Tandem SmI2-induced nitrone β-elimination/aldol-type reaction

Article abstract of DOI:10.1039/b910486k

Upon treatment with SmI₂, the carbohydrate-derived nitrones 1a,b undergo a β-elimination of the benzyloxy group at C-1, forming original samarium(III) oxy-enamine intermediates. The latter can be reacted with carbonyl compounds to produce aldol

Full text of DOI:10.1039/b910486k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Tandem SmI2-induced nitrone b-elimination/aldol-type reaction†
Emilie Racine and Sandrine Py*
Received 27th May 2009, Accepted 2nd July 2009
First published as an Advance Article on the web 15th July 2009
DOI: 10.1039/b910486k
Upon treatment with SmI2, the carbohydrate-derived ni-
trones 1a,b undergo a b-elimination of the benzyloxy group at
C-1, forming original samarium(III) oxy-enamine intermedi-
ates. The latter can be reacted with carbonyl compounds to
produce aldol-type adducts. The tandem process results in
the transformation of a C–O bond into a C–C bond.
Since its first applications presented by Kagan et al. in the
Scheme 2 Unexpected reactivity of nitrones 1a,b under SmI2-promoted
reductive coupling conditions.
early 1980’s,1 SmI2 has become an essential single-electron re-
ductant for organic chemists.2 A few years ago, this reagent
allowed the chemoselective reductive cross-coupling of nitrones
with aldehydes and ketones,3 with chiral sulfinyl imines,4 and
with a,b-unsaturated esters.5 As an extension of this last pro-
cess, the SmI2-mediated reductive cross-coupling of 5-membered-
ring carbohydrate-derived cyclic nitrones6 with ethyl acrylate
was applied to the synthesis of polyhydroxylated pyrrolizidines
(Scheme 1).7
dergoes b-elimination to form a samarium enolate.10 It is likely that
a similar process occurs when nitrones 1a,b react with samarium
diiodide. An original samarium(III) oxy-enamine intermediate
3 would be formed, which would then react with water, either
in the reaction medium or upon quenching (Scheme 3).11 This
mechanistic hypothesis was probed by unambiguous deuterium
incorporation at C-1 (forming nitrone 4) when the reaction was
performed in the presence of deuterium oxide.12
Scheme 1 Synthetic approach towards polyhydroxylated pyrrolizidines
using the SmI2-mediated nitrone umpolung.
In continuation of our work in this field, 6-membered ring cyclic
nitrones were considered as precursors of indolizidines. Nitrones
1a,b were readily prepared from inexpensive D-fructose and
L-sorbose, respectively.8 However, surprisingly, when these ni-
trones were treated with SmI2 using previously described
conditions,7 only the nitrones 2a,b were isolated from the reaction
mixtures, whether the electrophilic partner was ethyl acrylate or
cyclopentanone (Scheme 2).
The formation of nitrones 2a,b from 1a,b can be explained
by a SmI2-reduction of the C–N double bond, followed by
elimination of the benzyloxy group at C-1. This elimination
would parallel the known SmI2-promoted elimination occurring in
a-heterosubstituted carbonyl compounds.9 The latter has been
generally admitted to involve two sequential single-electron trans-
fers from SmI2 to a carbonyl group to produce a dianion, which un-
Scheme 3 Mechanism of formation of nitrones 2 and 4.
Recently, side-products resulting from b-elimination have also
been found in SmI2-induced reactions of two a-alkoxy-substituted
nitrones, by the group of Fisˇera.13 However, to the best of our
knowledge, the reactivity of anionic enamine equivalents from
nitrones (i.e. 3) is completely unknown. We thus decided to explore
the utility of the herein-described SmI2-induced b-elimination in
nitrones for regioselective functionalization. A single report on
nitrone cross-aldol alkylation exists in the literature.14 The method
(catalysed by L-proline) was applied only to highly electrophilic
carbonyl partners and modest yields were reported. If intermediate
3 was capable of reacting with electrophiles instead of H2O or
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-
2607, CNRS–Universite´ Joseph Fourier, BP 53, 38041 Grenoble Cedex 09,
France. E-mail: Sandrine.Py@ujf-grenoble.fr; Fax: +(33) 476 596 383;
Tel: +(33) 476 514 803
† Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of compounds 2 and 4–11, characterization
of compounds 2 and 4–11 including copies of their 1H and 13C NMR
spectra, and a copy of the ESI mass spectrum for compound 4. See DOI:
10.1039/b910486k
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Table 1 SmI2-mediated reaction of nitrones 1a,b with electrophilesa
Entry
Nitrone 1a,b
Electrophile
Coupling product (% Yield)b
drc
Nitrone 2a,b (% Yieldb)
1
2
3
4
5
6
7
8
9
1a
1b
1a
1a
1a
1a
1a
1a
1a
Cyclohexanone
Cyclohexanone
Cyclopentanone
3-Pentanone
Cyclohexane carboxaldehyde
Benzaldehyde
Ethyl glyoxylate
Ethyl trifluoromethylpyruvate
Allyl bromide
5a (53)
5b (60)
6a (63)
7a (31)
8a (77)
9a (56)
10a (40)
11a (27)
12a (0)
–
–
–
–
7:3
9:1
1:1
1:1
–
2a (38)
2b (20)
2a (24)
2a (52)
2a (14)
2a (16)
2a (52)
2a (28)
2a (50)
a Grignard conditions, see ESI.† b Isolated yields. c From NMR spectra of crude reaction mixtures.
D2O, tandem b-elimination/alkylation reactions could be effected,
resulting in the selective replacement of a C–O bond by a C–C
bond.
of the solvent in the formation of 2 (4 was not detected). The
addition of HMPA, DMPU, or NiI2 to the reaction mixtures did
not improve the yields of the alkylation products, in contrast to the
advantageous effect of these additives for alkylation of samarium
enolates.9
Nitrone 1a, was also converted to products 6a–11a by reaction
with various ketones and aldehydes, including the highly reducible
benzaldehyde and ethyl glyoxylate (Entries 3–8). However, its
reaction with allyl bromide was unsuccessful (entry 9).
When prochiral electrophiles were used, various degrees of
diasteroselectivity were observed. Adduct 9a was obtained from
the reaction of nitrone 1a with benzaldehyde, with excellent
stereoselectivity (dr = 9:1, entry 6). From cyclohexane car-
boxaldehyde, ethyl glyoxylate, or ethyl trifluoromethylpyruvate,
lower diastereoselectivities were observed (dr = 7:3 to 1:1,
entries 5, 7, 8).
In order to investigate this possibility, a solution of nitrone 1a
was treated with 2.2 equiv. SmI2 at -60 ◦C, in the presence of excess
(2.2 equiv.) cyclohexanone (Barbier conditions, see Scheme 4). En-
couragingly, the corresponding alkylated nitrone 5a was obtained
in 61% yield, establishing the validity of the approach. However,
when benzaldehyde was used as the electrophile, its pinacolic
homo-coupling was found to be a major side-reaction (quant.),
and nitrone 1a was recovered unreacted.
Remarkably, in none of these reactions were products arising
from alkylation at C-2 of the nitrones detected, contrasting
with the previously described SmI2-induced reductive coupling
reactions of nitrones with aldehydes and ketones.3 The good
conversions of nitrones 1a,b evidence their high propensity
to undergo reduction by SmI2, and subsequent regioselective
b-elimination. It appears that the other “allylic” benzyloxy group
(at the C-3 position, on the ring) cannot adopt a suitable
orientation for its elimination to proceed. The yields of the
carbonyl-compound-trapping reactions, however, are lowered by
the formation of nitrones 2a,b as byproducts, despite our efforts
to eliminate proton sources from the reaction mixtures.16
In conclusion, a novel type of regioselective alkylation of
nitrones in the presence of SmI2 is presented, which complements
the previously known reactions of nitrones, such as nucleophilic
additions, 1,3-dipolar cycloadditions and reductive coupling
reactions.17 The extension of this aldol-type reaction to other
a-heterosubstituted nitrones and the trapping of different classes
of electrophiles will be useful to delineate the scope and limits of
this reaction.
Scheme 4 SmI2-induced tandem b-elimination/alkylation of nitrone 1a
under Barbier conditions.
To broaden the scope of the process, the reactions were next
conducted under the so-called Grignard conditions: the nitrone
was pre-treated with SmI2 until total disappearence of the starting
material (1.5 h at -60 ◦C or 6 h at -78 ◦C), then the electrophile
was added (Scheme 5, Table 1).15 In these conditions, the reaction
of nitrone 1a with cyclohexanone afforded the expected product
5a in a moderate yield of 53% (entry 1). The related L-sorbose-
derived nitrone 1b, under the same conditions, afforded the
adduct 5b in 60% yield (entry 2). In both cases, the main
side product was nitrone 2a or 2b, respectively, resulting from
undesired protonation of the oxy-enamine intermediates in the
reaction mixtures. When the reaction was performed in d8-THF,
no deuterium incorporation occurred, ruling out the participation
Acknowledgements
This work was supported by the CNRS, the Universite´ Joseph
Fourier and the Agence Nationale pour la Recherche (grant ANR-
05-JCJC-0130-01). E. R. is grateful to the French Ministry of
Education, Research and Technology (MENRT) for a doctoral fel-
lowship. Drs B. Brasme and Y. Gimbert (De´partement de Chimie
Mole´culaire, Grenoble) are thanked for fruitful discussions.
Scheme 5 SmI2-induced reaction of nitrones 1a,b with electrophiles under
Grignard conditions.15
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9 Selected references: (a) G. A. Molander and G. Hahn, J. Org. Chem.,
1986, 51, 1135; (b) E. J. Enholm and S. Jiang, Tetrahedron Lett., 1992,
33, 6069; (c) E. J. Enholm and J. A. Schreier, J. Org. Chem., 1995, 60,
1110; (d) S. Ichikawa, S. Shuto and A. Matsuda, Tetrahedron Lett.,
1998, 39, 4525; (e) J.-L. Zhu, K-S. Shia and H.-J. Liu, Tetrahedron
Lett., 1999, 40, 7055; (f) M. Ricci, P. Blakskjaer and T. Skrydstrup,
J. Am. Chem. Soc., 2000, 122, 12413; (g) F. McKerlie, I. M. Rudkin,
G. Wynne and D. J. Procter, Org. Biomol. Chem., 2005, 3, 2805; (h) A.
Malapelle, Z. Abdallah, G. Doisneau and J.-M. Beau, Angew. Chem.,
Int. Ed., 2006, 45, 6016; (i) K. M. James, N. Willetts and D. J. Procter,
Org. Lett., 2008, 10, 1203.
10 I. M. Rudkin, L. C. Miller and D. J. Procter, Organomet. Chem., 2008,
34, 19.
11 Using only one equivalent of SmI2 led to 45% conversion of nitrone 1
to 2, suggesting that two equivalents of SmI2 are needed to complete
the reaction. In addition, benzyl alcohol was produced (from NMR
analysis of the crude reaction mixture).
Notes and references
1 (a) P. Girard, J.-L. Namy and H. B. Kagan, J. Am. Chem. Soc., 1980,
102, 2693; (b) H. B. Kagan, J.-L. Namy and P. Girard, Tetrahedron
Suppl., 1981, 37, 175.
2 For reviews on the use of SmI2 in organic synthesis, see: (a) G. A.
Molander and C. R. Harris, Chem. Rev., 1996, 96, 307; (b) A. Krief
and A.-M. Laval, Chem. Rev., 1999, 99, 745; (c) D. J. Edmonds, D.
Johnston and D. J. Procter, Chem. Rev., 2004, 104, 3371; (d) H. B.
Kagan, Tetrahedron, 2003, 59, 10351; (e) K. Gopalaiah and H. B.
Kagan, New J. Chem., 2008, 32, 607.
3 (a) G. Masson, S. Py and Y. Valle´e, Angew. Chem., Int. Ed., 2002, 41,
1772; (b) M. Chavarot, M. Rivard, F. Rose-Munch, E. Rose and S. Py,
Chem. Commun., 2004, 2330; (c) G. Masson, C. Philouze and S. Py,
Org. Biomol. Chem., 2005, 3, 2067; (d) O. N. Burchak, C. Philouze, P. Y.
Chavant and S. Py, Org. Lett., 2008, 10, 3021.
4 Y.-W. Zhong, K. Izumi, M.-H. Xu and G.-Q. Lin, Org. Lett., 2004, 6,
3953.
12 See ESI† for ESI-MS and NMR data.
13 (a) J. Reha´k, L. Fisˇera, J. Kozˇ´ısˇek, L. Perasˇ´ınova´, B. Steiner and M.
Koo´s, Arkivoc, 2008, viii, 18; (b) J. Reha´k, L. Fisˇera, G. Podolan, J.
Kozˇ´ısˇek and L. Perasˇ´ınova´, Synlett, 2008, 1260.
14 A. Bøgevig, K. V. Gothelf and K. A. Jørgensen, Chem.–Eur. J., 2002,
8, 5652.
15 Typical procedure: see ESI†.
16 For reproducible results, co-evaporation of the starting nitrone sev-
eral times with toluene, use of THF dried over molecular sieves, and
thorough purge of the reaction media using Schlenk techniques were
essential. Addition of proton sponge to the reaction mixtures did not
improve the yields in alkylation products.
17 For a general review on the chemistry of nitrones see: (a) P. Merino,
Science of Synthesis, 2004, 27, 511. See also: F. Cardona and A. Goti,
Angew. Chem., Int. Ed., 2005, 44, 7832.
5 (a) G. Masson, P. Cividino, S. Py and Y. Valle´e, Angew. Chem., Int.
Ed., 2003, 42, 2265; (b) D. Riber and T. Skrydstrup, Org. Lett., 2003,
5, 229; (c) G. Masson, W. Zeghida, P. Cividino, S. Py and Y. Valle´e,
Synlett, 2003, 10, 1527; (d) S. A. Johannesen, S. Albu, R. G. Hazell and
T. Skrydstrup, Chem. Commun., 2004, 1962; (e) P. Cividino, P. Delair,
S. Py and A. E. Greene, J. Org. Chem., 2007, 72, 485; (f) J. Reha´k, L.
Fisˇera and N. Pro´nayova´, Arkivoc, 2009, vi, 146.
6 For a recent review on enantiopure cyclic nitrones, see: J. Revuelta, S.
Cicchi, A. Goti and A. Brandi, Synthesis, 2007, 485.
7 (a) S. Desvergnes, S. Py and Y. Valle´e, J. Org. Chem., 2005, 70, 1459;
(b) S. Desvergnes, V. Desvergnes, O. R. Martin, K. Itoh, H-w. Liu and
S. Py, Bioorg. Med. Chem., 2007, 15, 6443.
8 E. Racine, C. Bello, S. Gerber-Lemaire, P. Vogel and S. Py, J. Org.
Chem., 2009, 74, 1766.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3385–3387 | 3387
©