Dual reactivity pattern of allenolates "on water": The chemical basis for efficient allenolate-driven organocatalytic systems

Article abstract of DOI:10.1002/chem.200700227

A study of the reactivity pattern associated with zwitterionic allenolates "on water" is reported. This study establishes the chemical basis for two organocatalyzed allenolate-driven reaction networks operating "on water". The first one is a chemodifferen

Full text of DOI:10.1002/chem.200700227

FULL PAPER
DOI: 10.1002/chem.200700227
Dual Reactivity Pattern of Allenolates “On Water”: The Chemical Basis
for Efficient Allenolate-Driven Organocatalytic Systems
David Gonzµlez-Cruz, David Tejedor, Pedro de Armas,* and Fernando García-Tellado*[a]
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Abstract: A study of the reactivity pat-
tern associated with zwitterionic alle-
nolates “on water” is reported. This
study establishes the chemical basis for
two organocatalyzed allenolate-driven
reaction networks operating “on
water”. The first one is a chemodiffer-
entiating three building block (ABB’)
three-component reaction (ABB’ 3CR)
manifold comprising terminal alky-
noates and aldehydes. The manifold
produces propargylic enol ethers 3 with
higher average efficiency than their ho-
mologues in organic solvents. The
second one is a novel organocatalytic
system elicited by the reaction of alky-
noates and nitrones in the presence of
tertiary amines or phosphines. While
terminal alkynoates afford 2,3,5-trisub-
stituted 2,3-dihydroisoxazoles
5 and
propargylic N-hydroxylamines 6, inter-
nal alkynoates selectively afford the
2,3,4,5-tetrasusbstituted
2,3-dihydro-
isoxazaole 10. Importantly, in both
cases, the 2,3-dihydroisoxazole ring is
obtained as a sole regioisomer.
Keywords: acetylides · allenolates ·
cycloaddition
· organocatalysis ·
water chemistry
Introduction
hydrogen-containing functionalities and allows the direct
use of water-soluble molecules without the need for lipophil-
ic derivatizations. Since the seminal finding of Breslow[3]
and Grieco[4] on the beneficial effect of water on the rate of
the Diels–Alder reactions compared to all organic solvents,
the number and type of productive aqueous organic reac-
tions have experienced an enormous increase. Besides
Diels–Alder reactions, a wide spectrum of organic reactions
are nowadays efficiently performed in water, including peri-
cyclic reactions, reactions of carbanion or carbocation equiv-
alents, reactions of radicals and carbenes, oxidation–reduc-
tion reactions, and transition-metal catalysis.[5] Many of
these reactions not only display the above-mentioned advan-
tages related with the reaction processing, but they also usu-
ally show impressive rate accelerations, better selectivity,
new reactivity profiles, and higher yields than their homo-
logues in organic solvents.[6] Remarkably, these beneficial ef-
fects are observed even when the reactants are sparingly
soluble or insoluble in water. Sharpless has coined this phe-
nomenon as the “on-water effect” to denote graphically this
unique reactivity of organic compounds in aqueous suspen-
sion.[7]
An important goal in modern organic chemistry is the devel-
opment of new, efficient, and environmentally benign syn-
thetic methodologies.[1] Progress toward this goal requires,
among other considerations, advanced use of alternative sol-
vents, design of safer chemicals, and development of new
atom-efficient catalytic processes.[2] The last decades have
witnessed significant advances in these areas, mainly in the
development of aqueous organic transformations and orga-
nocatalysis. The use of water as solvent offers many advan-
tages. The most obvious are cost, safety, and environmental
concerns, but also using water as the unique medium facili-
tates the experimental procedure, reduces the necessity of
tedious protection–deprotection strategies for certain acidic-
[a] D. Gonzµlez-Cruz,+ Dr. D. Tejedor,+ Dr. P. de Armas,+
Dr. F. García-Tellado+
Instituto de Productos Naturales y Agrobiología
Consejo Superior de Investigaciones Científicas
Astrofísico Francisco Sµnchez 3
38206 La Laguna, Tenerife Canary Islands (Spain)
Fax : (+34)922-260-135
On the other hand, organocatalysis has emerged as a
green complement to metal catalysis with remarkable ach-
E-mail: parmas@ipna.csic.es
fgarcia@ipna.csic.es
À
[+] All of the above are associate researchers at the Instituto Canario de
ievements in enantioselective C C bond-forming reactions,
Investigación del Cµncer (www.icic.es)
oxidations, and heterofunctionalizations.[8] Despite the con-
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siderable progress accumulated during the last decade, the
number of organocatalyzed reactions in pure water remains
relatively small and mainly concentrated around a reduced
group of reactions including direct aldol,[9] Mannich,[10] Mi-
chael-addition,[11] Baylis–Hillman,[12] and cycloaddition reac-
tions.[13] Obviously, not only the number but also the type of
reactions need to be increased. This challenge is currently a
sought after goal in chemistry and it provides new opportu-
nities for the design and study of new profiles of reactivity
and their catalytic implementation. In this article, we give a
full account of our study on the reactivity associated with
zwitterionic allenolates I on water (Scheme 1). Specifically,
Scheme 1. Zwitterionic allenolates I.
we describe the double reactivity profile displayed by these
species when they are generated in situ either in the pres-
ence of an electrophile (aldehyde) or an electrophilic 1,3-
dipole functionality (nitrone).[14] The results of this study es-
tablish the conditions for developing novel and robust alle-
nolate-driven organocatalytic systems operating on water
and they set a preliminary chemical scenario for the exten-
sion to a possible asymmetric version of these processes.
Scheme 2. Reactivity profile of zwitterionic allenolates I generated by ad-
dition of tertiary amines or phosphines on conjugated alkynoates.
ic studies of their reactivity in water have been accom-
plished.[14]
Allenolates as bases: ABB’ 3CRs based on terminal alky-
noates and aldehydes: In organic solvents, terminal alky-
noates and aliphatic aldehydes react in the presence of a
catalytic amount of tertiary amine to afford propargylic enol
ethers 3 through the well established catalytic cycle shown
in Scheme 3.[15] The reaction comprises a chemodifferentiat-
ing ABB’ 3CR manifold and it is both chemically efficient
(56–87%) and atom economical. Either DABCO
Results and Discussion
Reactivity profile of allenolates: In general, zwitterionic al-
lenolates I display a reactivity profile encoded by the charg-
ed heteroatom located at the b-position (Scheme 2). Only
the acid–base reaction affording b-substituted acrylates II is
general for both species.[15] The remaining transformations
are specific for the b-phosphonium allenolates.[16–18]
A main advantage that arises from the manner by which
the allenolates I are generated relies on the subsequent use
of these transient reactive zwitterions in a further complexi-
ty-generating transformation. We have productively used
this property in the construction of highly efficient synthetic
manifolds based on the chemodifferentiating three building
block (ABB’) three-component reactions (ABB’ 3CRs) of
terminal alkynoates and aldehydes or activated ketones.[15,19]
Despite of the apparent synthetic potential of this strategy,
not many attempts for rational designing and exploration of
new possibilities have been achieved.[16b]
Allenolate-driven organocatalytic processes on water: Al-
though some examples of the generation and reactivity of
these allenolates in water were reported early in the seven-
ties,[20] little attention has been since paid to the rational
design and development of efficient aqueous allenoate-
driven reactions. To the best of our knowledge, no systemat-
Scheme 3. Mechanism for the tertiary amine-catalyzed ABB’ 3CRs of
methyl propiolate and aliphatic aldehydes.
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Organocatalytic Systems
FULL PAPER
(DABCO=1,4-diazobicyclo
G
strate and in turn, the catalytic efficiency, this preassumed
beneficial effect was not observed (compare entries 4, 7
and 9). In reverse, a phenyl ring on the chain is less effective
than an ethyl group (entries 4 and 7).
With regard to the reaction processing, it was found that a
vigorous mixing and a rigorous order of addition of reac-
tants and catalyst are crucial to achieve good and repetitive
results, and that the amount of water was not important as
long as enough water was present to bring all of the reac-
tants in close contact.
ethylamine (08C) are good catalysts for these reactions. The
catalytic manifold is triggered by the Michael addition of
the catalyst on the alkynoate to generate the basic allenolate
I (kinetic reaction), which in turn, generates the ammonium
acetylide 1 (thermodynamic reaction). 1,2-Addition on the
aldehyde yields the ammonium alkoxide 2, which in turn, af-
fords propargylic enol ethers 3 and catalyst to restart the
cycle (Scheme 3). To our delight and in spite of the charged
nature of all of the participating intermediates, this organo-
catalytic manifold operates on water with higher average
chemical efficiency (71–95% yield) than the homologues in
organic solvent (Table 1). It is remarkable that the reactivity
profile displayed by the terminal alkynoate in the presence
of a tertiary amine and an aldehyde in organic media is fully
maintained on water.
Although the practical consequences of these ABB’ 3CRs
manifolds are obvious, the full chemical description of these
processes requires more experimental and theoretical work.
Allenolates as dipolarophiles and bases: the organocata-
lyzed reaction of alkynoates and nitrones: Nitrones are very
well suited synthetic functionalities because they are stable
compounds, which can react as electrophiles to afford N-hy-
Table 1. Tertiary amine-catalyzed ABB’ 3CRs of aliphatic aldehydes and
methyl propiolate on water.
À
droxylamines or as 1,3-dipoles to give the expected N O-
containing cycloadducts (Huisgen reaction).[23] This bifunc-
tional reactivity has been fully exploited in their metal-cata-
lyzed reactions with alkynes.[24,25] To the best of our knowl-
edge, the aqueous organocatalyzed versions of these reac-
tions has not been accomplished.
Entry
R
Catalyst
1
2
3
4
5
6
7
8
9
nPr
”
”
”
nHex
nDec
PhCH2CH2
iPr
DABCO
Et3N
quinuclidine
quinine
”
”
”
”
”
We initiated our studies by examining the ability of tri-
phenylphosphine to catalyze the reaction of nitrone 4a (R=
Ph) and methyl propiolate in organic solvent (Scheme 4).
Exploratory experiments showed a diminished reactivity of
this sparingly soluble nitrone. After some experimental
work, we found that triphenylphosphine (10 mol%) in tolu-
ene (or benzene, 1 mL) was able to catalyze this reaction, at
room temperature, to afford a roughly stoichiometric mix-
ture of the [3+2] cycloadduct 5a[25,26] and the 1,2-addition
product 6a[24] in very low yield. Dilution or change of sol-
vent (dichloromethane) did not increase the conversion. Al-
though the conversion was extremely low to elicit synthetic
interest, the observed chemical outcome was surprising and
in some way, unexpected: the reaction network utilizes each
and everyone of the latent reactivities of the nitrone and the
terminal alkynoate to construct two topologically well differ-
entiated sets of products. When the reaction was performed
cHex
[a] Aldehyde (1 mmol), methyl propiolate (3 mmol), catalyst
(0.18 mmol), 6m LiCl (2 mL), RT, overnight, vigorous stirring.
Table 1 shows several examples of this on water organoca-
talytic ABB’ 3CR. In all of the studied cases, the reaction
needed a minimal amount of 1.5 equivalents of the alky-
noate to be completed and the addition of LiCl to be effec-
tive.[21] With regard to the catalyst, no reaction was observed
between aldehydes and methyl propiolate in the absence of
catalyst. Among all of the tertiary amines assayed, quinine,
a
chiral catalyst, gave the best catalytic performance
(18 mol%, 85% average yield), but the asymmetric induc-
tion was practically zero. Other tertiary amines also cata-
lyzed the reaction, but with worse efficiency (entries 1–4).
With regard to the aldehyde, aromatic aldehydes failed to
give the reaction. This result is in full accordance with the
divergent reactivity displayed by these derivatives in organic
media.[22] In contrast, aliphatic aldehydes proved to be excel-
lent materials for these processes. Three general tendencies
were observed with regard to the ramification, length, and
substitution of the alkyl chain of the aldehyde. Firstly,
branching at the a-position significantly increased the effi-
ciency of these processes (compare entries 4–7 with 8 and 9).
Secondly, lengthening of the chain mildly decreased the effi-
ciency, but without a clear tendency (compare entries 4, 5
and 6). Thirdly, although the presence of an aromatic ring
on the chain would increase the hydrophobicity of the sub-
Scheme 4. Reaction of nitrones 4 with methyl propiolate in the presence
of triphenylphosphine.
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F. García-Tellado, P. de Armas et al.
on water the same roughly equimolecular mixture of prod-
ucts was obtained but with an impressive increment in yield
(90%) and reaction rate. Among other general considera-
tions, it was observed that 1) at least two equivalents of the
propiolate were needed to complete the reaction, 2) neither
the 1,2-addition reaction (1,2-AR) nor the 1,3-dipolar cyclo-
addition reaction (1,3-DCR) took place in the absence of
the tertiary phosphine, 3) the catalyst charge could be re-
duced to 1 mol% without detriment to the yield (we used a
standard catalyst charge of 5 mol% for better accuracy
measurements at the millimolar level), and again, 4) the re-
action processing required the same protocol as before.
Table 2 shows the general scope of this reaction with
regard to the nitrone substitution. In general, either aromat-
ic or aliphatic nitrones were good substrates for this reaction
Scheme 5. Reaction of methyl propiolate with the chiral nitrones 7a–b,
bearing an oxygenated function at the a-position.
ingly, the homologue uncatalyzed cycloaddition of nitrone
7a and methyl propiolate in refluxing toluene affords cyclo-
adduct 8a as a 1:1 mixture of diastereoisomers.[28]
Internal alkynoates 9a–e proved to be excellent substrates
for these organocatalytic reactions. Because the correspond-
ing internal allenolates cannot launch the 1,2-addition path-
way, only the expected 1,3-DCR cycloadducts 10 were ob-
served. We initiated our studies by examining the ability of
triphenylphosphine to catalyze the reaction of the scarcely
reactive N-benzyl-phenylnitrone (4a, R=Ph) and methyl 2-
octynoate (9a) on water (Scheme 6). After some experimen-
Table 2. Reaction of nitrones 4 with methyl propiolate in the presence of
triphenylphosphine (5 mol%) on water.[a]
Entry
R
4
Yield [%]
Ratio 5/6
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
90
91
93
95
90
80
80
85
1:0.90
1:0.93
1:0.85
1:0.83
1:0.73
1:0.85
1:0.77
1:0.75
pNO2-Ph
pOMe-Ph
nPr
nHex
iPr
cHex
CO2Me
[a] Nitrone (1 mmol), methyl propiolate (2.0 mmol), Ph3P (5%mol),
H2O, RT, vigorous stirring, 12 h.
(entries 1–6 and 7–9). Although the yield was uniformly
high in all of the cases, aromatic nitrones 4a–c displayed a
slightly superior average yield than the aliphatic nitrones
4d–h (92 versus 88%). Both linear and branched aliphatic
nitrones afforded products with high yields although with
different efficiency (compare entries 4–5 with entries 6
and 7). In the case of the aromatic nitrones, the precise elec-
tronic nature of the aromatic ring did not have a measurable
influence on the nitrone reactivity (entries 1–3). Other terti-
ary phosphines and amines, including triethylamine, quinu-
clidine, isoquinoline, and tributylphosphine, also catalyzed
the reaction with similar efficiency and chemical outcomes
(results are not shown).
Noteworthy, in all the studied cases, the 1,3-DCRs were
completely regioselective affording 2,3-dihydroxazoles 5 as
the unique cycloadducts.[27] In addition, although these reac-
tions afford a roughly equimolar mixtures of products 5 and
6, the latter can be easily and efficiently cyclized to the cor-
responding 2,3-diydroisoxazoles 5 by reaction with ZnI2-
DMAP.[26]
Scheme 6. Organocatalyzed 1,3-DCR of nitrones 4 and internal alky-
noates 9a–e.
tal work, we found that 2,3-dihydroisoxazole 10aa could be
obtained in a modest 10% yield when an aqueous suspen-
sion of nitrone, alkynoate, and catalyst was vigorously
stirred at 408C for 48 h. Importantly, the regioselectivity
pattern observed with terminal alkynoates was preserved
and the cycloadduct 10aa was obtained as the sole regioiso-
mer. Table 3 shows the effect of solvent, additives and cata-
lyst on the efficiency of this reaction. In general, we ob-
served 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 efficiency (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), and 5) no
reaction was observed under the same conditions in organic
solvents (entries 10–11). With regard to the reaction process-
ing, this called for the same precautions mentioned in previ-
ous experiments. The reaction showed a wide scope with
regard to nitrone and alkynoate (Table 4). Nitrone 4a, the
most reluctant dipole of the series, reacted with alkynoates
9b and 9d at room temperature, in pure water, and in the
Surprisingly, the reaction of methyl propiolate with the
chiral nitrones 7a–b, bearing an oxygenated function at the
a-position, selectively afforded the 1,3-cycloadducts 8a–b
with total regioselectivity (Scheme 5). While the diastereo-
isomeric ratios were within the expected values for a ni-
trone-stereocontrolled addition,[23,25,28] the kinetic inhibition
of the 1,2-addition pathway was very impressive.[29] Interest-
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Organocatalytic Systems
FULL PAPER
Table 3. Reaction of nitrone 4a (R=Ph) with methyl 2-octynoate (9a) in
ited the worst reactivity of all of the assayed alkynoates.
Only tertiary amines[30] were able to catalyze, with some ef-
ficiency, the 1,3-CDRs involving this alkynoate (entries 3
and 8). Remarkably, in all the cases, the intermediate b-
phosphonium allenolates I did not rearrange to the corre-
sponding dienoates III (Scheme 2).
Scheme 7 outlines a plausible catalytic mechanism ac-
counting for the observed results. Two catalytic cycles A and
B are postulated as a function of the alkynoate substitution.
the presence of a tertiary amine or phosphine.[a]
Entry
Solvent
Catalyst
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
H2O
Ph3P
no catalyst
Ph3P
40
”
”
”
”
”
”
”
”
”
”
48
”
12
”
”
”
”
”
”
24
”
10
”
nr[b]
68
H2O/LiCl[c]
”
”
”
”
”
”
Et3N
59
57
56
38
quinine
quinuclidine
DABCO
DMAP[d]
isoquinoline
Ph3P
36
9
10
11
51
toluene
CH2Cl2
nr[b]
nr[b]
Ph3P
[a] Nitrone (1 mmol), methyl propiolate (2 mmol), catalyst (5%mol), sol-
vent (1 mL), RT, vigorous stirring. [b] nr=no reaction. [c] Solution of
LiCl (3m) in water. [d] DMAP=4-dimethylaminopyridine.
Table 4. Synthesis of 2,3-dihydroisoxazoles 10 by the organocatalyzed
1,3-DCR of selected nitrones 4 and alkynoates 9a–e on water.[a]
Entry Nitrone Alkyne LiCl[b] Catalyst
T [8C] Yield [%]
1
2
4a
4a
9a
9b
+
À
À
+
À
+
À
À
À
À
À
À
À
+
+
+
+
+
+
Ph3P[c]
Ph3P
40
RT
RT
68
99
35
Ph3P
3
4a
9c
quinuclidine[d] 40
49
71
81
95
44
4
5
6
7
4a
4a
4d
4d
9d
9e
9a
9b
Ph3P
Ph3P
Ph3P
Ph3P
Et3N
quinuclidine
Ph3P
quinuclidine
Ph3P
Ph3P
RT
40
61
RT
RT
RT
RT26
RT
40
RT
40
40
40
40
40
40
8
4d
9c
94
70
9
4d
4d
4e
9d
9e
9a
81
10
11
54
75
43
75
37
79
quinuclidine
Ph3P
quinuclidine
Ph3P
Scheme 7. Proposed mechanism for the organocatalyzed reaction of ni-
trones and alkynoates on water.
12
13
4 f
4g
9a
9a
quinuclidine
Internal alkynoates react through the catalytic cycle A,
which is triggered by the addition of the catalyst (Nu) on al-
kynoate, to generate the zwitterionic allenolate I. Regiose-
lective 1,3-DCR of this dipolarophile intermediate and ni-
trone 4 affords the corresponding zwitterionic 1,3-cycload-
duct–enolate intermediate (1,3-CA–enolate), which incorpo-
rates a molecule of each one of the three educts: nitrone, al-
kynoate, and catalyst. Elimination of a molecule of catalyst
generates the 2,3-dihydroisoxazole ring 10, 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.[31] Cycle B operates
with terminal alkynoates (R=H). It is launched by the for-
mation of allenolate I (R=H) which, in the presence of the
acidic terminal alkynoate, forms the corresponding acetylide
salt. This salt reacts with nitrone 4 as a b-activated acrylate
dipolarophile to afford the corresponding charged 1,3-cyclo-
adduct intermediate (1,3-CA–ester), and as a reactive acety-
lide (1,2-AR) to yield the corresponding anionic 1,2-adduct.
The cycle B is closed by formation of the 2,3-dihydroisoxa-
[a] Reaction conditions: nitrone (1 mmol), alkynoate (2 mmol), catalyst
(10 mol%), water (or aqueous 3m LiCl solution) (1 mL), vigorous stir-
ring, 12 h, RTor 40 8C. [b] +=LiCl added, À=LiCl not added. [c] 48 h.
[d] 20 mol%.
presence of triphenylphosphine to give the cycloadducts
10ab and 10ad in good yields (entries 2 and 4). Less reactive
alkynoates 9a and 9e required the aid of LiCl and heating
(entries 1 and 5). Nitrone 4d, the most reactive dipole of the
selected set of nitrones, performed an efficient triphenyl-
phosphine-catalyzed cycloaddition with alkynoates 9a, 9b,
and 9d to give the corresponding cycloadducts 10da, 10 db,
and 10dd in excellent yields (entries 6, 7 and 9). Quinucli-
dine also proved to be a good catalyst for the reaction of
this nitrone with alkynoate 9d, although heating was re-
quired and the efficiency was slightly lower (entry 9). While
triphenylphosphine was found to be the best catalyst for re-
actions involving aromatic nitrone 4a, quinuclidine dis-
played a better catalyst activity for the reactions involving
aliphatic nitrones 4e–g (entries 11–13). Alkynoate 9c exhib-
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F. García-Tellado, P. de Armas et al.
General procedure for the synthesis of 2,3,5-trisubstituted 2,3-dihyroisox-
azoles 5 and propargylic N-hydroxylamines 6: Nitrone (1.0 mmol) sus-
pended on water (1 mL) was stirred until completely fused. Methyl pro-
piolate (2.0 mmol) was added dropwise to the suspension and then tri-
phenylphosphine (0.1 mmol) was carefully added. The resulting aqueous
suspension was vigorously stirred for 12 h. Extraction with CH2Cl2 (”2;
in most cases one extraction was enough), drying on Na2SO4, concentra-
tion, and fast flash chromatography (ethyl acetate/hexanes 20:80) deliv-
ered pure compounds 5 and 6. In those cases in which the 1,2-addition is
inhibited (nitrones 7a–b), a fast percolate through a short plug of silica
gel was enough to obtain pure cycloadducts (8a–b).
zole ring 5 with catalyst regeneration to reinitiate the cycle.
While the 1,3-DCR pathway is catalytic, the 1,2-AR is stoi-
chiometric: it consumes acetylide without catalyst regenera-
tion. This pathway survives because the anionic 1,2-adduct
intermediate (1,2-adduct) participates in the transformation
of the 1,3-CA-ester into dihydroisoxazole derivative 5, with
formation of propargylic N-hydroxylamine 6 together with
catalyst regeneration to reinitiate the cycle. Both processes
work perfectly coupled in an efficient chemical reaction net-
work able to successfully produce topologically different
products 5 and 6.
General procedure for the synthesis of 2,3,4,5-tetrasubstituted 2,3-dihyro-
isoxazoles 10: Nitrone (1.0 mmol) suspended on water (or aqueous 3m
LiCl solution) (1 mL) was stirred until completely fused. Alkynoate
(2.0 mmol) was added dropwise to the suspension and then the catalyst
(0.1 mmol) was carefully added. The resulting aqueous suspension was
vigorously stirred for 12 h at room temperature or at 408C. Extraction
with CH2Cl2 (”2; in most cases one extraction was enough), drying on
Na2SO4, concentration, and fast flash chromatography (ethyl acetate/hex-
anes 20:80) delivered analytically pure tetrasusbstituted 2,3-dihydroisoxa-
zole 10.
Conclusion
The study of the reactivity pattern associated with zwitter-
ionic allenolates I on water has been accomplished. These
reactivity profiles have been productively exploited in the
rational design and development of organocatalyzed alleno-
late-driven reaction networks operating on water. Specifical-
ly, we have explored the chemical basis for a chemo-differ-
entiating ABB’ 3CR manifold comprising terminal alky-
noates and aldehydes. The organocatalytic systems elicited
by the reaction of alkynoates and nitrones in the presence
of tertiary amines or phosphines has also been studied. This
work establishes the chemical basis for developing novel
and robust allenolate-driven organocatalytic systems operat-
ing on water and it sets up the preliminary chemical scenar-
io for the possible extension to its asymmetric version. Such
studies are ongoing in our lab and the results will be pub-
lished in due course.
Methyl
1H NMR (400 MHz, CDCl3, 258C): d=0.85 (t, 3J
1.23–1.31 (m, 14H), 1.40–1.47 (m, 2H), 1.81–1.91 (m, 2H), 3.68 (s, 3H),
3.76 (s, 3H), 4.60 (d, 3J(H,H)=6.4 Hz, 3H), 5.34 (d, 3J
(H,H)=12.5 Hz,
1H), 7.51 ppm (d, 3J(H,H)=12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3,
4-((E)-2-(methoxycarbonyl)vinyloxy)tetradec-2-ynoate
(3c):
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
258C): d=14.0, 22.6, 24.7, 28.9, 29.2, 29.3, 29.4, 29.5, 31.8, 34.5, 51.2, 52.9,
70.5, 78.5, 83.0, 99.1, 153.1, 159.8, 167.6 ppm; IR (CHCl3): n˜ =2242.5,
1715.5, 1645.8, 1625.8 cmÀ1; MS (70 eV): m/z (%): 338 (0.7) [M+], 237
(100), 177 (29), 121 (27), 107 (32), 93 (39), 79 (31), 55 (34); elemental
analysis calcd (%) for C19H30O5: C 67.43, H 8.93; found: C 67.64, H 8.72.
Methyl 4-((E)-2-(methoxycarbonyl)vinyloxy)-6-phenylhex-2-ynoate (3d):
1H NMR (400 MHz, CDCl3, 258C): d=2.12–2.29 (m, 2H), 2.77–2.84 (m,
2H), 3.70 (s, 3H), 3.78 (s, 3H), 4.56 (dd, 3J
ACHTREUNG
(d, 3J
A
ACHTREUNG
12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=30.7, 36.0, 51.2,
52.9, 69.2, 78.8, 82.6, 99.3, 126.4, 128.4, 128.6, 139.6, 153.0, 159.7,
167.5 ppm; IR (CHCl3): n˜ =2241.9, 1715.9, 1646.3 cmÀ1; MS (70 eV): m/z
(%): 302 (0.2) [M+], 248 (12), 141 (20), 118 (8.6), 91 (100); elemental
analysis calcd (%) for C17H18O5: C 67.54, H 6.00; found: C 67.42, H 6.13.
Methyl
4-((E)-2-(methoxycarbonyl)vinyloxy)-4-cyclohexylbut-2-ynoate
(3 f): H NMR (400 MHz, CDCl3, 258C): d=1.08–1.26 (m, 5H), 1.64–1.85
(m, 6H), 3.68 (s, 3H), 3.76 (s, 3H), 4.40 (d, 3J
(H,H)=5.8 Hz, 1H), 5.34
(d, 3J(H,H)=12.5 Hz, 1H), 7.51 ppm (d, 3J
(H,H)=12.5 Hz, 1H);
1
Experimental Section
AHCTREUNG
General remarks: 1H NMR and 13C NMR spectra in CDCl3 were record-
ed either at 400 and 100 MHz or at 500 and 125 MHz (Bruker Ac 200
and AMX2–500), respectively. FTIR spectra were measured in chloro-
form solutions by using a Shimadzu IR-408 spectrophotometer. Mass
spectra (low resolution) (EI/CI) were obtained with a Hewlett–Packard
5995 gas chromatograph/mass spectrometer. High-resolution mass spectra
were recorded with a Micromass Autospec mass spectrometer. Micro-
analyses were performed with a Fisons Instruments EA 1108 carbon, hy-
drogen, and nitrogen analyzer. Analytical TLC plates used were E.
Merck Brinkman UV-active silica gel (Kieselgel 60 F254) on aluminum.
Flash column chromatography was carried out with E. Merck silica gel
60 (particle size less than 0.020 mm) by using appropriate mixtures of
ethyl acetate and hexanes as eluent. Starting nitrones 4a–j were prepared
by using standard procedures. All other materials were obtained from
commercial suppliers and used as received. The LiCl aqueous solutions
were freshly prepared before use. Compounds 3a,[15c] 3b,[15c] 3e,[15c] and
10aa[14] have been fully described in the indicated references.
N
ACHTREUNG
13C NMR (100 MHz, CDCl3, 258C): d=25.5, 25.5, 25.9, 28.0, 28.3, 42.1,
51.1, 52.8, 75.3, 79.0, 82.3, 98.9, 153.1, 160.2, 167.6 ppm; IR (CHCl3): n˜ =
2240.4, 1716.2, 1645.6 cmÀ1; MS (70 eV): m/z (%): 280 (1.1) [M+], 179
(51), 178 (51), 147 (31), 119 (100), 91 (43), 81 (60); elemental analysis
calcd (%) for C15H20O5: C 64.27, H 7.19; found: C 64.34, H 7.12.
Methyl
1H NMR (500 MHz, CDCl3, 258C): d=3.87 (s, 3H), 4.15 (d, 3J
12.9 Hz, 1H), 4.49 (d, 3J(H,H)=12.9 Hz, 1H), 5.10 (d, 3J (H,H)=3.0 Hz,
1H), 5.97 (d, 3J(H,H)=2.7 Hz, 1H), 7.23–7.42 ppm (m, 10H); 13C NMR
2-benzyl-3-phenyl-2,3-dihydro-5-isoxazolecarboxylate
(5a):
ACHTREUNG
AHCTREUNG
AHCTREUNG
(125 MHz, CDCl3, 258C): d=52.3, 63.0, 72.9, 110.5, 127.3 (2C), 128.4
(4C), 129.5 (4C), 135.4, 140.1, 145.2, 159.5 ppm; IR (CHCl3): n˜ =1733.5,
1642.5 cmÀ1; MS (70 eV): m/z (%): 295 (14.9) [M+], 278 (1.8), 264 (1.2),
236 (4.4), 218 (5.1), 204 (31.46), 144 (20.2), 131 (6), 117 (27), 91 (100), 77
(8.6), 65 (9.6); elemental analysis calcd (%) for C18H17NO3: C 73.20, H
5.80, N 4.74; found: C 73.26, H 5.98, N 4.70.
Methyl
2-benzyl-3-(4-nitrophenyl)-2,3-dihydro-5-isoxazolecarboxylate
(5b): 1H NMR (500 MHz, CDCl3, 258C): d=3.91 (s, 3H), 4.09 (d,
General procedure for the synthesis of propargylic enol ethers 3: Careful
dropwise addition of methyl propiolate (3.0 mmol) followed by addition
of the catalyst (0.18 mmol) to a vigorously stirred suspension of aldehyde
(1.0 mmol) in aqueous 6m LiCl solution (2 mL) resulted in a suspension
which was vigorously stirred at room temperature overnight. Extraction
with CH2Cl2 (”2; in most cases one extraction was enough), drying on
Na2SO4, concentration, and fast flash chromatography (ethyl acetate/hex-
anes 20:80) delivered pure propargylic enol ether 3.
3J
3J
A
ACHTREUNG
3
ACHTREUNG
(H,H)=3.0 Hz, 1H), 5.97 (d, J
7.41–7.43 (m, 2H), 8.20 ppm (d, 3J
ACHTREUNG
(125 MHz, CDCl3, 258C): d=52.5, 63.1, 71.8, 108.6, 123.5 (2C), 128.2
(2C), 128.6 (2C), 129.5 (2C), 134.5, 146.0, 147.3, 147.5, 159.0; IR
(HCCl3): n˜ =1733.5, 1642.5, 1523.3 cmÀ1; MS (70 eV): m/z (%): 340 (14.9)
[M+], 332 (0.5), 281 (2.2), 249 (32.5), 218 (3.8), 203 (2.6), 189 (7.2), 116
4828
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4823 – 4832

Organocatalytic Systems
FULL PAPER
(5.7), 91 (100), 89 (7.3), 85 (8.0), 84 (12.6), 65 (7.8), 48 (13.9); elemental
analysis calcd (%) for C18H16N2O5: C 63.52, H 4.74, N 8.23; found: C
63.79, H 4.95, N 8.09.
204 (3.5), 158 (6.0), 91 (100), 65 (7.3); elemental analysis calcd (%) for
C15H17NO5: C 61.85, H 5.88, N 4.81; found: C 61.86, H 5.91, N 4.75.
Methyl 4-[benzyl
(500 MHz, CDCl3, 258C): d=3.64 (s, 3H), 4.10 (d, 3J
1H), 4.37 (d, 3J
(H,H)=12.9 Hz, 1H), 5.13 (s, 1H), 7.23–7.52 ppm (m,
ACHTREUNG
Methyl 2-benzyl-3-(4-methoxyphenyl)-2,3-dihydro-5-isoxazolecarboxylate
ACHTREUNG
(5c): 1H NMR (500 MHz, CDCl3, 258C): d=3.76 (s, 3H), 3.82 (s, 3H),
ACHTREUNG
10H); 13C NMR (125 MHz, CDCl3, 258C): d=51.2, 63.6, 70.9, 110.5,
127.7 (2C), 128.4 (4C), 129.2 (4C), 135.4, 140.3, 145.3, 152.5 ppm; IR
(CHCl3): n˜ =3392.9, 2399.9, 1706.4, 1629.5 cmÀ1; MS (70 eV): m/z (%):
295 (10.3) [M+], 288 (9.7), 278 (6.7), 266 (1.6), 264 (1.2), 218 (2.8), 204
(18.0), 144 (5.8), 116 (9.4), 91 (100), 65 (6.4); elemental analysis calcd
(%) for C18H17NO3: C 73.20, H 5.80, N 4.74; found: C 73.40, H 5.87, N
4.66.
4.07 (d, 3J
3J
9.0 Hz, 2H), 7.09 (d, 3J
U
ACHTREUNG
U
ACHTREUNG
13C NMR (125 MHz, CDCl3, 258C): d=52.3, 55.3, 62.9, 72.5, 110.7, 114.0
(2C), 127.6, 128.3, 128.4 (2C), 129.5 (2C), 132.2, 135.4, 145.2, 159.4 ppm;
IR (HCCl3): n˜ =1733.2, 1644.8 cmÀ1; MS (70 eV): m/z (%): 325 (11.6)
[M+], 260 (0.3), 234 (34.7), 218 (9.9), 174 (15.6), 147 (23.4), 146 (12.6),
121 (5.9), 91 (100), 77 (7.7), 65 (8.6), 51 (4.6); elemental analysis calcd
(%) for C19H19NO4: C 70.14, H 5.89, N 4.31; found: C 70.26, H 5.76, N
4.05.
Methyl 4-[benzyl(hydroxy)amino]-4-(4-nitrophenyl)-2-butynoate (6b):
E
1H NMR (500 MHz, CDCl3, 258C): d=3.65 (s, 3H), 4.09 (d, 3J
A
3
12.9 Hz, 1H), 4.45 (d, J
A
4H), 7.42–7.45 ppm (m, 2H); 13C NMR (125 MHz, CDCl3, 258C): d=
51.4, 63.7, 70.0, 109.0, 123.5 (2C), 128.2 (2C), 128.6 (2C), 129.2 (2C),
134.5, 147.50, 147.66, 152.9, 163.5 ppm; IR (CHCl3): n˜ =3683.7, 2400.0,
1729.4, 1646.2 cmÀ1; MS (70 eV): m/z (%): 340 (9.6) [M+], 323 (2.8), 311
(1.9), 249 (14.2), 234 (2.1), 218 (3.1), 203 (1.7), 136 (20.1), 91 (100), 89
(7.7), 65 (7.7); elemental analysis calcd (%) for C18H16N2O5: C 63.52, H
4.74, N 8.23; found: C 63.72, H 4.80, N 7.89.
Methyl
1H NMR (500 MHz, CDCl3, 258C): d=0.75 (t, 3J
1.10–1.19 (m, 1H), 1.27–1.40 (m, 2H), 1.42–1.49 (m, 1H), 3.81 (s, 3H),
3.84 (d, 3J(H,H)=12.6 Hz, 1H), 3.88–3.91 (m, 1H), 4.28 (d, 3J
(H,H)=
12.6 Hz, 1H), 5.83 (d, 3J
(H,H)=2.9 Hz, 1H), 7.30–7.37 ppm (m, 5H);
2-benzyl-3-propyl-2,3-dihydro-5-isoxazolecarboxylate
(5d):
AHCTREUNG
G
ACHTREUNG
AHCTREUNG
13C NMR (125 MHz, CDCl3, 258C): d=13.6, 18.4, 37.4, 51.2, 62.9, 69.3,
110.8 (2C), 127.6, 128.3 (2C), 129.6 (2C), 135.5, 144.9, 152.6, 159.6; IR
(CHCl3): n˜ =1697.9, 1629.1 cmÀ1; MS (70 eV): m/z (%): 261 (1.8) [M+],
243 (1.6), 229 (5.8), 218 (15.8), 91 (100), 71 (11.2), 65 (6.6); elemental
analysis calcd (%) for C15H19NO3: C 68.94, H 7.33, N 5.36; found: C
68.90, H 7.20, N 5.55.
Methyl
(6c): 1H NMR (500 MHz, CDCl3, 258C): d=3.65 (s, 3H), 3.76 (s, 3H),
4.07 (d, 3J(H,H)=12.9 Hz, 1H), 4.33 (d, 3J
(H,H)=12.9 Hz, 1H), 5.08 (d,
3J
(H,H)=1.8 Hz, 1H), 6.80–6.82 (m, 2H), 7.28–7.36 ppm (m, 5H);
4-[benzyl
A
A
ACHTREUNG
AHCTREUNG
13C NMR (125 MHz, CDCl3, 258C): d=51.3, 55.2, 63.6, 70.6, 109.8, 110.8,
113.8 (2C), 127.9, 128.5 (4C), 129.3 (2C), 135.4, 152.6, 159.3, 164.1 ppm;
IR (CHCl3): n˜ =3392.4, 2399.7, 1700, 1628.4 cmÀ1; MS (70 eV): m/z (%):
325 (24.9) [M+], 308 (5.7), 234 (69.6), 218 (5.6), 206 (6.3), 202 (6.6), 174
(20.3), 160 (10.5), 146 (23.1), 121 (83.4), 104 (8.5), 91 (100), 89 (7.4), 77
(14.2), 65 (13.1), 51 (6.3); elemental analysis calcd (%) for C19H19NO4: C
70.14, H 5.89, N 4.31; found: C 70.29, H 6.08, N 3.87.
Methyl
1H NMR (500 MHz, CDCl3, 258C): d=0.82 (t, 3J
1.07–1.25 (m, 8H), 1.35–1.47 (m, 2H), 1.42–1.49 (m, 1H), 3.81 (s, 3H),
3.84 (d, 3J(H,H)=12.6 Hz, 1H), 3.86–3.90 (m, 1H), 4.28 (d, 3J
(H,H)=
12.3 Hz, 1H), 5.82 (d, 3J
(H,H)=2.7 Hz, 1H), 7.26–7.37 ppm (m, 5H);
2-benzyl-3-hexyl-2,3-dihydro-5-isoxazolecarboxylate
(5e):
AHCTREUNG
G
ACHTREUNG
AHCTREUNG
13C NMR (125 MHz, CDCl3, 258C): d=14.0, 22.4, 25.2, 28.8, 31.6, 35.3,
52.2, 62.9, 69.5, 110.9 (2C), 127.6, 128.3 (2C), 129.6 (2C), 135.6, 145.0,
159.6 ppm; IR (CHCl3): n˜ =1734.9, 1649.9 cmÀ1; MS (70 eV): m/z (%):
303 (1.1) [M+], 285 (0.6), 272 (0.2), 254 (0.2), 244 (1.8), 218 (23.0), 91
(100), 65 (4.2), 55 (3.6); elemental analysis calcd (%) for
C18H25NO3·xH2O: C 71.26, H 8.31, N 4.62; found: C 71.80, H 8.61, N
4.41; HRMS calcd for C18H25NO3: 303.183444; found: 303.182182.
Methyl
(500 MHz, CDCl3, 258C): d=0.79 (t, 3J
1H), 1.37 (m, 1H), 1.49 (m, 1H), 1.65–1.55 (m, 1H), 3.72 (s, 3H), 3.84
(d, 3J(H,H)=12.9 Hz, 1H), 4.04 (dq, 3J
(H,H)=1.6, 8.8 Hz, 1H), 4.20 (d,
3J(H,H)=12.9 Hz, 1H), 7.28–7.32 ppm (m, 5H); 13C NMR (125 MHz,
4-[benzyl
A
(6d):
1H NMR
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
CDCl3, 258C): d=13.7, 18.4, 36.7, 51.2, 63.8, 67.3, 109.3, 127.8, 128.4
(2C), 129.4 (2C), 135.5, 152.6, 164.5 ppm; IR (CHCl3): n˜ =3672.8, 2254.2,
1793.9, 1698, 1630 cmÀ1; MS (70 eV): m/z (%): 261 (1.9) [M+], 218 (27.5),
104 (2.5), 91 (100), 77 (2.6), 65 (8.2); elemental analysis calcd (%) for
C15H19NO3: C 68.94, H 7.33, N 5.36; found: C 69.02, H 7.23, N 5.67.
Methyl 2-benzyl-3-isopropyl-2,3-dihydro-5-isoxazolecarboxylate (5 f):
1H NMR (500 MHz, CDCl3, 258C): d=0.75 (t, 3J
A
3
1.60–1.62 (m, 1H), 3.68 (dd, J
A
3
3
ACHTREUNG
(d, J
C
ACHTREUNG
(hydroxy)amino]-2-decynoate (6e): 1H NMR (500 MHz,
(125 MHz, CDCl3, 258C): d=18.1, 18.3, 33.2, 52.2, 63.7, 75.7, 108.9 (2C),
127.7, 128.3 (2C), 129.8 (2C), 135.6, 145.3, 159.6 ppm; IR (HCCl3): n˜ =
1733.6, 1652.7 cmÀ1; MS (70 eV): m/z (%): 261 (2.4) [M+], 250 (0.7), 218
(24.0), 202 (3.9), 128 (5.0), 91 (100), 82 (4.5), 65 (6.6), 55 (4.7); elemental
analysis calcd (%) for C15H19NO3: C 68.94, H 7.33, N 5.36; found: C
69.11, H 7.30, N 5.30.
Methyl 4-[benzyl
CDCl3, 258C): d=0.84 (t, 3J
AHCTREUNG
1.30–1.34 (m, 1H), 1.45–1.52 (m, 1H), 1.57–1.63 (m, 1H), 3.72 (s, 3H),
3
3
ACHTREUNG
3.84 (d, J
G
(H,H)=1.6, 8.8 Hz, 1H), 4.21
3
(d, J
(H,H)=12.6 Hz, 1H), 7.28–7.32 ppm (m, 5H); 13C NMR (125 MHz,
CDCl3, 258C): d=14.0, 22.5, 25.1, 28.9, 31.7, 34.5, 51.2, 63.8, 67.4, 109.2,
127.8, 128.4 (2C), 129.5 (2C), 135.6, 152.6, 164.4 ppm; IR (HCCl3): n˜ =
3672.7, 2254.2, 1793.8, 1698.2, 1629.4 cmÀ1; MS (70 eV): m/z (%): 303
(1.9) [M+], 285 (5.3), 228 (8.9), 218 (17.7), 91 (100), 65 (5.3); elemental
analysis calcd (%) for C18H25NO3·xH2O: C 71.26, H 8.31, N 4.62; found:
C 71.77, H 8.74, N 4.55; HRMS calcd for C18H25NO3: 303.183444; found:
303.184525.
Methyl 2-benzyl-3-cyclohexyl-2,3-dihydro-5-isoxazolecarboxylate (5g):
1H NMR (500 MHz, CDCl3, 258C): d=0.73 (qd, 3J
ACHTREUNG
1H), 0.90 (qd, 3J
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
ACHTREUNG
Methyl 4-[benzyl
(hydroxy)amino]-5-methyl-2-hexynoate (6 f): 1H NMR
(H,H)=6.7 Hz, 3H), 0.82 (d,
(H,H)=6.7 Hz, 3H), 1.90–1.96 (m, 1H), 3.72 (s, 3H), 3.81 (d,
(H,H)=12.9 Hz, 1H), 3.98 (dd, 3J
(H,H)=1.6, 3.2 Hz, 1H), 4.19 (d,
(H,H)=12.9 Hz, 1H), 7.27–7.39 ppm (m, 5H); 13C NMR (125 MHz,
(125 MHz, CDCl3, 258C): d=25.8. 25.9, 26.3 (2C), 28.7, 42.8, 52.2, 63.6,
74.8, 109.2, 127.6, 128.3 (2C), 129.7 (2C), 135.7, 145.0, 152.8, 159.6 ppm;
IR (HCCl3): n˜ =1699.0, 1628.4 cmÀ1; MS (70 eV): m/z (%): 301 (1.5) [M+],
242 (1.5), 218 (26.5), 91 (100), 55 (5.6); elemental analysis calcd (%) for
C18H23NO3: C 71.73, H 7.69, N 4.65; found: C 71.74, H 7.81, N 4.85.
(500 MHz, CDCl3, 258C): d=0.76 (d, 3J
ACHTREUNG
3J
3J
3J
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
CDCl3, 258C): d=15.8, 19.1, 30.8, 51.2, 64.7, 72.4, 107.5, 127.8, 128.4
(2C), 129.5 (2C), 135.7, 152.9, 164.6 ppm; IR (HCCl3): n˜ =3566.1, 2360.3,
1792.0, 1771.6, 1699.5, 1635.2 cmÀ1; MS (70 eV): m/z (%): 261 (0.5) [M+],
218 (20), 91 (100), 65 (4.7); elemental analysis calcd (%) for C15H19NO3:
C 68.94, H 7.33, N 5.36; found: C 68.93, H 7.21, N 5.22.
3-Ethyl 5-methyl 2-benzyl-2,3-dihydro-3,5-isoxazoledicarboxylate (5h):
1H NMR (500 MHz, CDCl3, 258C): d=1.22
A
ACHTREUNG
3.82 (s, 3H), 4.07 (d, 3J
N
ACHTREUNG
3
3
ACHTREUNG
2H), 4.41 (d, J
C
C
CDCl3, 258C): d=18.4, 37.4, 51.2, 62.9, 69.3, 110.8, 127.6, 128.3 (2C),
129.6 (2C), 135.5, 144.9, 152.6, 159.6 ppm; IR (CHCl3): n˜ =1733.9, 1716.0,
1627.7 cmÀ1; MS (70 eV): m/z (%): 291 (7.5) [M+], 232 (26.9), 218 (6.8),
Methyl
1H NMR (500 MHz, CDCl3, 258C): d=1.07–1.27 (m, 5H), 1.55–1.67 (m,
6H), 3.73 (s, 3H), 3.80 (d, 3J
(H,H)=12.9 Hz, 1H), 3.94–3.95 (m, 1H),
4-[benzyl
A
(6g):
Chem. Eur. J. 2007, 13, 4823 – 4832
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4829

F. García-Tellado, P. de Armas et al.
4.16 (d, 3J
N
Diethyl 2-benzyl-3-phenyl-2,3-dihydroisoxazole-4,5-dicarboxylate (10ab):
(125 MHz, CDCl3, 258C): d=26.0 (2C), 26.3 (2C), 29.6, 40.8, 51.2, 64.5,
72.0, 106.9, 127.7, 128.3 (2C), 129.4 (2C), 135.8, 152.8, 164.6 ppm; IR
(HCCl3): n˜ =3392.0, 2362.1, 1699.0, 1628.3 cmÀ1; MS (70 eV): m/z (%):
301 (2.4) [M+], 272 (0.8), 270 (0.7), 218 (31.3), 91 (100), 55 (6.2); elemen-
tal analysis calcd (%) for C18H23NO3: C 71.73, H 7.69, N 4.65; found: C
71.69, H 7.90, N 4.65.
1H NMR (500 MHz, CDCl3, 258C): d=1.14 (t, 3J
ACHTREUNG
1.37 (t, 3J
A
ACHTREUNG
3J
3J
A
ACHTREUNG
AHCTREUNG
CDCl3, 258C): d=13.9, 29.6, 60.6, 62.7, 63.5, 72.7, 109.0, 127.3 (3C), 128.0
(3C), 128.5 (2C), 129.4, 134.8, 139.6, 151.9, 159.2, 162.2, 176.0 ppm; IR
(CHCl3): n˜ =3450, 2399.7, 1715, 1707.8, 1655.9 cmÀ1; MS (70 eV): m/z
(%): 381 (13) [M+], 308 (13), 77 (11), 290 (38), 262 (13), 203 (28), 144
(15), 117 (13), 91 (100); elemental analysis calcd (%) for C22H23NO5: C
69.28, H 6.08, N 3.67; found: C 68.9, H 6.47, N 3.40.
5-Ethyl 1-methyl 4-[benzyl
1H NMR (500 MHz, CDCl3, 258C): d=1.21 (t, 3J
3.70 (s, 3H), 4.08 (d, 3J
(H,H)=12.9 Hz, 1H), 4.16 (m, 2H), 4.35 (d,
3J(H,H)=12.9 Hz, 1H), 7.25–7.38 ppm (m, 5H); 13C NMR (125 MHz,
ACHTREUNG
CDCl3, 258C): d=13.7, 18.4, 36.7, 51.2, 63.8, 67.3, 109.3, 127.8, 128.4
(2C), 129.4 (2C), 135.5, 152.6, 164.5 ppm; IR (CHCl3): n˜ =3399.9, 2400.9,
1737.3, 1633.1 cmÀ1; MS (70 eV): m/z (%): 291 (0.5) [M+], 274 (0.3), 262
(1.5), 232 (0.9), 218 (19.9), 91 (100), 64 (7.0); elemental analysis calcd
(%) for C15H17NO5: C 61.85, H 5.88, N 4.81; found: C 61.99, H 5.93, N
4.80.
Ethyl
2-benzyl-4-methyl-3-phenyl-2,3-dihydroisoxazole-5-carboxylate
(10ac): 1H NMR (500 MHz, CDCl3, 258C): d=1.02 (t, 3J
ACHTREUNG
3H), 1.19 (s, 3H), 3.99 (q, 3J
A
ACHTREUNG
3
12.6 Hz, 1H), 4.11 (d, J
A
7.77 ppm (m, 2H); 13C NMR (125 MHz, CDCl3, 258C): d=12.3, 14.12,
59.67, 63.55, 72.63, 103.8, 127.3, 128.0, 129.3, 135.6, 141.5, 164.2, 164.6,
176.0 ppm; IR (CHCl3): n˜ =3154.6, 2253.3, 1793.8, 1693.3 cmÀ1
; MS
Methyl
(3R)-2-benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,3-dihy-
dro-5-isoxazolecarboxylate (8a, major diastereoisomer): [a]2D0 =+111.1
(c=0.47 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d=1.26 (s, 3H),
(70 eV): m/z (%): 323 (7.2) [M+], 246 (28), 232 (20), 144 (5), 117 (7.1),
91 (100), 77 (11), 65 (12); elemental analysis calcd (%) for C20H21NO3: C
74.28, H 6.55, N 4.33; found: C 74.05, H 6.79, N 4.11.
1.28 (s, 3H), 3.69–3.73 (m, 1H), 3.81 (s, 3H), 3.94 (d, 3J
ACHTREUNG
1H), 3.96–4.0 (m, 2H), 4.21 (dd, 3J
ACHTREUNG
Ethyl 2-benzyl-3,4-diphenyl-2,3-dihydroisoxazole-5-carboxylate (10ad):
3J
C
A
1H NMR (500 MHz, CDCl3, 258C): d=1.02 (t, 3J
ACHTREUNG
3.99 (q, 3J
3J
(H,H)=7.2 Hz, 2H), 4.11 (d, 3J
ACHTREUNG
63.3, 65.4, 71.6, 108.0, 109.6, 128.0, 128.5 (2C), 129.7 (2C), 134.7, 147.1,
AHCTREUNG
159.1 ppm; IR (CHCl3): n˜ =3390.0, 2400.1, 1735.3, 1643.7 cmÀ1
; MS
13C NMR (125 MHz, CDCl3, 258C): d=13.9, 60.0 (2C), 63.3 (2C), 73.7,
103.7, 127.3 (2C), 127.8 (3C), 128.2 (3C), 129.9 (3C), 130.1 (2C), 131.1,
135.5, 141.4, 162.1, 163.9 ppm; IR (HCCl3): n˜ =3154.7, 2253.4, 1793.7,
1692.4, 1641.5 cmÀ1; MS (70 eV): m/z (%): 385.17 (4.7) [M+], 308 (16),
294 (30), 167 (11), 105 (71), 91 (100), 77 (29); elemental analysis calcd
(%) for C25H23NO3: C 77.90, H 6.01, N 3.63; found: C 77.81, H 6.14, N
3.55.
(70 eV): m/z (%): 319 (0.4) [M+], 304 (1), 262 (0.6), 244 (1.1), 232 (0.2),
218 (19.9), 101 (6.4), 91 (100), 65 (4.7); elemental analysis calcd (%) for
C17H21NO5: C 63.94, H 6.63, N 4.39; found: C 64.05, H 6.53, N 4.17.
Methyl (3S)-2-benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,3-dihydro-
5-isoxazolecarboxylate (8a, minor diastereoisomer): [a]2D0 =À117.4 (c=
0.39 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d=1.27 (s, 3H), 1.33
(s, 3H), 3.34 (dd, 3J
ACHTREUNG
Ethyl 2-benzyl-4-cyclohexyl-3-phenyl-2,3-dihydroisoxazole-5-carboxylate
3J
3J
3J
A
ACHTREUNG
(10ae): 1H NMR (500 MHz, CDCl3, 258C): d=1.21 (t, 3J
ACHTREUNG
A
ACHTREUNG
3H), 1.30 (tq, 3J
ACHTREUNG
ACHTREUNG
3J
3J
3J
ACHTREUNG
CDCl3, 258C): d=25.2, 26.7, 52.4, 63.1, 66.9, 71.6, 108.0, 109.6, 128.1,
128.6 (2C), 129.8 (2C), 134.8, 146.0, 159.3 ppm; IR (CHCl3): n˜ =3382.3,
2400.1, 1787.6, 1732.1, 1626.4 cmÀ1; MS (70 eV): m/z (%): 319 (0.4) [M+],
304 (1.2), 262 (0.4), 260 (0.4), 244 (1.1), 232 (0.1), 218 (21.0), 101 (6.0), 91
(100), 65 (4.9); elemental analysis calcd (%) for C17H21NO5: C 63.94, H
6.63, N 4.39; found: C 64.05, H 6.38, N 3.90.
A
ACHTREUNG
C
A
ACHTREUNG
12.6 Hz, 1H), 5.13 (s, 1H), 7.37 ppm (m, 10H); 13C NMR (125 MHz,
CDCl3, 258C): d=14.1, 25.6 (2C), 25.8 (2C), 29.7, 36.0, 59.5, 63.5, 72.2,
127.0 (2C), 127.7 (2C), 128.2 (2C), 128.4 (2C), 129.5 (2C), 135.6, 141.8,
164.6, 171.5, 176.0 ppm; IR (CHCl3): n˜ =2933.2, 2235.4, 1709.09 cmÀ1; MS
(70 eV): m/z (%): 391 (33) [M+], 314 (84), 300 (68), 190 (15), 91 (100),
83 (18); elemental analysis calcd (%) for C25H29NO3: C 76.70, H 7.47, N
3.58; found: C 76.81, H 7.56, N 3.52.
(S)-Methyl 2-benzyl-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2,3-
U
dihydro-5-isoxazolecarboxylate (8b, syn): [a]2D0 =À258.2 (c=0.31 in
CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d=0.01 (s, 3H), À0.03 (s,
3H), 0.81 (s, 9H), 0.98 (d, 3J
C
G
Methyl
(10da): 1H NMR (500 MHz, CDCl3, 258C): d=0.77 (t, 3J
3H), 0.88–0.90 (m, 3H), 1.08–1.16 (m, 1H), 1.3–1.5 (m, 5H), 1.5–1.6 (m,
4H), 2.58 (dt, 3J(H,H)=13.9, 7.6 Hz, 1H), 2.72 (dt, 3J
(H,H)=13.9,
7.6 Hz, 1H), 3.72 (s, 3H), 3.77 (d, 3J
(H,H)=12.7 Hz, 1H), 3.99 (dd,
3J(H,H)=8.8, 2.8 Hz, 1H), 4.15 (d, 3J
(H,H)=12.7 Hz, 1H), 7.29–
2-benzyl-4-pentyl-3-propyl-2,3-dihydro-5-isoxazolecarboxylate
ACHTREUNG
3J
3J
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
A
ACHTREUNG
CDCl3, 258C): d=À4.8 (2C), 19.7, 25.8 (3C), 51.2, 63.6, 70.4, 75.8, 107.1,
127.7, 128.3, 129.2 (2C), 129.8 (2C), 135.4, 153.9, 159.5 ppm; IR (CHCl3):
n˜ =3019.1, 2399.9, 1733.8, 1684.0 cmÀ1; MS (70 eV): m/z (%): 377 (1.1)
[M+], 362 (0.5), 320 (7.9), 218 (72.3), 159 (7.5), 115 (4.6), 91 (100), 89
(4.6), 73 (27.3), 59 (4.0); elemental analysis calcd (%) for C20H31NO4Si:
C 63.62, H 8.28, N 3.71; found: C 63.60, H 8.44, N 3.77.
AHCTREUNG
A
ACHTREUNG
7.37 ppm (m, 5H); 13C NMR (125 MHz, CDCl3, 258C): d=13.7, 13.9,
18.5, 22.3, 26.1, 26.6, 31.3, 37.0, 50.9, 53.4, 63.4, 68.6, 102.6, 127.7, 128.4
(2C), 129.6 (2C), 135.9, 165.4, 168.2 ppm; IR (CHCl3): n˜ =3391.1, 2399.9,
1692.1, 1646.0 cmÀ1; MS (70 eV): m/z (%): 331 (2.6) [M+], 313 (0.3), 288
(26.7), 91 (100), 65 (3.0); elemental analysis calcd (%) for C20H29NO3: C
72.49, H 8.82, N 4.23; found: C 72.57, H 8.57, N 4.02.
(R)-Methyl 2-benzyl-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2,3-
U
dihydro-5-isoxazolecarboxylate (8b, anti): [a]2D0 =À258.2 (c=0.31 in
CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d=0.01 (s, 3H), 0.02 (s,
3
3H), 0.86 (s, 9H), 0.98 (d, 3J
C
(H,H)=7.3,
Diethyl 2-benzyl-3-propyl-2,3-dihydro-4,5-isoxazoledicarboxylate (10 db):
1H NMR (500 MHz, CDCl3, 258C): d=0.77 (t, 3J
ACHTREUNG
1.11–1.19 (m, 1H), 1.26 (t, 3J
7.2 Hz, 3H), 1.35–1.43 (m, 1H), 1.56 (m, 2H), 3.85 (d, J
1H), 4.11 (appt, 3J
2H), 4.29 (d, 3J
A
ACHTREUNG
3J
3J
A
3
AHCTREUNG
ACHTREUNG
A
ACHTREUNG
CDCl3, 258C): d=À4.8, À4.9, 18.6, 25.8 (3C), 51.2, 63.6, 71.3, 75.8,
109.33, 127.7, 128.3, 129.2 (2C), 129.8 (2C), 135.4, 153.9, 159.5 ppm; IR
(HCCl3): n˜ =3019.1, 2399.9, 1733.8, 1684.0 cmÀ1; MS (70 eV): m/z (%):
A
ACHTREUNG
7.27–7.36 ppm (m, 5H); 13C NMR (125 MHz, CDCl3, 258C): d=13.5,
13.8, 14.0, 18.3, 36.2, 62.5, 63.3, 69.0, 108.7, 127.9, 128.4 (2C), 129.6 (2C),
135.0, 151.8, 151.9, 159.5 ppm; IR (CHCl3): n˜ =3394.2, 2336.7, 1716.2,
1655.1 cmÀ1; MS (70 eV): m/z (%): 347 (2.6) [M+], 329 (0.7), 304 (20.6),
377 (1.93) [M+], 362 (0.5), 320 (12.7), 218 (33.0), 159 (0.9), 101
ACHTREUNG
ACHTREUNG
4830
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4823 – 4832

Organocatalytic Systems
FULL PAPER
3
3
125 (7.6), 91 (100), 53 (6.6); elemental analysis calcd (%) for C17H21NO5:
C 65.69, H 7.25, N 4.03; found: C 65.54, H 7.59, N 3.97.
3H), 3.72 (d, J
(d, 3J
(H,H)=12.6 Hz, 1H), 3.91 (d, J
U
(H,H)=12.6 Hz, 1H), 7.31 ppm (m, 5H); 13C NMR (125 MHz,
CDCl3, 258C): d=13.8, 22.2, 26.1 (2C), 26.3 (2C), 26.4, 26.7, 29.7, 31.4,
Ethyl
2-benzyl-4-methyl-3-propyl-2,3-dihydroisoxazole-5-carboxylate
(H,H)=7.2 Hz,
(H,H)=7.2 Hz, 3H), 1.49 (m, 2H), 2.19 (s,
(H,H)=12.6 Hz, 1H), 4.01 (dd, 3J
(H,H)=8.5, 2.2 Hz,
(H,H)=7.2 Hz, 1H), 4.20
(10dc): 1H NMR (500 MHz, CDCl3, 258C): d=0.78 (t, 3J
AHCTREUNG
41.2, 50.8, 64.1, 73.3, 100.1, 127.6, 128.2 (2C), 129.6 (2C), 135.9, 165.6,
168.4 ppm; IR (HCCl3): n˜ =2927.8, 2360.7, 2338.4, 1701.4, 1645.9 cmÀ1
;
3H), 1.16 (m, 2H), 1.18 (t, 3J
ACHTREUNG
MS (70 eV): m/z (%): 371 (8.5) [M+], 290 (8.1), 289 (66), 288 (100), 272
(9.6), 166 (3.2), 91 (52); elemental analysis calcd (%) for C23H33NO3:
C 74.36, H 8.95, N 3.77; found: C 74.41, H 8.99, N 3.73.
3H), 3.80 (d, 3J
A
ACHTREUNG
3
3
ACHTREUNG
1H), 4.15 (d, J
A
(q, 3J(H,H)=7.2 Hz, 1H), 7.32 ppm (m, 5H); 13C NMR (125 MHz,
C
CDCl3, 258C): d=12.3, 13.7, 14.3, 18.4, 36.8, 59.6, 63.5, 68.7, 103.2, 127.6,
128.3 (2C), 129.5 (2C), 135.8, 164.0, 165.0 ppm; IR (CHCl3): n˜ =2958.4,
2360.7, 1698.5, 1654.4 cmÀ1; MS (70 eV): m/z (%): 289 (0.9) [M+], 246
(19), 198 (11), 188 (13), 152 (30), 139 (12), 91 (100); elemental analysis
calcd (%) for C17H23NO3: C 70.56, H 8.01, N 4.84; found: C 70.68, H
8.09, N 4.48.
Acknowledgements
This research was supported by the Spanish Ministerio de Educación y
Ciencia and the European Regional Development Fund (CTQ2005–
09074-C02-02). D.T. is the recipient of a postdoctoral I3P Fellowship
from the C.S.I.C. D.G.C. thanks Spanish MEC for a FPI grant.
Ethyl
2-benzyl-4-phenyl-3-propyl-2,3-dihydroisoxazole-5-carboxylate
(H,H)=7.4 Hz,
(H,H)=7.2 Hz, 3H), 1.47 (m, 1H), 1.56 (s, 1H), 1.63 (m,
(10dd): 1H NMR (500 MHz, CDCl3, 258C): d=0.82 (t, 3J
AHCTREUNG
3H), 1.21 (t, 3J
ACHTREUNG
2H), 3.92 (d, 3J
A
ACHTREUNG
3
3
ACHTREUNG
2H), 4.20 (d, J
A
(m, 8H), 7.75 ppm (m, 2H); 13C NMR (125 MHz, CDCl3, 258C): d=13.7,
14.1, 18.6, 29.7, 36.9, 59.9, 63.0, 70.0, 103.5, 127.7 (2C), 128.4 (2C), 129.4
(2C), 129.7 (2C), 129.8 (2C), 130.8 (2C), 135.8, 161.9, 164.2 ppm; IR
(CHCl3): n˜ =3018.6, 2929.3, 1686.0, 1634.3 cmÀ1; MS (70 eV): m/z (%):
351 (2.1) [M+], 308 (59), 105 (37), 91 (100), 77 (28), 65 (10); elemental
analysis calcd (%) for C22H25NO3: C 75. 19, H 7.17, N 3.99; found: C
74.88, H 7.61, N 3.52.
[1] For origins, status, and future challenges of this current topic see:
P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002, 35, 686–694.
[2] a) Handbook of Green Chemistry and Technology (Eds.: J. Clark, D.
Macquarrie), Blackwell, Oxford, 2002; b) for a pharmaceutical per-
spective of this issue see: J. L. Tucker, Org. Process Res. Dev. 2006,
10, 315–319; c) for contribution of chemistry to the sustainable de-
velopment see: M. Eissen, J. O. Metzger, E. Schmidt, U. Schneide-
wind, Angew. Chem. 2002, 114, 402–425; Angew. Chem. Int. Ed.
2002, 41, 414–436.
[3] a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816–
7817; b) for a full account of the hydrophobic effects on simple or-
ganic reactions in water see R. Breslow, Acc. Chem. Res. 1991, 24,
159–164.
Ethyl 2-benzyl-4-cyclohexyl-3-propyl-2,3-dihydroisoxazole-5-carboxylate
(10de): 1H NMR (500 MHz, CDCl3, 258C): d=0.75 (t, 3J
(H,H)=7.2 Hz,
3
3H), 1.15 (m, 4H), 1.27 (t, J
ACHTREUNG
3J
3J
3J
A
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
[4] P. A. Grieco, P. Garner, H. Zhen-Min, Tetrahedron Lett. 1983, 24,
1897–1900.
258C): d=13.7, 14.0, 25.6, 25.9, 29.6, 29.8, 31.4, 36.9, 37.0, 59.5, 61.7, 63.3,
68.4, 101.2, 127.6, 128.3 (2C), 129.5 (2C), 135.9, 171.3, 176.0 ppm; IR
(HCCl3): n˜ =3020.3, 2870.2, 1729.0 cmÀ1; MS (70 eV): m/z (%): 357 (0.5)
[M+], 314 (25), 193 (3), 135 (3.2), 91 (100), 55 (7.8); elemental analysis
calcd (%) for C22H31NO3: C 73.95, H 8.74, N 3.92; found: C 74.10, H
8.84, N 3.52.
[5] a) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie Academic
and Professional, London, UK, 1998; b) R. Breslow, Water as a sol-
vent for chemical reactions in Green Chemistry: Frontiers in Benign
Chemical Syntheses and Processes (Eds.: P. T. Anastas, T. C. William-
son), Oxford University Press, New York, 1998, Chapter 13.
[6] a) C.-J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68–82; b) C.-J. Li,
Chem. Rev. 2005, 105, 3095–3166; c) U. M. Lindstrçm, Chem. Rev.
2002, 102, 2751–2772; for excellent discussions on the acceleration
of organic reactions through aqueous solvent effects see: d) M. C.
Pirrung, Chem. Eur. J. 2005, 12, 1312–1317; e) S. Otto, J. B. F. N. En-
gerberts, Org. Biomol. Chem. 2003, 1, 2809–2820.
[7] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B.
Sharpless, Angew. Chem. 2005, 117, 3339–3343; Angew. Chem. Int.
Ed. 2005, 44, 3275–3279.
[8] a) A. Berkessel, H. Groerger, Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, Germany, 2005; b) P. I. Dalko, L. Moisan, Angew.
Chem. 2004, 116, 5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–
5175; c) Special issue on asymmetric organocatalysis, Acc. Chem.
Res. 2004, 37 (Eds.: K. N. Houk, B. List).
[9] For selected examples of organocatalyzed direct aldol reactions in
water see: a) Z. Jiang, Z. Liang, X. Wu, Y. Lu, Chem. Commun.
2006, 2801–2803; b) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K.
Takabe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
734–735; c) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Ur-
ushima, M. Shoji, Angew. Chem. 2006, 118, 972–975; Angew. Chem.
Int. Ed. 2006, 45, 958–961; d) P. Dziedzic, W. Zou, H. Weibiao, J.
Hafren, A. Cordova, Org. Biomol. Chem. 2006, 4, 38–40; e) A. Cor-
dova, W. Zou, P. Dziedzic, I. Ibrahem, E. Reyes, Y. Xu, Chem. Eur.
J. 2006, 12, 5383–5397; f) S. S. Chimni, D. Mahajan, Tetrahedron
2005, 61, 5019–5025; g) S. S. Chimni, D. Mahajan, V. V. S. Babu, Tet-
rahedron Lett. 2005, 46, 5617–5619; h) Y.-S. Wun, Y. Chen, D.-S.
Deng, J. Cai, Synlett 2005, 1627–1629; i) C. J. Rogers, T. J. Dicker-
son, A. P. Brogan, K. D. Janda, J. Org. Chem. 2005, 70, 3705–3708;
j) A. Cordova, W. Notz, C. F. Barbas III, Chem. Commun. 2002,
3024–3025; k) T. Dickerson, K. D. Janda, J. Am. Chem. Soc. 2002,
Ethyl
(10ea): 1H NMR (500 MHz, CDCl3, 258C): d=0.84 (t, 3J
3H), 0.87 (t, 3J
(H,H)=7.2 Hz, 3H), 1.10–1.25 (m, 7H), 1.25–1.35 (m,
5H), 1.37–1.47 (m, 1H), 1.47–1.60 (m, 3H), 2.59 (dt, 3J
(H,H)=13.8,
(H,H)=13.8, 7.6 Hz, 1H), 3.71 (s, 3H), 3.77 (d,
(H,H)=12.7 Hz, 1H), 3.97 (dd, 3J
(H,H)=8.9, 2.6 Hz, 1H), 4.15 (d,
(H,H)=12.7 Hz, 1H), 7.32 ppm (m, 5H); 13C NMR (125 MHz, CDCl3,
2-benzyl-3-hexyl-4-pentyl-2,3-dihydroisoxazole-5-carboxylate
AHCTREUNG
ACHTREUNG
AHCTREUNG
7.6 Hz, 1H), 2.70 (dt, 3J
ACHTREUNG
3J
3J
G
ACHTREUNG
ACHTREUNG
258C): d=13.8, 14.0, 22.2, 22.5, 25.2, 26.0, 26.6, 28.9, 31.3, 31.7, 34.7, 50.8,
63.4, 68.7, 127.6, 128.3 (2C), 129.6 (2C), 135.8, 165.4, 168.1, 176.0 ppm;
IR (CHCl3): n˜ =3434.3, 2929.4, 2360.8, 1703.3, 1647.22 cmÀ1; MS (70 eV):
m/z (%): 373 (8.1) [M+], 288 (100), 274 (10), 230 (37), 91 (53); elemental
analysis calcd (%) for C23H35NO3: C 73.96, H 9.44, N 3.75; found: C
73.98, H 9.49, N 3.88.
Ethyl
(10 fa): 1H NMR (500 MHz, CDCl3, 258C): d=0.73 (t, 3J
3H), 0.78 (t, 3J(H,H)=7.2 Hz, 3H), 0.87 (t, 3J
(H,H)=7.2 Hz, 3H), 1.32
(m, 4H), 1.55 (m, 2H), 1.86 (m, 1H), 2.59 (dt, 3J
(H,H)=13.8, 7.6 Hz,
(H,H)=13.8, 7.6 Hz, 1H), 3.71 (s, 3H), 3.74 (d,
(H,H)=12.6 Hz, 1H), 3.94 (d, 3J
(H,H)=3.1 Hz, 1H), 4.13 (d,
(H,H)=12.6 Hz, 1H), 7.31 ppm (m, 5H); 13C NMR (125 MHz, CDCl3,
2-benzyl-3-isopropyl-4-pentyl-2,3-dihydroisoxazole-5-carboxylate
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
1H), 2.70 (dt, 3J
ACHTREUNG
3J
3J
A
ACHTREUNG
ACHTREUNG
258C): d=13.8, 15.8, 19.1, 22.2, 26.1 (2C), 26.7, 31.2, 31.4, 50.7, 64.3, 73.7,
77.2, 127.6, 128.2 (2C), 129.6 (2C), 135.9, 168.5 ppm; IR (CHCl3): n˜ =
2958.1, 2360.7, 1702.8, 1646.3 cmÀ1; MS (70 eV): m/z (%): 331 (1.9) [M+],
288 (88), 179 (2.9), 91 (100), 65 (7.8), 55 (4.8); elemental analysis calcd
(%) for C20H29NO3: C 73.01, H 9.04, N 4.05; found: C 73.15, H 8.87, N
4.34.
Ethyl 2-benzyl-3-cyclohexyl-4-pentyl-2,3-dihydroisoxazole-5-carboxylate
(10ga): 1H NMR (500 MHz, CDCl3, 258C): d=0.87 (t, 3J
ACHTREUNG
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4831

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Received: February 7, 2007
Published online: April 20, 2007
4832
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4823 – 4832