingly, 1-benzylimidazolidin-4-ones 4q and 4r were synthesized
starting from C-phenyl-N-benzylnitrone, phenylacetelyne,
tosyl azide and benzenesulfonyl azide with syn-isomer as
A useful feature of this cascade reaction is that the
building blocks can be readily varied. After initial catalyst
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411. (b) Namitharan, K.; Kumarraja, M.; Pitchumani, K. Chem.;Eur.
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107–115.
5730
Org. Lett., Vol. 13, No. 21, 2011

major product (as evident from proton NMR). The structure
with syn-orientation was unambiguously confirmed by single
crystal (after repeated recrystallizations) X-ray analysis.
offer the oxadiazolidine B intermediate. Subsequent NꢀO
cleavage20 followed by diradical recombination generated
diastereomeric mixtures of product 4.
Scheme 2. Copper(I)-Catalyzed Cascade Synthesis of Imidazo-
lidin-4-ones from N-Benzylnitrones
Scheme 4. Proposed Mechanistic Pathway
This methodology was also extended to an one-pot
sequential synthesis of imidazolidin-4-ones. To begin with,
4-chlorobenzaldehyde and phenylhydroxylamine were
allowed to react in the presence of CuI-zeolite for 30 min.
After the complete consumption of hydroxylamine (from
TLC), tosyl azide, TEA and phenylacetylene were added.
The overall process proceeded smoothly to afford the
corresponding imidazolidin-4-one in slightly lower yields
(Scheme 3). Meanwhile, the recovery and reuse of CuI-
zeolite were also investigated, and the recovered catalyst
exhibited a good activity up to 4 consecutive cycles (see
Supporting Information).
In conclusion, we have described a novel cascade reac-
tion of nitrones with sulfonyl azides and alkynes mediated
by copper(I) for the one-step synthesis of a diverse range of
imidazolidin-4-ones. This reaction proceeds via sulfonyl
azideꢀalkyne/ketenimineꢀnitrone double cycloaddition
sequences, which are normally rare. The reported protocol
involves nitrone as the cycloaddition partner, which was
significant in itself, as the addition proceeds across CdN
bonds of N-sulfonyketenimines, where additions to CdC
bonds are most common. The use of a copper(I)-Y zeolite
as a heterogeneous Cu(I) source allows for fast and simple
isolation of the reaction products by simple filtration in
addition to other advantages such as recyclability and
minimization of metallic waste. Detailed studies on the
mechanism and applications of nitrile oxides and nitrile
imines as dipoles are underway.
Scheme 3. Copper(I)-Catalyzed One-Pot Synthesis of Imidazol-
idin-4-one from an Aldehyde, Phenylhydroxylamine, Tosyl
Azide, and Phenylacetylene
Acknowledgment. We thank Department of Science
and Technology (DST), New Delhi for financing under
FIST and IRPHA facility.
A plausiblemechanisticpathwayfor the present reaction
cascade is depicted in Scheme 4. Sulfonyl azide 1 reacted
readily with the terminalalkyne2 in the presence of CuIꢀY
and Et3N to give a ketenimine intermediate A, which then
underwent a formal [3 þ 2] cycloaddition with nitrone 3 to
Supporting Information Available. Experimental pro-
cedure, characterization data, copies of 1H and 13C NMR
spectra for all products, and X-ray data for compound 4b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 13, No. 21, 2011
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