Me2Zn as a radical source in Reformatsky-type reactions

Article abstract of DOI:10.1039/b818437b

Experimental evidence for the generation of radicals by Me₂Zn used in Reformatsky reactions was unequivocally established with a radical trap. The Royal Society of Chemistry.

Full text of DOI:10.1039/b818437b

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Me2Zn as a radical source in Reformatsky-type reactions
Elisabetta Mileo,a Fides Benfatti,b Pier Giorgio Cozzi*b and Marco Lucarini*a
Received (in Cambridge, UK) 21st October 2008, Accepted 25th November 2008
First published as an Advance Article on the web 10th December 2008
DOI: 10.1039/b818437b
Experimental evidence for the generation of radicals by Me2Zn
used in Reformatsky reactions was unequivocally established
with a radical trap.
A renewed interest in the classical Reformatsky reaction, from
the point of view of stereoselectivity, has emerged in recent
literature.1 We,2 and Feringa et al.,3 have recently described
catalytic enantioselective Reformatsky reactions of Me2Zn and
iodoacetate, with ketones, aldehydes and imines, in the presence
of catalytic amounts of ClMn(salen) (20 mol%), N-methyle-
phedrine (20–30 mol%) and 3,30-trimethylsilylBINOL (20 mol%)
derivatives as the chiral catalysts. In all these protocols,
Me2Zn was used as a transmetallating reagent with iodo-
Fig. 1 Proposed catalytic cycle for the oxidatively promoted Reformatsky
reactions.
acetate. Although it was reported that the transmetallation
between R2Zn and iodoacetate was feasible, discordant results
were also obtained.4 In these cases the most reactive Et2Zn was
used. Me2Zn was by itself not able to transmetallate with ethyl
iodoacetate, even if it was used in large excess. We have used
air and other oxidants to promote the Reformatsky reac-
tion, in order to favour the transmetallation.2d,5 During
these preliminary studies, both Feringa et al. and ourselves
have suggested that a radical cycle (Fig. 1), established by the
admission of air, or by other oxidants, was responsible
for the effective generation of the Reformatsky reagent, by
formation of methyl radical.2,3
Scheme 1
In recent years there has been an increased interest in
various radical additions initiated by the R2Zn–O2 system,
especially regarding organic substrates which contain donor
sites capable of forming the Lewis acid/base adducts with
R2Zn that are actually involved in the reaction with O2.6
Lewinski and co-workers have shed light on the reaction
´
between Me2Zn and air, showing that the formation of
unstable peroxo species is favoured.7 In this communication,
we present spectroscopic evidence for the presence of radical
intermediates in our and Feringa et al.’s Reformatsky reac-
tions2,3 by trapping the ethoxycarbonylmethyl radical (1) with
phenyl tert-butyl nitrone (PBN), (Scheme 1).
When CH2Cl2 solutions of ethyl iodoacetate (0.08 M) and
PBN in the presence of Zn2Me (0.08M) were analyzed by EPR
spectroscopy, a doublet of triplets was observed (Fig. 2a).
The spectrum was attributed to spin adduct 2, resulting
from addition of radical 1 to PBN (Scheme 1), as suggested by
the value of the spectroscopic parameters (aN = 14.94 G,
aH = 4.63 G, g = 2.0058) which are very close to those
previously reported for the same radical adduct in benzene.8
Fig. 2 EPR spectra of spin adducts 2 (a) and 3 (b) generated from
reaction of Me2Zn and air in the presence (a) and in the absence (b) of
ethyl iodoacetate in CH2Cl2 and PBN as the spin trap at room tempera-
ture (microwave power, 5 mW; modulation frequency, 100 kHz; modula-
tion amplitude, 0.4 G). (c) EPR spectrum of CH2Cl2 solution containing
ethyl iodoacetate and PBN.
a Department of Organic Chemistry ‘‘A. Mangini’’, Via S. Giacomo
11, 40126 Bologna, Italy. E-mail: marco.lucarini@unibo.it
b Department of Chemistry ‘‘G. Ciamician’’, Via Selmi 2, 40126
Bologna, Italy. E-mail: piergiorgio.cozzi@unibo.it
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 469–470 | 469

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Of particular relevance is the relatively high value of the a-
hydrogen coupling in the spin adduct (4.63 G) which has been
attributed to an increase in the spin density on nitrogen, as a
consequence of the stable pentacyclic conformation that can
be adopted by the radical, in which the a-hydrogen is accom-
modated in a pseudoaxial position.8
2006 (research project ‘‘Free Radical Processes in Chemistry and
Biology: Fundamental Aspects and Applications in Environ-
ment and Material Sciences’’). Financial support from the
European Community (CATAFLU.OR project) is acknowl-
edged for a fellowship to F. B.
When the same experiment is repeated in the absence of
ethyl iodoacetate the spectrum due to spin adduct 3, resulting
from addition of methyl radical to PBN, was instead observed
(see Fig. 2b). Again, the EPR signal was assigned to the methyl
Notes and references
1 S. Reformatsky, Ber. Dtsch. Chem. Ges., 1887, 20, 1210. For a
review, see: (a) R. Ocampo and W. R. Dolbier, Jr, Tetrahedron,
2004, 60, 9325; (b) P. G. Cozzi, Angew. Chem., Int. Ed., 2007, 46,
2568.
adduct on the basis of the spectroscopic parameters (aN
=
2 (a) P. G. Cozzi, Angew. Chem., Int. Ed., 2006, 45, 2951;
(b) P. G. Cozzi, Adv. Synth. Catal., 2006, 348, 207;
(c) P. G. Cozzi, A. Mignogna and L. Zoli, Pure Appl. Chem.,
2008, 80, 891; (d) P. G. Cozzi, A. Mignogna and P. Vicennati, Adv.
Synth. Catal., 2008, 350, 975.
15.13 G, aH = 3.38 G, g = 2.0059) which are very close to
those previously reported for the same radical adduct in
benzene.9 This was the only radical species detected by
EPR, indicating that oxygenated radical species are not
significantly formed under this condition. Blank experiments
performed in the absence of Me2Zn gave no EPR signals
(see Fig. 2c).
3 (a) M. A. Ferna
B. L. Feringa, Angew. Chem., Int. Ed., 2008, 47, 1317;
(b) M. A. Fernandez-Ibanez, B. Macia, A. J. Minnaard and
B. L. Feringa, Chem. Commun., 2008, 2571;
(c) M. A. Fernandez-Ibanez, B. Macia, A. J. Minnaard and
B. L. Feringa, Org. Lett., 2008, 10, 4041.
ndez-Ibanez, B. Macia, A. J. Minnaard and
´ ´ ´
´
´
´
´
´
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The above results clearly suggest dimethylzinc and oxygen
can initiate the reaction by releasing a methyl radical that, in
the absence of ethyl iodoacetate and in the presence of PBN, is
preferentially captured by the spin trap. In the presence of the
halogenated compound, the rate of the halogen abstraction by
the methyl radical is so fast10 that the intermediate radical 1 is
instead captured by the spin trap.
4 (a) I. Sato, Y. Takizawa and K. Soai, Bull. Chem. Soc. Jpn., 2000,
73, 2825; (b) K. Maruoka, N. Hirayama and H. Yamamoto,
Polyhedron, 1990, 9, 223.
5 P. G. Cozzi, F. Benfatti, M. G. Capdevila and A. Mignogna,
Chem. Commun., 2008, 3317.
6 For selected recent examples, see: (a) T. Cohen, H. Gibney,
R. Ivanov, E. A.-H. Yeh, I. Marek and D. P. Curran, J. Am.
Chem. Soc., 2007, 129, 15405; (b) F. Cougnon, S. Feray, S. Bazin
and M. P. Bertrand, Tetrahedron, 2007, 63, 11959;
(c) K.-I. Yamada, Y. Yamamoto, M. Maekawa, T. Akindele,
H. Umeki and K. T. Omioka, Org. Lett., 2006, 8, 87; (d) for a
review, see: M. P. Bertrand, S. Feray and C. Gastaldi, Chimia,
2002, 56, 623.
Recently Lewinski et al. pointed out as a basic assumption
´
that in Me2Zn radical mediated reactions, alkyl radicals R
(generated through the oxygenation reaction) act as the chain
carriers. The most effective initiation system involves
Me2Zn,11 which, according to recent findings,7 can be selec-
tively transformed into MeZnOMe by 1,4-diazabutadiene
derivatives without the generation of free methyl radicals.
The transformation of MeZnOOMe induced by the presence
of ligands can be an alternative way to provide radical species
in radical organic reactions promoted by the R2Zn–O2 system.
The present results, however, show that the presence of ligands
is not required to efficiently produce alkyl radicals in Me2Zn
radical mediated reactions.
´
7 J. Lewinski, W. Sliwinski, M. Dranka, I. Justiniak and
´
´
J. Lipkowski, Angew. Chem., Int. Ed., 2006, 45, 4826.
8 L. Julia, M. P. Bosch, S. Rodriguez and A. Guerrero, J. Org.
Chem., 2000, 65, 5098.
9 E. G. Janzen and B. J. Blackburn, J. Am. Chem. Soc., 1968, 90,
5909.
10 A methyl radical is less stable than an alkyl radical in the a position
with respect to the carbonyl as suggested by the corresponding
C–H BDE: 439 kJ molꢁ1 (H–CH3) vs. 400 kJ molꢁ1
(H–CH2C(QO)OEt). Y.-R. Luo, Handbook of Bond Dissociation
Energies in Organic Compounds, CRC Press, Boca Raton, FL,
2003, pp. 11, 67.
To summarize, we report the spin trapping by a nitrone of
alkyl radicals generated from Me2Zn and promoted by air.
Dimethylzinc and oxygen would initiate the reaction by
releasing a methyl radical, which then abstracts an iodine atom
from ethyl iodoacetate to generate radical 1. Although radical
generation with diethylzinc involving halogen abstraction has
already been reported in the literature,12 spectroscopic evidence
for the generation of radical by Me2Zn in the presence of air13
was unequivocally established in Reformatsky reactions by
spectroscopic methodology.
11 J. Lewinski, K. Suwa"a, M. Kubisiak, Z. Ochal, I. Justyniak and
´
J. Lipkowski, Angew. Chem., Int. Ed., 2008, 47, 7888.
12 (a) K. Yamada, H. Fujihara, Y. Yamamoto, Y. Miwa, T. Taga and
K. Tomioka, Org. Lett., 2002, 4, 3509; (b) M. P. Bertrand,
S. Coantic, L. Feray, R. Nouguier and P. Perfetti, Tetrahedron,
2000, 56, 3951; (c) M. P. Bertrand, L. Feray, R. Nouguier and
P. Perfetti, J. Org. Chem., 1999, 64, 9189; (d) M. P. Bertrand,
L. Feray, R. Nouguier and P. Perfetti, Synlett, 1999, 1148;
(e) I. Ryu, F. Araki, S. Minakata and M. Komatsu, Tetrahedron
Lett., 1998, 39, 6335.
13 Spin trapping experiments showing radical generation with diethylzinc
promoted by organic peroxides has already been reported.
(a) V. A. Dodonov and D. F. Grishin, Zh. Obshch. Khim., 1985, 55,
80; (b) M. Rouge, R. Spitz and A. Guyot, J. Chim. Phys. Phys.–Chim.
Biol., 1975, 72, 611.
This work was supported by PRIN 2005 (Progetto Nazionale:
Sintesi e Stereocontrollo di Molecole Organiche per lo Sviluppo
di Metodologie Innovative di Interesse Applicativo) and PRIN
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This journal is The Royal Society of Chemistry 2009
470 | Chem. Commun., 2009, 469–470