Organocatalysis "on water". Regioselective [3 + 2]-cycloaddition of nitrones and allenolates

Article abstract of DOI:10.1039/b606096j

The first example of a regioselective and organocatalyzed 1,3-dipolar cycloaddition reaction between conjugated alkynoates and nitrones "on water" is described. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606096j

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Organocatalysis ‘‘on water’’. Regioselective [3 + 2]-cycloaddition of
nitrones and allenolates{
David Gonza´lez-Cruz,ab David Tejedor,ab Pedro de Armas,*ab Ezequiel Q. Moralesa and
Fernando Garc´ıa-Tellado*ab
Received (in Cambridge, UK) 28th April 2006, Accepted 11th May 2006
First published as an Advance Article on the web 26th May 2006
DOI: 10.1039/b606096j
We initiated our studies by examining the ability of triphenyl-
phosphine to catalyze the reaction of the scarcely reactive phenyl
N-benzylnitrone (1a) and methyl 2-octynoate (2a) in water. After
some experimental work, we found that 2,3-dihydroisoxazole
3aa{8 could be obtained in a modest 10% yield when an aqueous
suspension9 of nitrone, alkynoate and catalyst was vigorously
stirred at 40 uC for 48 h. Importantly, product 3aa was obtained as
the sole regioisomer (Table 1, entry 1). Addition of LiCl10
increased the reaction yield up to a significant 68% (Table 1, entry
3). Once a suitable reaction medium was established, we next
performed several experiments to meet the best reaction conditions
and the best catalyst (Table 1). It was found that: (1) at least two
equivalents of the alkynoate were needed to complete the reaction;
(2) both tertiary amines and tertiary phosphines catalyzed the
reaction, although with different efficiencies (entries 3–9); (3) no
reaction took place in the absence of catalyst (entry 2); (4) addition
of LiCl increased the catalytic efficiency (entries 1 and 3); (5) the
amount of water was not important as long as enough water was
present to fuse the solid nitrone and bring all of the reactants in
close contact; (6) the intermediate b-phosphonium allenolates I did
not rearrange to the corresponding dienoates III (Scheme 1);5 (7)
vigorous mixing and a rigorous order of addition of reactants and
catalyst were crucial to achieve good results, and finally, (8) no
reaction was observed under the same conditions in organic
solvents (entries 10–11).
The first example of a regioselective and organocatalyzed 1,3-
dipolar cycloaddition reaction between conjugated alkynoates
and nitrones ‘‘on water’’ is described.
A plethora of organic reactions are now efficiently performed in
water displaying, in some cases, impressive rate accelerations,
selectivity, new reactivity and high yields.1,2 Despite the consider-
able progress accumulated, the number of organocatalyzed
reactions in pure water remains small3 and therefore there is a
clear demand for new, direct and efficient applications.
We4 and others5 have shown that the chemical reactivity
associated with b-phosphonium or ammonium allenolates I is
instrumental in dictating the outcome of many interesting chemical
processes. In general, these reactive functionalities are generated in
an organic medium by the addition of catalytic amounts of tertiary
phosphines (X = P) or amines (X = N) to conjugated alkynoates
and they display a chemical reactivity profile governed by the
nature of the heteroatom located at the b-position (Scheme 1).
Although some examples of generation and reactivity of these
allenolates in water were reported early in the seventies,6 little
attention has since been paid to the design and development of
efficient aqueous-processed allenolate-driven reactions. In this
communication, we report on the first example of the productive
utilization of b-phosphonium (or ammonium) allenolates I as
reactive dipolarophiles in aqueous-processed 1,3-dipolar cyclo-
additions (1,3-DCRs) (Huisgen reactions).7
Table 1 1,3-DCR between nitrone 1a and alkynoate 2aa
Entry
Solvent
H2O
Catalyst
T/uC
Time
48 h
Yieldb
1
2
3
4
5
6
7
8
9
Ph3P
40
10%
NRd
68%
59%
57%
56%
38%
36%
51%
NRd
NRd
No catalyst
Ph3P
Et3N
Quinine
Quinuclidine
DABCO
DMAP
Isoquinoline
Ph3P
H2O–LiClc
Scheme 1 Reactivity profile of zwitterionic allenolates generated by
addition of tertiary amines or phosphines to conjugated alkynoates.
aInstituto de Productos Naturales y Agrobiolog´ıa, CSIC, Astrof´ısico
Francisco Sa´nchez 3, 38206 La Laguna, Tenerife, Islas Canarias, Spain.
E-mail: fgarcia@ipna.csic.es; parmas@ipna.csic.es;
Fax: +34922-260135; Tel: +34922-256847
10
11
a
Toluene
CH2Cl2
24 h
Ph3P
Nitrone (0.5 mmol), alkynoate (1 mmol), catalyst (0.05 mmol),
bInstituto Canario de Investigacio´n del Ca´ncer.www.icic.es
{ Dedicated to Professor Yoshito Kishi on the occasion of his 70th
birthday.
b
solvent (1 ml). Yield of isolated, analytically pure product. 3 M
c
d
solution of LiCl in water. No reaction.
2798 | Chem. Commun., 2006, 2798–2800
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Table 2 Organocatalyzed 1,3-DCR of nitrones 1a–e and alkynoates
2a–d ‘‘on water’’a
Scheme 2 Organocatalyzed 1,3-DCR between nitrones 1 and alkynoates
2 ‘‘on water’’.
Entry Nitrone Alkyne LiCl (¡) Catalyst
T/uC Yieldb
1
2
3
1a
1a
1a
2a
2b
2c
+
Ph3Pc
Ph3P
Ph3P
40
68%
99%
35%
49%
61%
71%
81%
95%
44%
26%
94%
81%
70%
43%
75%
37%
79%
54%
75%
2
2
+
RT
RT
shows a good tolerance of this 1,3-DCR with regard to the nitrone,
alkynoate and catalyst nature.
Quinuclidined 40
4
5
6
7
8
1a
1a
1b
1b
1b
2d
2e
2a
2b
2c
2
+
Ph3P
Ph3P
Ph3P
Ph3P
Et3N
Quinuclidine RT
Ph3P RT
Quinuclidine 40
RT
40
Three features of this aqueous 1,3-DCR are remarkable. Firstly,
reagents do not need to be water-soluble; furthermore, they react
when suspended in water (‘‘on water’’).9 Secondly, a catalytic
amount of allenolate I (dipolarophile) forms in water, at 40 uC,
with sufficient half-life to react with the nitrone (dipole). Thirdly,
the 2,3,4,5-tetrasubstituted 2,3-dihydroisoxazoles 3 are obtained as
the sole cycloadducts (complete regioselectivity).12
2
2
2
2
2
2
2
+
RT
RT
RT
9
1b
2d
10
11
1b
1c
2e
2a
Ph3P
Ph3P
RT
40
Scheme 2 outlines a plausible catalytic mechanism accounting
for the observed results. The catalytic cycle is triggered by the
addition of the catalyst (Nu) to an alkynoate to generate the
zwitterionic allenolate I. Regioselective 1,3-DCR of this dipolar-
ophile intermediate and nitrone affords the zwitterionic cycload-
duct intermediate 4, which incorporates a molecule of each one of
the three educts: nitrone, alkynoate and catalyst. Elimination of a
molecule of catalyst generates the 2,3-dihydroisoxazole ring 3,
reinitiating the cycle. Remarkably, in spite of the marked electronic
and structural differences between tertiary phosphines and amines,
they perform the same catalytic task: generation of the reactive
dipolarophile allenolate I.13 Preliminary theoretical calculations
support the proposed catalytic model with the zwitterionic
allenolates I acting as the reactive dipolarophiles. The experimen-
tally observed regiochemical outcome is theoretically predicted by
the energetically favored nitrone-LUMO controlled 1,3-DCR
operating in this cycle.
+
+
+
+
Quinuclidine 40
Ph3P 40
Quinuclidine 40
Ph3P 40
Quinuclidine 40
12
13
a
1d
1e
2a
2a
+
Reaction conditions: an aqueous (or 3 M LiCl) suspension of
nitrone (0.5 mmol in ml) was stirred until the nitrone was
1
completely fused. Alkynoate (0.1 mmol) was added dropwise to the
suspension and then the catalyst (10 mol%; 0.05 mmol) was carefully
added. The resulting aqueous suspension is vigorously stirred for 12 h
at room temperature or 40 uC. Dichloromethane extraction followed
by flash chromatography afforded the analytically pure product.
b
c
d
Yield of isolated, analytically pure product. 48 h. 20 mol%.
Table 2 shows the scope of this novel aqueous 1,3-DCR with
regard to the nitrone and alkynoate. Nitrone 1a, the most reluctant
dipole of the series, reacted with alkynoates 2b and 2d at room
temperature, in pure water and in the presence of triphenylpho-
sphine to give the cycloadducts 3ab and 3ad in good yields (entries
2 and 4). Less reactive alkynoates 2a and 2e required the aid of
LiCl and heating (entries 1 and 5). Nitrone 1b, the most reactive
dipole of the selected set of nitrones, performed an efficient
triphenylphosphine-catalyzed cycloaddition with alkynoates 2a, 2b
and 2d to give the corresponding cycloadducts 3ba, 3bb and 3bd in
excellent yields (entries 6, 7 and 9). Quinuclidine also proved to be
a good catalyst for the reaction of this nitrone with alkynoate 2d,
although heating was required and the efficiency was slightly lower
(entry 9). While triphenylphosphine was the best catalyst for
reactions involving aromatic nitrone 1a, quinuclidine displayed a
better catalyst activity for the reactions involving aliphatic nitrones
1c–e (entries 11–13). Alkynoate 2c exhibited the worst reactivity of
all of the assayed alkynoates. Only tertiary amines11 were able to
catalyze, with some efficiency, the 1,3-DCRs involving this
alkynoate (entries 3 and 8). In general, the data from Table 2
In summary, we have established the first example of a
regioselective and organocatalyzed 1,3-DCR between conjugated
alkynoates and nitrones ‘‘on water’’. The scenario described
introduces a new catalytic system based on the in situ generation of
reactive b-phosphonium (or ammonium) allenolates
I and
constitutes a powerful synthetic manifold for the construction of
2,3,4,5-tetrasubstituted 2,3-dihydroisoxazoles 3. Importantly, these
reactive zwitterionic dipolarophile intermediates incorporate a
molecule of catalyst directly attached to the reactive double bond
and it is expected that this property can be fully exploited by chiral
organocatalysts to exercise a measurable effect on the stereo-
selective course of these 1,3-DCRs. The study of this issue and its
application to other related chemical processes are in progress in
our lab.
This research was supported by the Spanish Ministerio de
Educacio´n y Ciencia and the European Regional Development
Fund (CTQ2005-09074-C02-02) and the Instituto Canario de
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2798–2800 | 2799

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Investigacio´n del Ca´ncer (ISCiii, RTICCC ICI-GI-Na10/200). D.
T. thanks CSIC for an I3P postdoctoral position. D. G.-C. thanks
MEC for an FPI grant. The authors thank Prof. Julio Delgado
Mart´ın for his helpful comments.
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Notes and references
{ 1H NMR (CDCl3, 500 MHz): d 0.92 (t, 3H, J = 7 Hz), 1.37 (m, 4H),
1.66 (q, 2H, J = 7.5 Hz), 2.72 (dt, 1H, J = 7.5 and 13.8 Hz), 2.80 (dt, 1H, J =
7.5 and 13.8 Hz), 3.62 (s, 3H), 4.05 (d, 1H, J = 12.8 Hz), 4.33 (d, 1H, J =
12.8 Hz), 5.10 (s, 1H), 7.19 (m, 2H), 7.30 (m, 8H), 7.57 (d, 1H, J = 12.0 Hz).
13C NMR (CDCl3, 100 MHz): d 13.9, 22.3, 26.1, 26.7, 31.4, 50.9, 63.6, 72.3,
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2800 | Chem. Commun., 2006, 2798–2800
This journal is ß The Royal Society of Chemistry 2006