A flexible, stereoselective dimethylzinc-mediated radical-anionic cascade: Dramatic influence of additional Lewis acids

Article abstract of DOI:10.1021/ol101519w

Dimethylzinc-mediated addition of acyloxymethyl radicals to diethyl fumarate led to the highly stereoselective formation of disubstituted γ-lactones in mean to good yields; this cascade provides a new example of a one-pot process mediated by dimethylzinc involving a tandem radical-anionic reaction; the chemoselectivity of the reaction was totally modified by additional Lewis acids.

Full text of DOI:10.1021/ol101519w

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3590-3593
A Flexible, Stereoselective
Dimethylzinc-Mediated Radical-Anionic
Cascade: Dramatic Influence of
Additional Lewis Acids
Julien Maury, Laurence Feray,* Patricia Perfetti, and Miche`le P. Bertrand*
Laboratoire Chimie ProVence, UMR 6264, Equipe CMO, case 562, UniVersite´
Aix-Marseille, FST Saint-Je´roˆme, aV. Escadrille Normandie Niemen,
13397 Marseille cedex 20
laurence.feray@uniV-cezanne.fr; michele.bertrand@uniV-cezanne.fr
Received May 27, 2010
ABSTRACT
Dimethylzinc-mediated addition of acyloxymethyl radicals to diethyl fumarate led to the highly stereoselective formation of disubstituted γ-lactones
in mean to good yields; this cascade provides a new example of a one-pot process mediated by dimethylzinc involving a tandem radical-
anionic reaction; the chemoselectivity of the reaction was totally modified by additional Lewis acids.
In the context of tin-free radical methodology development,
our group is currently investigating the synthetic potential
of dialkylzincs as new tools for radical chemistry in aerobic
medium.1 Dialkylzinc-mediated alkyl radical addition to
various acceptors such as CdN double bond,2 CdC activated
double bond,3 and Ct C activated triple bond4 have been
investigated. An interesting feature of dialkylzincs resides
in the possibility they offer to generate nucleophilic species
from an initial radical elementary step and therefore to
(2) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
1999, 64, 9189. (c) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.;
Perfetti, P. Tetrahedron 2000, 56, 3951. (d) Bertrand, M. P.; Feray, L.;
Gastaldi, S. C. R. Chim. 2002, 623.
(3) (a) Bazin, S.; Feray, L.; Naubron, J.-V.; Siri, D.; Bertrand, M. P.
J. Chem. Soc., Chem. Commun. 2002, 2506. (b) Bazin, S.; Feray, L.;
Vanthuyne, N.; Bertrand, M. P. Tetrahedron 2005, 61, 4261. (c) Bazin, S.;
Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P. Tetrahedron 2007, 63,
77.
(1) For a review, see: Bazin, S.; Feray, L.; Bertrand, M. P. Chimia 2006,
60, 260.
10.1021/ol101519w  2010 American Chemical Society
Published on Web 07/28/2010

perform tandem radical-anionic reactions. Domino processes
were devised to prepare in one step trisubstituted γ-lactones
such as racemic nephrosteranic acid3c or R-alkylidene-γ-
lactams.4 Both dimethylzinc and diethylzinc were used; each
reagent presents its own specificity.
Optimization of the reaction of iodomethyl pivalate 1a with
ethyl fumarate (Scheme 1)12 showed that 5 equiv of the
starting iodide were needed to completely avoid the competi-
tive addition of methyl radical. Three equivalents of dim-
ethylzinc were necessary to reach completion, within 18 h
at room temperature. Under these experimental conditions,
disubstituted lactone 2a was isolated in 98% yield.13
The major limitation to the use of the diethylzinc/alkyl
iodide couple as the alkyl radical precursor is the risk of
competitive addition of ethyl radical when the radical
acceptor is highly reactive. Whereas the method can be
chemoselective when using secondary and tertiary alkyl
iodides, it is not suited to the use of primary alkyl radicals
owing to unfavorable enthalpic factors.
Scheme 1
In this respect, even though the oxidation of dimethylzinc
is slow compared to that of diethylzinc,5 the use of
dimethylzinc can be advantageous since methyl radical
(produced during the reaction of dimethylzinc with oxygen)
enables the use of a larger range of radical precursors.6 At
the same time, methyl radical is less reactive than ethyl
radical with regard to most radical acceptors. Dimethylzinc
was used to generate different types of functionalized primary
radicals, including R-alkoxy radicals from methoxymethyl
iodide3c and from ethers.7 Only one example of dimethylzinc-
mediated generation and addition of pivaloyloxymethyl
radical (derived from the corresponding iodide 1a) to
N-tosylphenylimine has been reported in the literature.8,9 The
use of dimethylzinc to generate acyloxymethyl radicals from
the corresponding iodides can be expanded to conjugate
addition.
When the reaction was mediated by diethylzinc, under the
same experimental conditions, the addition of ethyl radical
competed with the addition of acyloxymethyl radical even
when only 1.5 equiv of diethylzinc was used.14 It must be
emphasized that dimethylzinc is the mediator of choice for
this reaction that could not be performed in the presence of
triethylborane.15
As shown in Scheme 2, the acyloxymethyl radical formed
through iodine atom transfer (step 1)16 adds to the activated
double bond (step 2). The resulting R-acyloxy radical
undergoes homolytic substitution at zinc leading to a zinc
enolate (step 3) which evolves via intramolecular acyl
transfer (step 4).17 The resulting zinc alkoxide affords the
We report in this paper a new example of a radical-polar
crossover reaction, that is, dimethylzinc-mediated γ-lactone
synthesis from acyloxymethyl iodides and ethyl fumarate.10
Through a sequence involving successively iodine atom
transfer, radical addition, homolytic substitution at zinc,
intramolecular acyl transfer, and lactonization, disubstituted
trans-γ-lactones 2 were obtained stereoselectively.
Iodomethyl pivalate 1a was prepared from commercially
available chloromethyl pivalate. Iodomethyl esters 1b-e
were prepared in two steps from the corresponding acyl
chloride according to a literature procedure.11
(12) The reaction was tested also with chloromethyl pivalate. No
evolution was observed in this case.
(13) A typical procedure: To a solution of ethyl fumarate (100 mL, 0.61
mmol) 0.3 M in dichloromethane was added at room temperature 5 equiv
of iodomethyl pivalate (1a) (740 mg, 3.05 mmol) under an argon
atmosphere. Dimethylzinc (3 equiv, 1.8 mL, 1 M in heptane) was then added,
whereas air was introduced in the reaction mixture through a syringe pump
(40 mL for 2 h). After being stirred for 18 h at room temperature, the
reaction was quenched with saturated NH4Cl. The layers were separated,
and the aqueous layer was extracted twice with CH2Cl2. The combined
organic phases were dried (MgSO4), filtered, and concentrated in vacuo.
Flash column chromatography on silica gel using pentane/diethyl ether as
eluent afforded 4-(2,2-dimethyl-propionyl)-5-oxo-tetrahydrofuran-3-car-
boxylic acid ethyl ester (2a) in 98% (148 mg, 0,60 mmol, 92:8 mixture of
(4) Feray, L.; Bertrand, M. P. Eur. J. Org. Chem. 2008, 3164.
(5) Seyferth, D. Organometallics 2001, 20, 2940, and references cited
therein.
(6) For a review, see: Akindele, T.; Yamada, K.-I.; Tomioka, K. Acc.
Chem. Res. 2009, 42, 345.
(7) (a) Yamada, K.-I.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga,
T.; Tomioka, K. Org. Lett. 2002, 4, 3509. (b) Yamada, K.-I.; Yamamoto,
Y.; Tomioka, K. Org. Lett. 2003, 5, 1797. (c) Yamamoto, Y.; Maekawa,
M.; Akindele, T.; Yamada, K.-I.; Tomioka, K. Tetrahedron 2005, 61, 379.
(d) Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada, K.-
I.; Tomioka, K. Org. Lett. 2005, 8, 5729. For dimethylzinc-mediated direct
aminoalkylation of cycloalkanes, see: (e) Yamada, K.-I.; Yamamoto, Y.;
Maekawa, M.; Chen, J.; Tomioka, K. Tetrahedron Lett. 2004, 45, 6595.
(8) Yamada, K.-I.; Nakano, M.; Maekawa, M.; Akindele, T.; Tomioka,
1
isomers). H NMR (CDCl3, 300 MHz): d 1.27 (s, 9H), 1.29 (t, J ) 7.2,
3H), 3.85 (dt, J ) 8.7, 7.6, 1H), 4.22 (q, J ) 7.2, 2H), 4.42 (dd, J ) 7.4,
9.1, 1H), 4.5 (d, J ) 7.9, 1H), 4.65 (t, J ) 9.1, 1H). 13C NMR (CDCl3, 75
MHz): d 14.4 (CH3), 26.2 (CH3), 45.2 (CH), 45.8 (C), 49.7 (CH), 62.4
(CH2), 68.2 (CH2), 170.5 (CdO), 171.8 (CdO), 209.0 (CdO). HRMS calcd
for C12H19O5 [MH+]: 243.1227, found 243.1227.
K. Org. Lett. 2008, 10, 3805
.
(14) The adduct of ethyl radical was detected with lactone 2a in a 24:
76 NMR ratio.
(9) In Tomioka’s article, triethylborane was preferred to dimethylzinc
to achieve radical additions of acyloxymethyl radicals derived from 1a and
1b to N-tosylimines; see ref 8.
(15) Reactions were carried out with and without Et2O·BF3. None of
these experiments led to any lactone or lactol, only telomeric material was
1
(10) Acrylic esters are by far less reactive and more sensitive to
polymerization than fumaric esters. They led to polymeric materials or to
moderate yields in oxidized adducts depending on the nature of the Lewis
acid.
(11) (a) Iyer, R. P.; Yu, D.; Ho, N.-H.; Agrawal, S. Synth. Commun.
1995, 25, 2739. (b) Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am.
Chem. Soc. 2001, 123, 8139.
detected from the H NMR spectra of the crude mixture. This result was
not surprizing since R-alkoxycarbonyl radicals are known not to undergo
homolytic substitution at boron, see: Ollivier, C.; Renaud, P. Chem. ReV.
2001, 101, 3415.
(16) The intermediacy of bis(pivaloyloxymethyl)zinc, formed through
zinc-iodine exchange in the first step, can be ruled out since irradiation
was shown to be required to preform this intermediate; see ref 11b.
Org. Lett., Vol. 12, No. 16, 2010
3591

disubstituted γ-lactone through intramolecular nucleophilic
substitution at the ester group (step 5).
Scheme 3
Scheme 2. Proposed Mechanism
isolated in 72% yield. Conversely, iodomethyl p-methoxy-
benzoate 1d led to the expected lactone in only 42% yield.
When the reaction was conducted with iodide 1e, the desired
lactone was also formed in modest yield.19
It is to be noted that all the reactions were highly
stereoselective and led to trans lactones 2b-f.20 The presence
of trace amounts of the cis diastereomers could only be
suspected from the proton NMR spectra of the crude
mixtures; none could be isolated or fully characterized.21
Scheme 4
The formation of a seven-membered chelated enolate that
fixes the ethoxycarbonyl substituant in the axial position is
likely to explain the trans stereoselectivity of the reaction
(Scheme 2).18 Additional activation of the acyl transfer upon
zinc tetracoordination can also be envisaged. Moreover, the
carbon atom in R position relative to the two carbonyl groups
is highly epimerizable, and deprotonation by zinc alkoxides
formed in the reaction medium could not be ruled out at
this stage.
This mechanism was supported by the experiment con-
ducted on diethyl fumarate in the presence of 5 equiv of
iodoester 3 and 3 equiv of dimethylzinc that led to cyclo-
pentanone 4 via Dieckmann cyclization. Ketone 4 was
isolated in 45% yield as a single stereoisomer that we
assumed to be trans (Scheme 3).
Iodomethyl benzoates 1b-d proved also to be good radical
precursors provided that the substituent on the aromatic group
was electron-withdrawing (Scheme 1). The presence of the
fluorine atom on the aromatic ring in 1c enhances the
electrophilicity of the carbonyl group and favors the transfer
of the acyl group in step 4 (Scheme 2). Lactone 2c was
The introduction of a stronger Lewis acid, i.e., BF3·OEt2,
with the prospect of activating the acyl group transfer, and
consequently to increase the yield in lactone 2, resulted in a
(19) In this case, the adduct of R-acyloxy radical, resulting from the
hydrolysis of the corresponding zinc enolate intermediate before the acyl
group transfer has occurred, was isolated in a 1:1 ratio with 2e while the
starting material was recovered in 30% yield.
(20) In order to determine which stereoisomer of the lactone 2 was
formed during the process, epimerization reactions were conducted on
lactones 2c and 2e in the presence of 1.2 equiv of DBU in DMF (0.1 M).
After one night, no evolution was observed in both cases. This strongly
suggested that the starting lactones were already in the most stable trans
configuration. In addition, the coupling constants between H2 and H3 in
lactones 2b-e were close to 6.8 Hz, and this is in agreement with a trans
relationship, see: (a) Yamauchi, S.; Sugahara, T.; Nakashima, Y.; Okada,
A.; Akiyama, K.; Kishida, T.; Maruyama, M.; Masuda, T. Biosci. Biotechnol.
Biochem. 2006, 70, 1934. (b) Bennett, S. A.; Rickards, R. W. Tetrahedron
Lett. 2003, 44, 6927.
(17) A mechanism involving intramolecular acyl group transfer has been
proposed recently for the bis(iodozincio)methane mediated 1,3-diketone
synthesis, see: Sada, M.; Matsubara, S. J. Am. Chem. Soc. 2010, 132, 432.
(18) Such an intermediate has already been proposed to explain the
formation of the major stereoisomer in diethylzinc-mediated radical-polar
cascade leading to trisubstituted lactones; see ref 3b,c. For their involvement
in the syn selective aldol consensation of zinc enolates, see also: Lai, S.;
Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J. Org. Lett. 2001,
3, 4169.
(21) The presence in trace amount of the cis isomer could not be
ascertained. A doublet (J ) 8-9 Hz) was detected in the proton NMR
spectra of the crude mixtures. However, no evolution of the spectra was
observed when either 2c or 2e was treated with DBU.
3592
Org. Lett., Vol. 12, No. 16, 2010

complete change in the chemoselectivity of the reaction. It
may be envisaged that BF3 inhibits the chelation of the
ethoxycarbonyl group which adopts preferentially an equato-
rial position in the transition state of the acyl group transfer.
In such a situation, severe steric interactions in the eclipsed
conformation prevent the formation of the cis-lactone, and
only lactol 5e was detected in the crude mixture instead. The
absence of any trans-2e in the crude mixture, which also
contains zinc alkoxides in excess, argues against the zinc
alkoxide promoted formation of the latter through epimer-
ization of any cis-2e.
Lactol 5e was isolated in 60% yield after purification on
silica gel (Scheme 4).22 Treating the crude mixture with DBU
did not lead to any epimerization susceptible to induce the
formation of lactone 2e. The only product was dihydrofuran
6e, isolated in 64% yield (Scheme 5).
Scheme 6
Scheme 7
Scheme 5
In conclusion, this paper describes a new tandem radical-
anionic reaction mediated by dimethylzinc. The use of
iodomethyl esters as radical precursors was extended to
fumaric ester radical acceptors. The reaction resulted in a
straightforward stereoselective synthesis of trans 2,3-disub-
stituted γ-lactones. The addition of monodentate or poly-
dentate Lewis acids resulted in a dramatic change in the
chemoselectivity of the reaction.
An improved experimental protocol in which both hy-
drolysis and dehydration were achieved during workup is
described in Scheme 6; 6b was directly isolated in 68% yield.
The outcome of the reaction was changed upon addition
of 1.2 equiv of Yb(OTf)3. In this case, the acyl group transfer
was suppressed, and only the adduct of acyloxymethyl radical
was isolated in 72% yield from 1e (Scheme 7).
Acknowledgment. We gratefully acknowledge the ANR
(D2R2; ANR-09-JCJC-0081) for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) During purification on silica gel, lactol 5e was partially dehydrated
and degraded. Therefore, the signals of impurities appeared in the
corresponding NMR spectra. This is the reason why complete transformation
into 6e was preferred before purification.
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