Organocatalyzed synthesis of isoxazolidin-5-ones: The meldrum's acid approach

Article abstract of DOI:10.1002/adsc.201300465

Meldrum's acid has turned out to be a useful ketene equivalent when faced to nitrone dipoles to form various isoxazolidin-5-one derivatives under very mild Bronsted base organocatalytic conditions. The first asymmetric version of this original domino anionic formal [3+2] cycloaddition- decarboxylation reaction was demonstrated by means of quinine-based organocatalysts. Copyright

Full text of DOI:10.1002/adsc.201300465

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DOI: 10.1002/adsc.201300465
Organocatalyzed Synthesis of Isoxazolidin-5-ones: The Meldrumꢀs
Acid Approach
Svetlana Postikova,a Tony Tite,a Vincent Levacher,a and Jean-FranÅois Briꢀrea,*
a
Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesniꢀre, 76821
Mont Saint Aignan cedex, France
Fax : (+33)-(0)-2-3552-2962; e-mail: jean-francois.briere@insa-rouen.fr
Received: May 27, 2013; Published online: August 28, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200465.
Abstract: Meldrumꢁs acid has turned out to be
a useful ketene equivalent when faced to nitrone di-
poles to form various isoxazolidin-5-one derivatives
under very mild Brønsted base organocatalytic con-
ditions. The first asymmetric version of this original
domino anionic formal [3+2]cycloaddition–decar-
boxylation reaction was demonstrated by means of
quinine-based organocatalysts.
thetic approaches to isoxazolidin-5-one structures 3,[3]
the one step catalytic and/or enantioselective con-
struction of this heterocyclic framework has elicited
few research programs thus far.[4] Sibi and co-workers
reported a unique asymmetric version based on the
addition of N-benzylhydroxylamine to activated acryl-
amides in the presence of chiral magnesium Lewis
acid complexes.[5] Zhang and Ying developed an N-
heterocyclic carbene organocatalyzed reaction of ni-
trosobenzene to enals giving rise to the formation of
unstable N-phenylisoxazolidin-5-ones 3 (R2 =Ph).[6]
One enantioselective example was described with
44.5% ee. On the other hand, Cꢂrdova and colleagues
achieved an elegant enantioselective aza-Michael re-
action of N-carbamate-hydroxylamine, promoted by
a catalytic amount of iminium salt intermediates, fol-
Keywords: cycloaddition; isoxazolidinones; ketene
equivalents; Meldrumꢁs acid; organic catalysis; or-
ganocatalysis
Isoxazolidin-5-one derivatives 3 belong to those archi- lowed by an oxidation process of the obtained 5-hy-
tectures which are not only considered as useful het- droxyisoxazolidines.[7] This sequence provides a power-
erocyclic platforms for the design of bioactive com- ful but indirect two-steps approach to some isoxazoli-
pounds (Scheme 1),[1] but are also versatile intermedi- din-5-one derivatives 3. Alternatively, the nucleophilic
ates in organic synthesis. In just a few chemical trans- addition of ketene acetals, either as enolate or silyl
formations, for instance, this building block provides derivatives, to nitrones furnished a straightforward
an expeditious access to nucleoside mimics,[2] or b- approach to isoxazolidin-5-ones after an intramolecu-
amino acids,[3] currently relevant compounds in me- lar lactonization event.[8] The catalytic activity of thio-
dicinal chemistry. However, beside stoichiometric syn- ureas or TMSOTf was proven in some cases.[9] None-
theless, the use of strong bases or the implications of
moisture sensitive nucleophiles were required.
In that context, we would like to report on a practi-
cal, yet innovative, organocatalytic synthetic approach
to isoxazolidin-5-ones 3 from nitrone dipoles 2 based
on an anionic formal [3+2]cycloaddition reaction
(Scheme 1).[4,10] Notably, we highlight hereby the re-
markable facile addition reaction of Meldrumꢁs acid
dipolarophile behaving as a user-friendly ketene
equivalent formed upon a smooth catalytic deproto-
nation event.[11,12] We believe this original strategy af-
fords new opportunity beside the known [3+2]cyclo-
addition processes involving ketene equivalents.[3d,13,14]
At the origin of this project, we were intrigued by
Scheme 1. Organocatalytic formal [3+2]cycloaddition.
the formation of isoxazolidinone 3a simply by mixing
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Svetlana Postikova et al.
Table 2. Optimization of solvents with Hꢄnigꢁs base.[a]
COMMUNICATIONS
Table 1. Optimization of Brønsted base catalysts.[a]
Entry
Solvent
Conversion [%][b]
1
2
3
4
5
6
7
DMF
DMSO
EtOH
ethyl acetate
dichloroethane
methylcyclohexane
toluene
0
0
22
36
19
35
68
Entry
Base
Temp. [8C]
Conversion [%][b]
1
2
3
4
5
6
7
8
9
10
–
40
40
40
40
40
40
40
40
60
20
10[c,d]
62
57
58
DABCO
DMAP
Et3N
DBU
TBD
TMP
T
T
ACHTUNGTRENNUNG
[a]
Reaction conditions: Meldrumꢁs acid 1a (1.1 equiv.), N-
benzylnitrone 2a (1 equiv.), (i-Pr)2EtN (0.2 equiv.), sol-
vent (0.1M), 2 h.
42
42
41
[b]
Determined from the 1H NMR spectrum of the crude
product with respect to the remaining nitrone.
68 (64),[c] (86)[c,e]
79
14
Table 3. Scope and limitations.[a]
[a]
Reaction conditions: Meldrumꢁs acid 1a (1.1 equiv.), N-
benzylnitrone 2a (1 equiv.), base (0.2 equiv.), toluene
(0.1M), 2 h.
[b]
[c]
Determined from the 1H NMR spectrum of the crude
product with respect to the remaining nitrone.
Isolated yield after purification by column chromatogra-
phy.
[d]
[e]
After 18 h of reaction.
At 0.5M.
Nitrone/Product R1 R2
R3
Yield [%][b]
2a/3a
2b/3b
2c/3c
2a/3d
2d/3e
2e/3f
2f/3g
2g/3h
2h/3k
2k/3l
H
H
H
Bn
Ph
Ph
Ph
76
81[c]
12 (63)[e]
55[f]
76
Boc[d] CH2CH2Ph
N-benzylnitrone 2a and Meldrumꢁs acid 1a at 408C
for 18 h, albeit in low yield (Table 1, entry 1). Pleas-
ingly, this likely domino process was markedly accel-
erated in the presence of DABCO, DMAP or Et3N.
These bases displayed similar catalytic reactivity
giving nearly 60% of conversion after 2 h (entries 2–
4). Stronger bases such as DBU or triazabicyclo-
Bn Bn
Ph
H
H
H
H
H
H
Bn
Me
Bn
Bn
Bn
Bn
4-ClC6H4
4-MeOC6H4
CH2CH2Ph
Cy
CH2NHBoc
CO2Et
73
85
91
52 (61)[e]
41
ACHTUNGTRENNUNG[4.4.0]dec-5-ene (TBD) led to slower reaction rates
(entries 5 and 6). Obviously, all these amines also pos-
sess a nucleophilic character, and it is conceivable
that they react as such with Meldrumꢁs acid derivative
3a, through the formation of an acylketene spe-
cies.[14,15] Nevertheless, when reactants 1a and 2a were
subjected to sterically hindered and non-nucleophilic
tetramethylpiperidine (TMP) a 41% of conversion
was measured too (entry 7). Eventually, it was found
that Hꢄnigꢁs base furnished the best result affording
64% isolated yield with 68% of conversion (entry 8).
This transformation was improved by working at
0.5M to afford 86% yield (entry 8). However, precipi-
tation events during the reaction led to somewhat
capricious outcomes along different attempts. More-
over, the reaction rate could be accelerated at 608C
(entries 9 and 10).
2l/3m
H
H
Bn
–
73[g]
2m/3n
58[h]
[a]
Representative reaction conditions: Meldrumꢁs acid 1a
(1.5 equiv.), N-benzylnitrone 2a (0.5 mmol, 1 equiv.), (i-
Pr)2EtN (0.2 equiv.), toluene (0.1M), 18 h, 408C.
Isolated yield after purification by column chromatogra-
phy.
Yield determined on the basis of the crude product by
means of an internal standard.
Nitrone 2c generated in situ with 1.2 equivalents of (i-
Pr)2EtN from the corresponding phenylsulfonylalkyl-N-
hydroxycarbamates 2c’.
[b]
[c]
[d]
[e]
[f]
Obtained at room temperature for 18 h.
>98:2 anti/syn ratio from the H NMR spectrum of the
1
A rapid journey along the reaction conditions re-
vealed an incompatibility of this process with dipolar
aprotic solvents (Table 2, entries 1 and 2) and a poor
transformation into isoxazolidinone 3a in ethanol
(entry 3). Slightly better reaction rates were measured
crude product after 48 h at 408C.
>73:27 anti/syn ratio from the H NMR spectrum of the
crude product.
91% of conversion at 608C for 42 h (75% of conversion
at 408C for 18 h).
[g]
[h]
1
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Organocatalyzed Synthesis of Isoxazolidin-5-ones: The Meldrumꢁs Acid Approach
with less polar media (entries 4–6), although none of erature.[19] Interestingly, a mixture of diethyl malonate
them surpassed toluene with regard to the conversion with N-benzylnitrone 2a in the presence of either (i-
in 2 h (entry 7).
Pr)2EtN or TBD bases (stirred at 408C in toluene for
Then, we probed the scope and limitation of this two hours) led to the recovery of reactants. Then, we
new methodology by means of various types of nitro- tried to probe the possible fragmentation of Mel-
nes (Table 3). The reactions were carried out at 408C drumꢁs acid into highly reactive acylketene species by
for 18 h, which secure a complete conversion in most means of EtOH as trapping nucleophile.[20] Neverthe-
cases. N-Benzyl 2a and N-phenyl nitrones 2b were less, after 22 h at 408C in an NMR tube (CDCl3), the
completely transformed into the corresponding isoxa- 1H NMR spectra did not reveal any decomposition of
zolidinones 3a and 3b in good 76% and 81% isolated Meldrumꢁs acid 1a in the presence of (i-Pr)2EtN and
yields, respectively. Product 3b could not be purified EtOH (1 equivalent for each). In that context, we
due to its known instability on silica gel but an easy proposed the following stepwise process (Scheme 2).
rearrangement into valuable b-amino acid derivatives
is achievable under acidic conditions as demonstrated
by Zhang and Ying.[6] We subsequently evaluated the
rather reactive N-Boc nitrone 2c,[16] easily generated
in situ by means of 1.2 equivalents of Hꢄnigꢁs base
from the corresponding phenylsulfonylalkyl-N-hy-
droxycarbamates 2c’ [1.0 equivalent of (i-Pr)2EtN to
trap the liberated sulfinic acid]. Gratifyingly, the cata-
lytically formed Meldrumꢁs acid 1a anion afforded
63% yield of the corresponding N-Boc heterocycle 3c
at room temperature. The known instability of nitrone
2c might explain why only 12% of product 3c was
formed at 408C.[16a] C-Benzyl-Meldrumꢁs acid 1b fur-
Scheme 2. Mechanistic proposal.
nished the disubtituted compound 3d, albeit a longer
reaction time was required and some decomposition
was observed. Pleasingly, the reaction proved to be First of all, a formal anionic [3+2]cycloaddition
highly stereoselective as the sole anti-diastereoisomer would take place through a Mannich reaction fol-
1
could be detected in the H NMR spectrum of the lowed by a cyclization event giving rise to 4 (or in
crude product.[5b] This [3+2]cycloaddition type of pro- a concerted manner).[3a] The obtained tetrahedral in-
cess was also successful to construct isoxazolidinones termediate 4 rapidly undergoes a fragmentation to
derived from electron-poor and electron-rich aromatic give carboxylate 5 by releasing a molecule of acetone;
aldehydes 3e and 3f, together with aliphatic linear or preventing thereby any equilibrated processes. This
branched ones 3g and 3h in good yields. We also eval- domino Mannich–cyclocondensation reaction would
uated the reaction with nitrones bearing more sensi- explain the difference in reactivity with ethyl malo-
tive functional groups without further optimization. nate which is much more nucleophilic than Meldrumꢁs
The NHBoc (3k)[17] and ester (3l) functionalities were acid but less prone to undergo an electrophilic addi-
tolerated albeit giving moderate yield in the last case, tion during the annulation reaction, critical to drive
due to the possible hydrolytic sensitivity of the elec- the whole process towards more stable products.[21,22]
trophilic nitrone 2k as testified by its complete trans- Moreover, in line with the elegant and recent Grassiꢁs
formation. Interestingly, the formal [3+2]cycloaddi- study,[23] involving the reaction between enolizable
tion sequence took place with acetal-protected d-glyc- 1,3-diketone compounds with electron-poor nitrones,
eraldehyde with 73% yield and a 73:27 anti/syn ratio. we assume an activation of the nitrone through hy-
This outcome parallels the one previously obtained by drogen bonding with the tertiary ammonium salt.[9b,24]
Merino and co-worker, who obtained up to 95:5 anti/ As a matter of fact, the low pKa of Meldrumꢁs acid
syn ratio for the addition of ester enolates but in the (pKa =4.93 in water) maximizes both concentration
presence of a Lewis acid.[8b,18] Eventually, this strategy and acidity of the ion-pair intermediate 1c+(i-
was applied to the tetrahydroisoquinoline derived ni- Pr)2EtNH+.[25] Then, a decarboxylation occurs to form
trone 2m which yielded heterocycle 3n with 58% the enolate anion 6, sufficiently basic to trap the am-
yield at 608C, demonstrating the slightly lower reac- monium proton atom and liberating thereby the terti-
tivity of this cyclic dipole under those conditions.
In order to get an insight into this unique reactivity
ary amine base for a new catalytic cycle.
Next, we turned our attention to an enantioselec-
pattern of Meldrumꢁs acid, we performed a couple of tive version by means of chiral bases (Table 4). A
test reactions. First of all, a facile Mannich addition screening endeavor revealed quinine derivatives as
reaction was questioned by means of a more nucleo- promising organocatalysts (see the Supporting Infor-
philic malonate anion, as already mentioned in the lit- mation). N-Benzylnitrone 2a was transformed into
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Svetlana Postikova et al.
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Table 4. Enantioselective approach.[a]
[3+2]cycloaddition takes place under very mild basic
organocatalytic reaction conditions, thanks to the high
acidity of Meldrumꢁs acid whose conjugated base be-
haves as a useful ketene equivalent. The first asym-
metric version was demonstrated with quinine derived
bases. We are currently carrying out a mechanistic in-
vestigation in order to broaden the scope and achieve
an effective enantioselective version of this original
process.
Experimental Section
Representative Procedure for Isoxazolidin-5-one
Synthesis
To a mixture of N-benzylnitrone 2a (0.5 mmol) and Mel-
drumꢁs acid 1a (0.75 mmol, 1.5 equiv.) were added toluene
(5 mL) and (i-Pr)2NEt (17.4 mL, 0.1 mmol, 20 mol%). The
resulting solution was stirred at 408C for 18 h, then cooled
to room temperature and concentrated under vacuum. The
crude product was purified by a column chromatography to
give the desired 2-benzyl-3-phenylisoxazolidin-5-one 3a.
Entry Cat. [equiv.] External base Yield [%][a] ee [%][b]
1
2
3
4
5
7 [0.2][c]
8 [0.2][c]
7 [1.2][d]
8 [1.2][d]
7 [0.2][d,e]
–
–
–
–
79
56
99
99
72
3a 35 (S)
3a 48 (R)
3c 61
3c 63
3c 43
K2CO3
[a]
Isolated yield after purification by column chromatogra-
phy.
Determined by chiral HPLC.
Reaction conditions: Meldrumꢁs acid 1a (1.5 equiv.), N-
benzylnitrone 2a (1 equiv.), catalyst (0.2 equiv.), toluene
(0.1M), 408C, 18 h.
Reaction conditions: Meldrumꢁs acid 1a (1.1 equiv.), phe-
nylsulfonylalkyl-N-hydroxycarbamate 2c’ (1 equiv.), cata-
lyst (0.2–1.2 equiv.), toluene (0.1M), room temperature,
3 h.
Acknowledgements
[b]
[c]
This work has been partially supported by INSA Rouen,
Rouen University, CNRS, EFRD and Labex SynOrg (ANR-
11-LABX-0029), together with the “Rꢀgion Haute-Norman-
die”. This project has also been funded in part by the Euro-
pean Union through a FEDER support (BIOFLUORG con-
vention No. 33236) engaged in region Haute-Normandie.
[d]
[e]
At 08C for 24 h.
References
´
isoxazolidinone 3a with up to 48% ee making use of
thiourea-derived catalyst 8 (entry 2). Unfortunately,
this sterically more demanding catalyst 8 gave lower
yields than the corresponding quinine 7 (entries 1 and
2), despite providing higher ee. On the other hand, it
was found that N-Boc nitrone precursor 2c’ was more
reactive and provided the corresponding N-Boc-isoxa-
zolidinone 3c with high yields and similar enantiomer-
ic excesses (61–63% ee) with both quinine promoters
7 and 8, used in excess.[16] Thus far, any attempts to
promote an organocatalytic process (entry 5), by
means of 20 mol% of chiral amine and a stoichiomet-
ric mineral base to trap the liberated sulfenic acid, re-
vealed a strong background reaction decreasing the ee
to 43% albeit maintaining good yields (see the Sup-
porting Information).
[1] a) I. Panfil, Z. Urbanczyk-Lipkowska, M. Chmielewski,
Carbohydr. Res. 1998, 306, 505–515; b) T. Janecki, T.
Wa˛sek, M. Rꢂz˙alski, U. Krajewska, K. Studzian, A. Ja-
necka, Bioorg. Med. Chem. Lett. 2006, 16, 1430–1433;
c) Shamsuzzaman, H. Khanam, A. Mashrai, N. Siddi-
qui, Tetrahedron Lett. 2013, 54, 874–877.
[2] a) M. J. Mulvihill, M. J. Miller, Tetrahedron 1998, 54,
6605–6626; b) P. Merino, E. M. delAlamo, M. Bona, S.
Franco, F. L. Merchan, T. Tejero, O. Vieceli, Tetrahe-
dron Lett. 2000, 41, 9239–9243.
[3] For representative important recent examples, see:
a) M. Shindo, K. Itoh, C. Tsuchiya, K. Shishido, Org.
Lett. 2002, 4, 3119–3121; b) R. Luisi, V. Capriati, S.
Florio, T. Vista, J. Org. Chem. 2003, 68, 9861–9864;
c) S. A. Bentley, S. G. Davies, J. A. Lee, P. M. Roberts,
A. J. Russell, J. E. Thomson, S. M. Toms, Tetrahedron
2010, 66, 4604–4620; d) M. E. Juarez-Garcia, S. Yu,
J. W. Bode, Tetrahedron 2010, 66, 4841–4853, and refer-
ences cited therein.
In conclusion, we have developed a straightforward
and original domino Mannich–cyclocondensation–de-
carboxylation reaction towards the construction of
isoxazolidin-5-one derivatives from a variety of nitro-
nes and Meldrumꢁs acid. This practical formal anionic
[4] For the synthesis of isoxazolidines through [3+2]cyclo-
addition reactions, see reviews: a) K. V. Gothelf, K. A.
Jørgensen, Chem. Rev. 1998, 98, 863; b) M. Kissane,
A. R. Maguire, Chem. Soc. Rev. 2010, 39, 845–883;
2516
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2513 – 2517

Organocatalyzed Synthesis of Isoxazolidin-5-ones: The Meldrumꢁs Acid Approach
c) C. Nꢅjera, J. M. Sansano, M. Yus, J. Braz. Chem.
Soc. 2010, 21, 377–412; d) T. B. Nguyen, A. Martel, C.
Gaulon, R. Dhal, G. Dujardin, Org. Prep. Proced. Int.
2010, 42, 387–431.
Vallꢆe, J.-N. Denis, Org. Lett. 2005, 7, 5147–5150; b) C.
Gioia, F. Fini, A. Mazzanti, L. Bernardi, A. Ricci, J.
Am. Chem. Soc. 2009, 131, 9614–9615.
[17] H. Chalaye-Mauger, J.-N. Denis, M.-T. Averbuch-Pou-
chot, Y. Vallꢆe, Tetrahedron 2000, 56, 791–804.
[18] a) P. Merino, S. Franco, N. Garces, F. L. Merchan, T.
Tejero, Chem. Commun. 1998, 493–494; b) M. Shindo,
K. Itoh, K. Ohtsuki, C. Tsuchiya, K. Shishido, Synthesis
2003, 1441–1445.
[19] a) L. S. Kaminsky, M. Lamchen, J. Chem. Soc. C 1967,
1683–1685; b) H. Stamm, J. Hoenicke, Justus Liebigs
Ann. Chem. 1971, 143–153; c) V. S. Velezheva, V. N.
Azev, A. G. Kornienko, A. S. Peregudov, I. A. Godovi-
kov, Y. L. Sebyakin, Tetrahedron Lett. 2010, 51, 6594–
6597.
[20] M. Sato, H. Ban, C. Kaneko, Tetrahedron Lett. 1997,
38, 6689–6692.
[21] For an insightful discussion on Meldrumꢁs acid reactivi-
ty, see: E. Fillion, D. Fishlock, Tetrahedron 2009, 65,
6682–6695.
[22] We cannot rule out at that stage a direct and regiose-
lective [3+2]cycloaddition reaction to the C=C double
bond of the stable enolate form of Meldrumꢁs acid, see
ref.[23] for a discussion.
[23] M. Cordaro, F. Risitano, A. Scala, A. Rescifina, U.
Chiacchio, G. Grassi, J. Org. Chem. 2013, 78, 3972–
3979, and references cited therein.
[24] P. Jiao, D. Nakashima, H. Yamamoto, Angew. Chem.
2008, 120, 2445–2447; Angew. Chem. Int. Ed. 2008, 47,
2411–2413.
[5] a) M. P. Sibi, M. Liu, Org. Lett. 2000, 2, 3393–3396;
b) M. P. Sibi, N. Prabagaran, S. G. Ghorpade, C. P. Jas-
perse, J. Am. Chem. Soc. 2003, 125, 11796–11797.
[6] J. Seayad, P. K. Patra, Y. Zhang, J. Y. Ying, Org. Lett.
2008, 10, 953–956.
[7] I. Ibrahem, R. Rios, J. Vesely, G.-L. Zhao, A. Cꢂrdova,
Chem. Commun. 2007, 849–851.
[8] For reviews, see: a) M. Lombardo, C. Trombini, Synthe-
sis 2000, 759–774; b) P. Merino, Compt. Rend. Chim.
2005, 8, 775–788.
[9] a) C. Camiletti, D. D. Dhavale, F. Donati, C. Trombini,
Tetrahedron Lett. 1995, 36, 7293–7296; b) T. Okino, Y.
Hoashi, Y. Takemoto, Tetrahedron Lett. 2003, 44, 2817–
2821.
[10] For reviews on organocatalytic cycloadditions, see:
a) A. Moyano, R. Rios, Chem. Rev. 2011, 111, 4703–
4832; b) H. Pellissier, Tetrahedron 2012, 68, 2197–2232.
[11] For a review on ketene equivalents, see: S. Rangana-
than, D. Ranganathan, A. K. Mehrotra, Synthesis 1977,
289–296.
[12] For reviews on Meldrumꢁs acid, see: a) A. S. Ivanov,
Chem. Soc. Rev. 2008, 37, 789–811; b) A. M. Dumas, E.
Fillion, Acc. Chem. Res. 2010, 43, 440–454.
[13] For an original ketene equivalent approach towards
isoxazolidinones, see: R. Bejot, S. Anjaiah, J. R. Falck,
C. Mioskowski, Eur. J. Org. Chem. 2007, 2007, 101–107,
and references cited therein.
[25] A moderate transformation of nitrone 2a into isoxazoli-
dinone 3a was observed with K2CO3 as a base, even in
the presence of an ammonium phase-transfer catalyst,
showing the importance of the deprotonated Mel-
[14] For a review on acylketenes from Meldrumꢁs acid, see:
K. P. Reber, S. D. Tilley, E. J. Sorensen, Chem. Soc.
Rev. 2009, 38, 3022–3034.
[15] T. T. Tidwell, Eur. J. Org. Chem. 2006, 563–576.
[16] For the pioneering development of N-Boc nitrones in
cycloaddition processes, see: a) X. Guinchard, Y.
drumꢁs acid ion-pair structure in action, namely R4N+
+
À
vs. R3N H .
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