Free radicals and Lewis acid. Chelation-controlled radical allylations of substituted α-halo- or α- phenylseleno-β-alkoxy esters. The endocyclic effect

Article abstract of DOI:10.1139/v00-074

The radical allylation of a series of (α-halo or (α-phenylseleno-β-alkoxy esters in the presence of MgBr₂·OEt₂ is reported and compared with analogous reactions under non-chelating conditions. The addition of MgBr₂·OEt

Full text of DOI:10.1139/v00-074

852
Free radicals and Lewis acid. Chelation-controlled
radical allylations of substituted α -halo- or α -
phenylseleno-β-alkoxy esters. The endocyclic
effect.
B. Guérin, C. Chabot, N. Mackintosh, W.W. Ogilvie, and Y. Guindon
Abstract: The radical allylation of a series of α-halo or α-phenylseleno-β -alkoxy esters in the presence of MgBr2·OEt2
is reported and compared with analogous reactions under non-chelating conditions. The addition of MgBr2·OEt2 gives
excellent selectivity favoring anti products; in some cases ratios >100:1 are obtained. Varying the substrate substituents
reveals that these reactions are quite tolerant of alkyl functionalities at the β -position. Changes to the alkoxy function
indicate that a chelate is involved in the reaction. The reactions are successful with secondary iodides, bromides, and
phenylselenides, as well as tertiary iodides, which all give very high ratios under chelation control. Performing less
well under the same conditions are substrates with a radical exocyclic to a tetrahydrofuran ring. EDTA titration is used
to determine the amount of Mg2+ dissolved in the allylation reaction mixture, and 13C NMR is employed to better de-
fine the nature of the complex formed (chelate or monodentate) prior to the reaction. Competition experiments suggest
that the chelate and monodentate pathways are in competition for the radical allylation with allyltributyltin.
Key words: allylation, radicals, Lewis acid, stereoselectivity, 1,2-induction.
Résumé : Les allylations radicalaires, pour une série d’esters α-halo or phenylseleno-β -alkoxylés, en présence de
MgBr2·OEt2, sont rapportées et comparées aux réactions analogues sans acide de Lewis. L’addition de MgBr2·OEt2 con-
duit à une excellente sélectivité en faveur des produits anti, pour certains cas, des ratios >100:1 ont été obtenus. Les
variations des substituants sur les substrats montrent que ces réactions tolèrent une variété de fonctions alkyles en posi-
tion β . Les changements de la fonction alkoxy suggèrent qu’un chelate est impliqué lors de la réaction. Les allylations
fonctionnent bien avec les iodures, les bromures ainsi qu’avec les phénylsélenures secondaires. Les iodures tertiaires
donnent des ratios très élevés en présence d’acide de Lewis. Les substrats générant un radical exocyclique à un cycle
tetrahydrofurane donnent de moins bons résultats sous ces conditions. Le titrage à l’EDTA a été utilisé pour déterminer
la quantité de Mg2+ dissous dans le mélange réactionnel lors de l’allylation, et les données RMN 13C ont été utilisées
pour mieux définir la nature des complexes formés (chelate ou monodentate) avant la réaction. Les expériences de
compétition suggèrent que les deux chemins réactionnels, chelate et monodentate, sont en compétition pour l’allylation
radicalaire avec l’allyle d’étain.
Mots clés : allylation, radicaux, acide de Lewis, stéréoselectivité, induction-1,2. Guérin et al. 867
1. Introduction
tions has been expanded by using mono (5) or bidentate
Lewis acids (6, 7), solvent complexation (8), and intramole-
cular hydrogen bonding (9). Additionally, reagent control
approaches employing chiral Lewis acid or chiral tin hydride
have been recently devised (10).
We have been particularly interested in studying the reac-
tivity of radicals flanked by an ester and a stereogenic center
bearing a heteroatom in reactions involving hydrogen-atom
This decade (1) has shown that free radical based reac-
tions could be useful synthetic approaches for making acy-
clic molecules with high levels of diastereoselectivity and
enantioselectivity. Significant levels of stereocontrol have
been achieved in strategies involving pre-existing chiral cen-
ters (2, 3) or chiral auxiliaries (4). The scope of these reac-
Received December 6, 1999. Accepted March 28, 2000. Published on the NRC Research Press Website on June 13, 2000.
This article is dedicated to Professor Stephen Hanessian on the occasion of his 65th birthday. It is an accolade to my mentor,
colleague, and friend, written in celebration of his many years of scientific achievement and the many more to come.
B. Guérin and Y. Guindon.1,2 Institut de recherches cliniques de Montréal (IRCM), Bio-organic Chemistry Laboratory, 110,
avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
C. Chabot, N. Mackintosh, and W.W. Ogilvie. Bio-Méga/Boehringer Ingelheim Research, Inc., 2100 rue Cunard, Laval, QC H7S
2G5, Canada.
1Also at: Department of Pharmacology and Department of Chemistry, Université de Montréal, Montréal, QC H3C 3J7, Canada.
2Author to whom correspondence may be addressed. Telephone: (514) 987–5785. Fax: (514) 987–5789.
e-mail: guindoy@ircm.qc.ca.
Can. J. Chem. 78: 852–867 (2000)
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Guérin et al.
Table 1. Preparation of substrates 9–21 by alkoxy-etherification.
853
Entry
olefin
R1
X2
R2
R3
Substrate
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
3
4
4
4
4
5c
5c
5c
6
7
8
Me
i-Pr
c-C6H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
I2
I2
I2
I2
H
H
H
H
H
H
H
I
Br
PhSe
Me
Me
Me
I
I
I
I
9
10
11
12
13a
14
15
16
17
18
19
20d
21d
60
38
45
78
61
70
90
77
78
93
66
81
42
I2
I
Br
PhSe
H
H
H
I
I
I
Br2
PhSeBrb
I2
Br2
PhSeBrb
I2
I2
I2
Ph
Me
Et
aBenzylalcohol was used to give the β-benzyloxy-α-iodo-ester.
bPhSeBr was used with AgOTf.
cMethyl-Z-cinnamate was used to give syn substrate.
dEthyl ester was used.
repulsion (3) and hyperconjugative stabilization (3e). Thus,
the syn isomer is the major compound obtained when such a
radical intermediate, originating from the homolytic extru-
sion of a phenylseleno ether or a halogen, is reacted with
allyltributyltin.
Scheme 1. (a) In absence of MgBr2·OEt2; (b) In presence of
MgBr2·OEt2.
In response to this finding, our group hypothesized that a
bidentate Lewis acid could, through complexation with the
oxygen of the stereogenic center and the carbonyl of the es-
ter, reposition the R1 group onto the opposite face of the rad-
ical, thus allowing for a preferred attack on the top side
leading to the anti product (Scheme 1b, transition state B).
Our previous work in hydrogen-atom transfer reactions (7a, e)
had shown that this approach could be feasible. Those find-
ings inspired studies to show that the facial selectivity of a
radical based allylation could be inverted (from syn to anti)
through the simple expedient of adding MgBr2·OEt2 to the
reaction mixture (7b). This strategy was further shown by
both our group (7c) and Porter’s group (11) to be successful
in atom transfer reactions. Reported now are the full experi-
mental details of chelation-controlled allylations of β-alkoxy
esters, including studies on the importance of the
stereochemistry of the starting material in such radical pro-
cesses and on the possible formation of bidentate intermedi-
ates. Preliminary experiments that explain the need for an
excess of MgBr2·OEt2 in the reaction and that elucidate fur-
ther mechanistic details will also be presented.
transfer (3), additions to olefins (7e), cyclizations (3f), and
allylation reactions (3b, 3g, 7b). Our first studies dealing
with the induction of new chiral centers on acyclic mole-
cules, using free radical chemistry, spawned from unex-
pected experimental results. The realization that the
planarity of radicals adjacent to an ester or amide group
might resemble Z-enolates led to the hypothesis that allylic
1,3-strain (1a, 2c) could be one of the factors controlling
stereoselectivity. The stereochemical outcome of the
allylation reaction has been best rationalized by transition
state A (Scheme 1a) (1, 2, 3, 4), which takes into account al-
lylic 1,3-strain and electronic factors such as dipole–dipole
2. Preparation of materials and standards
Secondary and tertiary iodides 9–13, 16, 19–21, and bro-
mides 14 and 17, were prepared, by halo-etherification reac-
tion, from the corresponding olefins 1–8 as shown in Table 1
(12, 13). Phenylselenides 15 and 18 were synthesized using
a modification of the same method wherein AgOTf, a solu-
ble silver salt, was used in place of AgNO3. Syn substrates
16–18 were prepared from the appropriate Z olefin using
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Can. J. Chem. Vol. 78, 2000
Scheme 2. (a) DIBAL-H, CH2Cl2, –78°C; (b) Ph3=C(R)CO2Me
(ethyl ester was used when R=Me), PhCO2H, THF, reflux; (c) I2,
NaHCO3, THF, 25°C; (d) m-CPBA, Et2O, H2O, 0 to 25°C;
(e) TBSOTf, CH2Cl2, 2,6-lutidine, 0°C.
has been shown (vide infra) to require the presence of an
excess of MgBr2·OEt2. In the absence of MgBr2·OEt2, sub-
strate 9 showed a preference for the syn product, but poor
selectivity was observed (entry 2). Other acyclic secondary
iodides performed well under chelation-controlled condi-
tions, affording anti isomers with excellent diastereofacial
selectivity (entries 3, 5, 7). These substrates displayed a
preference for the syn adduct in the absence of MgBr2·OEt2
(entries 4, 6, 8). A greater selectivity was observed for sub-
strate 12 when the reaction was conducted in toluene at
–78°C (entry 8 versus 9).
Modifications to the β-alkoxy group (X) and their effects
on the allylation reactions are shown in entries 7–15. Re-
placement of the methoxy group by a benzyloxy ether led to
an erosion of anti diastereoselectivity under chelation-con-
trolled conditions (entries 7 and 10). When the methoxy
group was replaced by a silyl ether, the Lewis acid lost its
influence in controlling the stereochemical outcome (entries
7, 8, 12–15). Generally, the steric congestion offered by the
larger silyl groups (relative to Me) should preclude chelation
of the oxygen with Lewis acid (19). As was hypothesized at
the onset of this study, these results strongly suggest that the
formation of cyclic intermediates, through MgBr2·OEt2
complexation with the oxygens of the alkoxy and the car-
bonyl functions, is required in order to obtain anti adducts in
this series of molecules.
In addition to anti iodide 12, anti bromide 14 and anti
phenylselenide 15 were also transformed into their corre-
sponding allyl derivatives with excellent selectivity and yield
when MgBr2·OEt2 was present (entries 7, 16, and 18). For
each substrate, the anti isomer was formed preferentially to
the extent of 38:1, 19:1, and 65:1, respectively. Under the
same conditions, syn iodide 16 led to reduced levels of
diastereoselectivity and gave a 5:1 ratio in favor of the anti
product (entry 20). By contrast, ratios greater than 20:1 were
observed for syn bromide 17 and syn phenylselenide 18 (en-
tries 22 and 24). Without Lewis acid, the allylation reactions
favored the syn isomer (entries 8, 17, 19, 21, 23, and 25) in a
consistent ratio of approximately 5:1. One should note that
the presence of Lewis acid usually reverses the facial bias
and is accompanied by a significant increase in diastereo-
selectivity (entries 7, 16, and 18 versus 8, 17, and 19, re-
spectively).
procedures analogous to those of the corresponding anti sub-
strate (12). Silyl ethers 24–26 were readily derivated from
the secondary alcohols (14) as described previously
(Scheme 2) (15). Tetrahydrofurans 27–28 and tetrahydropyrans
29–30 were prepared in three steps as outlined in Scheme 2
(3d, 7c). DIBAL reduction of γ-butyrolatone or δ-valero-
lactone followed by Wittig olefination of the resultant lactols
afforded the corresponding α ,β-unsaturated esters. Cycli-
zation of the olefins under kinetic conditions (I2, NaHCO3,
THF, 25°C) (16) produced the expected iodoesters. Tetrahy-
drofurans 31 and 32 (17) were prepared by treating
dihydrofuran with m-CPBA (H2O–Et2O, 82%) to give the
hemiacetal that was then subjected to Ph3P=C(R)CO2Et
(THF, reflux). An iodocyclization reaction was done on the
resulting compound. Protection of alcohols 31 and 32 (t-
BuMe2SiOTf, CH2Cl2, 2,6-lutidine, 0°C) gave either 33 or
34 (Scheme 2).
The relative configurations of the allylated products were
established by independent synthesis and correlation of the
NMR spectra (7c). In every case, the difference in chemical
shift between the NMR resonances of the methylene protons
in the allyl side chain (∆υ) for the anti diastereoisomers was
greater than the ∆υ values for the syn diastereoisomers. The
chemical shifts of the resonances of the same hydrogens in
the anti series were also consistently upfield to the reso-
nances of the corresponding syn counterparts (18).
Tertiary iodides displayed excellent diastereoselectivity in
chelation-controlled allylations (entries 26, 28, and 30).
Since asymmetric quaternary centers are difficult to form,
these reactions clearly have interesting synthetic utility (20).
Compared to the secondary iodides, the tertiary iodides in
the absence of MgBr2·OEt2 showed lower reactivity3 but
slightly higher diastereoselectivity favoring the syn product
(entries 2, 4, 6, and 8 versus 27, 29, and 31).
Assuming that the cyclic intermediate bearing a carbon-
based radical was at the origin of the anti diastereoselectivity
noted for the chelation-controlled allylation (the endocyclic
effect) (Scheme 1b), we were anxious to evaluate the effect
of a ring adjacent to the radical. Indeed, a bicyclic interme-
diate had to then be considered in this scenario.
3. The radical-mediated allylations of α -
halo- or α -phenylseleno-β-alkoxy esters
Treating a solution of 3-methyl-3-methoxy-2-iodopropionate
9 with allyltributyltin and 3 equivalents of MgBr2·OEt2 gave
a mixture of adducts in a 51:1 ratio favoring the anti product
(Table 2, entry 1). Achieving interesting diastereoselectivity
Table 3 lists some preliminary results from this study.
Note that entries 1 and 3 indicate a lower preference for the
3 The lower reactivity is reflected by longer reaction times, even when conducted in hexanes at reflux.
© 2000 NRC Canada

Guérin et al.
Table 2. Radical allylation of various substrates under chelation and non-chelation control.
855
aA:2.0 equiv of allylSnBu3, 3.0 equiv of MgBr2·OEt2, 0.2 equiv of Et3B, CH2Cl2, –78°C. B:2.0 equiv of allylSnBu3, 0.2 equiv of AIBN,
hexanes, reflux.
b2.0 equiv of allylSnBu3, 0.2 equiv of Et3B, CH2Cl2, –78°C.
c2.0 equiv of allylSnBu3, 0.2 equiv of Et3B, toluene, –78°C.
dEthyl ester was used.
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856
Can. J. Chem. Vol. 78, 2000
Table 3. Radical allylation of tetrahydrofuran and tetrahydropyran derivatives under chelation and non-chelation control.
aA:2.0 equiv of allylSnBu3, 3.0 equiv of MgBr2·OEt2, 0.2 equiv of Et3B, CH2Cl2, –78°C. B:2.0 equiv of allylSnBu3, 0.2 equiv of AIBN,
hexanes, reflux.
anti product when the carbon bearing the radical was adja-
cent to a tetrahydrofuran (THF) ring and when MgBr2·OEt2
was present. This trend is magnified in the tertiary iodide se-
ries (entries 1 and 3 versus 5 and 7), where a 7:1 ratio
favoring the anti isomer was the best selectivity obtained. In
contrast, substrates bearing a tetrahydropyran (THP) ring α
to the radical gave excellent diastereoselectivity under
chelation-controlled conditions (entries 9 and 11). From the
THF and THP substrates, syn isomers were obtained in good
ratios in the absence of Lewis acid, considering that the re-
actions were performed in hexanes at reflux (entries 2, 4, 6,
8, 10, and 12). The bicyclic intermediate chelate with two 6-
membered rings was clearly more efficient in inducing anti
diastereoselectivity than the bicyclic intermediate with one
5- and one 6-membered ring.
iodide 12, gave ratios of 1.6:1, 7:1, and 38:1, respectively;
however, no increase in ratio was noted with 5 equivalents
of MgBr2·OEt2 (see entry 4). The results were surprising be-
cause the subequimolar amount of MgBr2·OEt2 was accom-
panied by insoluble material in the reaction medium. We
had, of course, expected that one equimolar amount of
Lewis acid would be sufficient for the chelation (vide infra),
but our assumption had not taken into account the possibility
of other competing intermediates.
To shed some light on the above results, we decided to de-
termine the amount of Mg2+ actually present in the reaction
mixture. The first step in doing so was to allow the Lewis
acid to equilibrate at –78°C in the presence of iodide 12
(5 mL of 0.1 M solution) and allyltributyltin. After 10 min,
3 mL of the solution was filtered and analyzed for magne-
sium content by EDTA titration (21). Et3B was added to the
remaining solution to measure allylation efficacy and
diastereoselectivity.
The amount of Mg2+ dissolved in solution increased con-
comitantly with the amount of MgBr2·OEt2 introduced at the
beginning of the reaction (entries 1, 2, and 3). A maximum
of 1.6 equivalents of dissolved Mg2+ was reached in the
reaction containing 3 equivalents of MgBr2·OEt2 (entry 3).
Concurrently, the anti:syn ratio of the allylated products
steadily increased, giving a maximum selectivity of 38:1
4. The role of MgBr2·OEt2. Determination of
the amount of Mg2+ present in the allylation
reaction by EDTA titration
With conditions for the chelation-controlled allylation op-
timized, we turned our attention to the problem of why an
excess of MgBr2·OEt2 (3 equivalents) was needed to maxi-
mize diastereoselectivity. Table 4 (entries 1–3) shows that
0.25, 1, and 3 equivalents of MgBr2·OEt2, complexed with
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Guérin et al.
857
Table 4. Determination of the amount of magnesium dissolved in allylation reaction mixtures by filtration and
EDTA titration.
aEquivalents of MgBr2·OEt2 relative to the amount of substrate.
bEquivalents of Mg2+ measured relative to the amount of substrate.
cExperiment run under identical conditions relative to reactions with substrate present.
when the 3 equivalents of MgBr2·OEt2 were used. More than
3 equivalents of MgBr2·OEt2 did not increase further either
the amount of Mg2+ in solution or the allylation ratio (entry
4).
tion but much less impressive diastereoselectivity, as already
noted (entry 6).
One equivalent of Mg2+ was found for silyl compound de-
rivative 25 in the presence of MgBr2·OEt2 compared to 0.25
equivalent without the substrate (entry 7 versus 1). There-
fore, around 0.7 equivalent was brought in solution by the
substrate. Qualitatively, this result is not so surprising. The
Lewis acid can easily form a monodentate complex with
substrate 25 since the latter presents a Lewis base function-
ality, the ester.
In the absence of the substrate, the solubility of Mg2+ in
CH2Cl2 at –78°C, relative to the amount of substrate nor-
mally used, was found to be 0.25 equivalent (entry 5). Note
that the number of equivalents reported is always relative to
the number of mmoles of substrate normally used. From the
above results can be concluded that the intrinsic solubility of
MgBr2·OEt2 in CH2Cl2 is low and that the substrate brings
into solution an additional equivalent of Mg2+, suggesting a
strong interaction between the substrate and the Lewis acid.
Note that there is a ca 30% excess of the added MgBr2·OEt2
that does not go into solution (entries 1 and 2), and that this
amount in suspension can vary depending on the source of
Lewis acid.4 However, the ratio being the same with or with-
out filtration strongly indicates that the insoluble materials
have no effect on the outcome of the reactions.
Similarly, THF derivative 27 (entry 8) and silyl compound
25 (entry 7), which formed a monodentate complex, ex-
tracted almost the same amount of Mg2+. This contrasts the
result for THP 29, which brought into solution 1.85 equiva-
lents of Mg2+ (entry 9). This is as much as methyl ether 12,
the bidentate chelate, brought. One has to remember that
THF derivative 27 gave a much poorer ratio in favor of the
anti product than THP derivative 29 afforded (entries 8 ver-
sus 9).
This experimental protocol was repeated for syn isomer
16, which gave the same amount of Mg2+ dissolved in solu-
These measurements of Mg2+ dissolved in solution indi-
cate that an equimolar complex with MgBr2·OEt2 is formed
4 The material in suspension could be less soluble magnesium salts.
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Can. J. Chem. Vol. 78, 2000
Table 5. H and 13C data of MgBr2·OEt2 in CD2Cl2 at –23 and 23°C in the presence and absence of 12.
1
Entry
Mixture
Temperature
(°C)
δ CH2CH3 (ppm)
δ CH2CH3 (ppm)
1H
13C
1H
13C
1
2
3
4
5
6
12 + MgBr2·OEt2
MgBr2·OEt2
OEt2
12 + MgBr2·OEt2
MgBr2·OEt2
OEt2
–23
–23
–23
23
23
23
3.97
3.90
3.40
3.89
3.80
3.44
66.1
66.4
65.9
66.7
66.7
66.1
1.30
1.29
1.12
1.31
1.29
1.15
14.0
14.2
15.3
14.8
14.8
15.5
Table 6. 13C data of β -alkoxyesters in presence of saturating
amount of MgBr2·OEt2 in CD2Cl2 at –23°C.
with iodides 12 and 29, which suggests a chelation. Such a
condition seems to be essential for achieving good anti
diastereoselection in this series of substrates. However, it
may not be a sufficient condition, considering the modest
diastereoselectivity noted for syn iodide 16. This realization
1
led us to another set of experiments, but this time using H
and 13C NMR studies.
5. NMR studies of MgBr2·OEt2 complexes
The first consideration for this study was whether or not
diethyl ether was present as a ligand on magnesium. Table 5
1
shows the H and 13C chemical shifts of diethyl ether mea-
sured alone (entries 3 and 6), in solution as part of the
MgBr2·OEt2 (entries 2 and 5), or in chelate form using io-
dide 12 (entries 1 and 4). The latter two results being the
same indicates that most if not all of the diethyl ether is still
attached to the magnesium following the formation of com-
plexes with 12, regardless of temperature (entries 1–2, 4–5).
Previous studies done by Eliel (22), on chelates as inter-
mediates in nucleophilic additions to α- and β-alkoxy ke-
tones, have suggested that a strong chelation is consistent
with a greater extent of change in the 13C chemical shift of
the carbonyl. Table 6 presents comparable NMR studies that
consider various substrates in the presence of 3 equivalents
of MgBr2·OEt2.
As seen in entry 1, the carbonyl signal of the ester for
silyl ether 25 shifted only slightly downfield (2.7 ppm) when
Lewis acid was present in the reaction, suggesting a prefer-
ence for the formation of a monodentate complex with the
ester. The difference in carbonyl chemical shift was signifi-
cantly higher for methyl ether 12 (7.5 ppm), which is consis-
tent with chelation (entry 2). The magnitude of these shifts
concurs with Eliel’s results (22).
Syn iodide 16 gave a shift of 4.8 ppm. As already shown
by the solubility experiments, syn iodide 16 formed a com-
plex with MgBr2·OEt2 strong enough to bring into solution
an amount of Lewis acid equivalent to that obtained from
anti iodide 12 (Table 4, entry 6 versus 3). Yet, the 13C data
suggests that the syn iodide chelate should be qualitatively
less strong than the one formed by the anti iodide (4.8 ver-
sus 7.5, Table 6, entries 2–3).5 This would be consistent with
the lower stereocontrol observed for 16 in chelation-
controlled radical allylations.
aChemical shift of substrate with 3 equiv of MgBr2·OEt2 – chemical
shift of substrate.
bSee Table 1.
addition of MgBr2·OEt2 (entries 4–6) that correlate with
strong chelation and high selectivity in the allylation. It
would seem that the greater the carbonyl signal shift, the
greater the anti preference; but this statement would need to
be validated by additional experiments.
So far, the solubility experiments have shown that both
monodentate and bidentate species bring Mg2+ in solution.
The NMR studies have facilitated the ability to differentiate
Anti phenylselenide 15, as well as bromides 14 and 17,
showed large displacements of the carbonyl signal upon the
5 The study of the THF derivative 27 and the THP derivative 29 under the same conditions did not give spectra of sufficient quality to be
used in this study.
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Guérin et al.
859
Table 7. Competition experiments.
a0.5 equiv of allylSnBu3, 0.5 equiv of substrates A and B.
breaction was performed with Bu3SnH, see ref 7e.
between these species prior to the reaction. Remaining to be
determined is whether or not the species participate competi-
tively in the establishment of the final product distribution
resulting from the allylation reaction. Preliminary experi-
ments involving competition reactions have been designed
to shed some light in this regard. (Vide infra.)
equivalent of allyltributyltin was used to obtain 50%
conversion to the allylated products. NMR spectra of the
crude reaction isolates were recorded to determine the rela-
tive conversion of each reactant. The results of these experi-
ments are summarized in Table 7.
As seen in entry 1, a 1:1.8 ratio of unreacted methyl ether
12 to unreacted silyl ether 25 was noted, indicating that the
methyl ether reacted faster than the silyl ether in the absence
of Lewis acid. Similar results were obtained when
MgBr2·OEt2 was present in the reaction mixture (entry 2).
For the analogous bromide series, the consumption of
methyl ether 14 (bidentate) was found to be slightly higher
than that of silyl ether 26 (monodentate) in the presence of
6. Competition reactions
All of the competition experiments were performed with
two substrates of equimolar amounts, which were dissolved
in CH2Cl2 together with allyltributyltin in either the absence
or presence of MgBr2·OEt2 (3 equivalents). Only half an
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860
Can. J. Chem. Vol. 78, 2000
MgBr2·OEt2 (entry 4). In the control experiment (entry 3),
performed in the absence of Lewis acid, species 14 and 26
reacted at the same rate.
monodentate complex form. Both C and D are syn predic-
tive transition states.
The rate of halogen abstraction by an electropositive tin
radical should be enhanced by the presence of an adjacent
electron-withdrawing group, such as an ester. A more
electrophilic ester, obtained via coordination with a Lewis
acid, should further facilitate the abstraction rate. The rate of
addition should also be improved by the reaction of a more
electrophilic radical with an electron rich double bond, such
as the one on the allyltributyltin. Therefore, transition state
E should be of lower energy than C. Indeed, allylation was
apparently faster with MgBr2·OEt2 in the parallel reactions
performed for the competition experiments.
One should note that transition states D and E both bene-
fit from activation by the Lewis acid. The fact that the
methoxy and silyloxy derivatives reacted at comparable rates
in competitive experiments suggests the possibility that the
monodentate acyclic pathway could actually be as rapid as,
and therefore an alternative to, the cyclic pathway. As de-
picted in Scheme 3, a potential equilibrium could exist be-
tween 74 and 75 (or 70 and 71). After all, these species
differ by only a simple folding of the substrate molecule. If
such equilibrium were to exist, the difference in energy be-
tween transition states D and E would likely dictate the out-
come of the reaction.
The comparable reaction rates of the silyloxy and
methoxy derivatives suggest that transition states D and E
are of similar energy in the allylation. This result contrasts
that of competition experiments involving hydrogen-atom trans-
fer reactions, which showed the monodentate pathway to be
favored over the bidentate (7e), indicating that a transition
state similar to D would be lower in energy than a transition
state analogous to E when tributyltin hydride is involved. It
should be noted that the major product obtained originated,
in both cases, from the attack on the top face of the radical
(transition state E) in the presence of MgBr2·OEt2.
It should be remembered that significant levels of selectiv-
ity and differences in ratios, depending upon the stereo-
chemistry of the halides and selenides (precursors to the
same radical), were noted for the allylation reactions (vide
supra). These results, along with those obtained from com-
petition experiments, are more consistent with the equilib-
rium between 74 and 75 being rather slow, which suggests
that the reactions are dependent upon the pre-existing mix-
ture of complexes 70, 71, and 72.
Next, the relative stereochemistry of bromides, selenides,
and iodides was examined. In the presence of Lewis acid,
anti and syn bromides 14 and 17 reacted at the same rate, as
did the corresponding selenides 15 and 18 (entries 6 and 8).
Syn iodide 16 reacted faster than anti iodide 12 both in the
presence and absence of Lewis acid (entries 9 and 10). Nota-
bly, both syn selenide 18 and syn iodide 166 reacted faster
than their anti counterparts in the control experiments (en-
tries 7 and 9). This result is without explanation at this time.
Two reactions were then done in parallel with anti
silyloxy iodide 25 under standard conditions. The sole vari-
able was MgBr2·OEt2, which was present in only one of the
reactions. Comparable yields of allylated products (80%)
were repeatedly obtained; however, the time to complete the
reaction was shorter when Lewis acid was present.
Apparent from these studies is that the chelate intermedi-
ate, proposed in the case of the methyl ethers, does not have
a significant advantage from a reactivity standpoint over the
silyl ethers, which reacted only as monodentate complexes
or free substrates. As demonstrated by entries 4 and 12, un-
der chelation-controlled conditions, the allylation reaction
differs from the hydrogen-atom transfer reactions (7e) with
the bromide substrates. In the latter case, silyl ether 68 was
consumed eight times faster than methyl ether 67, indicating
that the bidentate pathway was at a strong disadvantage.
7. Discussion
The chelation of the Lewis acid to the β-alkoxy ester is
envisioned as the initial step of the allylation process
(Scheme 3).7 Subsequent homolytic cleavage of the α-halide
or α-phenylselenide by attack of the tin radical (Bu3Sn·)
gives a cyclic free-radical intermediate, which may benefit
from the endocyclic (chelated) effect. Note that variations in
the alkoxy function, and their ultimate effect on the ratio,
support strongly the involvement of an endocyclic radical
(Table 2, entries 7–15). The presence of the chelate prior to
the generation of the radical is also supported by our 13C
NMR studies. The chelate is strong enough to bring into so-
lution an equimolar amount of magnesium.
Once formed, the chelated radical may exist in two con-
formers, 75 and 76, that lead to transition states E and F, re-
spectively. The anti predictive transition state E should be
favored over the syn predictive F on both electronic and
steric grounds. Electronically, the electron-poor radical should
be better stabilized, through hyperconjugation, by the over-
lap of the C—R (R = alkyl) bond in E than by that of the
C—H bond in F (3e). From a steric standpoint, when R2 is a
methyl group, an additional allylic 1,2-strain between R and
R2 should increase the energy of transition state F relative to
that of E.
This dependency can explain the low selectivity obtained
for the THF derivatives. A potential rationale illustrated by
Scheme 4 shows that, for these substrates, the formation of a
bicyclic intermediate may be impaired by the development
of eclipsing interactions between the C–O bond and an Mg–
Br bond in the cis bicyclo complex. An additional eclipsing
interaction could be observed between the C–I bond and the
Mg–Br (or Mg–OEt2) bond if the geometry of the magne-
sium is either square planar pyramidal or bipyramidal
trigonal. Such interaction implies that the preexisting com-
plex mixture could have contained monodentate complexes
or uncomplexed substrates. The smaller amount of Mg2+
found in solution supports this argument. By contrast, less
Two other transition states should also be examined. Tran-
sition state C considers the radical in the absence of Lewis
acid, while transition state D reflects the radical in a
1
6 The ratios were also verified by H NMR prior to the allylation.
7 The ligands on Mg2+ have been excluded for simplicity.
© 2000 NRC Canada

Guérin et al.
861
Scheme 3.
steric interaction is present for the bicyclo complex with
THP. The pre-equilibrium for the THP substrates seems to
favor the chelate formation. This conclusion is further sup-
ported by the high level of selectivity obtained for this series
and by the amount of Mg2+ found in solution.
This discussion may not have sufficiently appreciated an
important contributor: the MgBr2·OEt2. What is the nature of
the complexes formed with the alkoxy esters and the
MgBr2·OEt2? For instance, could there be two alkoxy esters
serving as ligands on a magnesium (23) for the monodentate
© 2000 NRC Canada

862
Can. J. Chem. Vol. 78, 2000
Scheme 4.
or α-phenylseleno-β-alkoxy esters. This reaction tolerates a
wide variety of substitutions and, except for THF and syn io-
dide substrates, gives a high level of diastereoselectivity fa-
voring anti products. This is true even for secondary iodides,
bromides, and phenylselenides, as well as tertiary iodides.
The requirement of radical initiation and the fact that the re-
action can be inhibited are indicative of a free radical pro-
cess. Other types of acyclic radical-based reactions are
presently being evaluated. The influence of Lewis acid on
the outcome of these reactions will also be studied.
9. Experimental section
General methods
All reactions requiring anhydrous conditions were con-
ducted under a positive nitrogen atmosphere in oven-dried
glassware using standard syringe techniques. The anhydrous
solvents were purchased from Aldrich and were used as re-
ceived. i-Pr2NH and Et3N were freshly distilled from CaH2
under N2 atmosphere. Allyltributyltin and triethylborane
(1 M solution in hexane) were also purchased from Aldrich
and used as received. Flash chromatography was performed
on Merck silica gel 60 (0.040–0.063 mm) using nitrogen
pressure. Analytical thin-layer chromatography (TLC) was
carried out on precoated (0.25 mm) Merck silica gel F-254
plates. The uncorrected melting points were determined on
an electrothermal melting point apparatus. NMR spectra
were recorded via Bruker AC200, AMX300, ARX400, or
Varian VXR-400S spectrometers, with chemical shifts re-
ported relative to residual chloroform at 7.26 ppm. IR spec-
tra were recorded on a Perkin-Elmer 781 spectrophotometer.
CI and EI mass spectra were recorded on an MF 50 TATC
instrument operating at 70 eV. FAB mass spectra were per-
formed on a VG AutospecQ. Capillary GC analyses were
performed on a Shimadzu GC-9AM instrument or a HP
6890 instrument using 0.25 mm × 30 m Supelcowax™10
and SE-30 columns.
complex (70′, Scheme 5)?7 If so, an excess of MgBr2·OEt2
could then be important in the pre-equilibrium phase for as-
suring the formation of another species involving one alkoxy
ester as a ligand, depicted as bidentate complex 71
(Scheme 3). This would explain why the equilibrium
between 74 and 75 is slow. Indeed, a ligand (another sub-
strate) might have to be displaced in order for 74′ to reach
75; a process that may not be fast enough to allow for ki-
netic selection between the two pathways (Scheme 4).
Only recently has the structure of MgBr2·OEt2 been re-
solved (24). The structure of complexes generated by alkoxy
esters and MgBr2·OEt2 remain to be better defined. This is
the topic of ongoing research.
8. Conclusion
The described chemistry represents a significant advance
in the field of stereocontrol in radical reactions. Our studies
of substituent effects clearly establish the scope and limita-
tions of the chelation-controlled radical allylation of α-halo
Scheme 5.
© 2000 NRC Canada

Guérin et al.
863
(2.7 ppm). Anal. calcd. for C16H25BrO3Si: C 51.47, H 6.75;
found: C 51.55, H 6.92.
Preparation of starting materials
The preparation and characterization data of 9–12 (7d),
14–21 (7d), 25 (7d), 27–30 (3d, 7d), and 34 (7a) have been
reported previously.
Ethyl (±)-(2S*)-2-[(2S*,3R*)-3-((1,1-dimethylethyl)dimethyl-
silyl)oxytetrahydrofuran-2-yl]-2-iodopropanoate (33): Com-
pound 33 was prepared with iodoester 31 (17) (775 mg,
2.58 mmol) and t-butyldimethylsilyl trifluoromethanesulfo-
nate (0.90 mL, 3.87 mmol) following the procedure de-
scribed above for 24. Purification by flash chromatography
(5% EtOAc in hexanes) afforded silyl ether 33 (908 mg,
Methyl (±)-(2S*,3S*)-2-iodo-3-benzyloxy-3-phenylpropanoate
(13): To a solution of methyl cinnamate (381 mg, 2.35 mmol)
in benzylalcohol (3.5 mL) were added successively AgNO3
(305 mg, 2.82 mmol) and iodine (710 mg, 2.82 mmol). The
reaction mixture was stirred at room temperature in the dark
for 24h, then filtered through celite and concentrated. The
residue was taken up in EtOAc and washed with 10%
Na2S2O3, water, and brine. The organic layer was dried
(MgSO4), filtered, and concentrated to afford a residue,
which was then purified by flash chromatography (CH2Cl2)
to afford pure iodide 13 as a white solid (568 mg, 61%); mp
1
85%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 0.15
(s, 3H), 0.22 (s, 3H), 0.95 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H),
1.91–2.09 (m, 1H), 4.04–4.12 (m, 2H), 4.23 (q, J = 7.1 Hz,
2H), 4.35–4.36 (m, 2H), 4.53–4.55 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ –4.46, –4.09, 13.69, 18.01, 18.22,
25.92, 35.96, 61.79, 68.69, 72.64, 84.41, 170.54; IR (neat)
2960, 1740, 1470, 1260 cm–1; MS (CI, CH4) m/z 415 (MH+,
95), 399 (37), 369 (100), 357 (27), 283 (39), 155 (9). Anal.
calcd. for C14H27IO4Si: C 40.58, H 6.57; found: C 40.93, H
6.43.
1
50–51°C; H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 4.31
(d, J = 10.6 Hz, 1H), 4.40 (d, J = 10.6 Hz, 1H), 4.45 (d, J =
11.3 Hz, 1H), 4.80 (d, J = 11.3 Hz, 1H), 7.18–7.41 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 24.80, 52.99, 71.89,
82.89, 127.85, 127.97, 128.33, 128.49, 129.08, 137.46,
137.58, 170.80; IR (CHCl3) 3030, 2950, 1740, 1455 cm–1;
MS (FAB) 397 (MH, 8), 289 (35), 154 (49), 91 (100);
HRMS calcd. for C17H18O3I (MH): 397.0301, found:
397.0290 (2.7 ppm). Anal. calcd. for C17H17IO3: C 51.53, H
4.32; found: C 51.36, H 4.26.
Allylation products
The preparation and characterization data of 35–42, 47–
56, 63, and 64 have been reported previously (7d).
Methyl (±)-(2S*,3S*)-2-iodo-3-[(trimethylsilyl)oxy]-3-phenylpro-
panoate (24): To a solution of iodohydrin 22 (7d) (713 mg,
2.32 mmol) and 2,6-lutidine (540 µL, 4.64 mmol) in CH2Cl2
(25 mL) at –78°C was added slowly trimethylsilyl
trifluoromethanesulfonate (670 µL, 3.48 mmol). After the
reaction was judged complete by TLC, the mixture was di-
luted with ether and washed with water, saturated NH4Cl,
and brine. Drying over MgSO4 followed by flash chromatog-
raphy (4% EtOAc in hexanes) afforded silyl ether 24 as a
General procedure for the allylation of α-iodoesters under
chelation-controlled conditions (Conditions A)
To a stirred solution of α-iodoester (1 equiv) in dry
CH2Cl2 (0.1 M) at –78°C was added MgBr2·OEt2 (3 equiv).
The mixture was stirred for 15 min at the same temperature
before allyltributyltin (2 equiv) and Et3B (0.2 equiv of a
1.0 M solution in hexanes) were added. The resulting sus-
pension was stirred at –78°C, and 0.2 equivalent of Et3B was
added each 30 min until the reaction was judged complete
by TLC. 1,3-Dinitrobenzene (0.2 equiv) was then added to
the solution and the mixture was stirred an additional 15 min
at –78°C. The reaction mixture was poured into a saturated
NaHCO3 solution and extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure.
1
colorless oil (720 mg, 82%). H NMR (300 MHz, CDCl3) δ
–0.05 (s, 9H), 3.81 (s, 3H), 4.37 (d, J = 10.2 Hz, 1H), 5.05
(d, J = 10.1 Hz, 1H) 7.34–7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ –0.26, 27.44, 52.66, 77.21, 127.50,
128.03, 128.44, 140.32, 170.73; IR (neat) 2955, 1742, 1495,
1435, 1252, 1166, 1070, 873 cm–1; MS (FAB) 379 (MH,
11), 363 (24), 289 (77), 179 (100), 121 (42); HRMS calcd.
for C13H20IO3Si (MH) 379.0226, found: 379.0209
(4.6 ppm). Anal. calcd. for C13H19IO3Si: C 41.28, H 5.06;
found: C 41.11, H 4.80.
Methyl (±)-(2S*,3S*)-2-[propen-3-yl]-3-benzyloxy-3-phenyl-
propanoate (43): Compound 43 was prepared with iodoester
13 (97 mg, 0.24 mmol) following the general procedure de-
scribed above. A 5:1 ratio of anti:syn products was deter-
Methyl (±)-(2S*,3S*)-2-bromo-3-[((1,1-dimethylethyl)dimethyl-
silyl)oxy]-3-phenylpropanoate (26): Compound 26 was pre-
pared with bromohydrin 23 (14) (1.20 g, 4.62 mmol) and t-
butyldimethylsilyl trifluoromethanesulfonate (1.60 mL,
6.92 mmol) following the procedure described above for 24.
Purification by flash chromatography (CH2Cl2) afforded silyl
1
mined by GC and H NMR analyses of the crude isolate.
Purification by flash chromatography (5% EtOAc in hex-
anes) afforded allylated products 43 and 44 (40 mg, 52%).
1
43: Colorless oil; H NMR (400 MHz, CDCl3) δ 1.77–1.83
(m, 1H), 2.05–2.18 (m, 1H), 2.81–2.94 (m, 1H), 3.73 (s,
3H), 4.21 (d, J = 11.8 Hz, 1H), 4.39 (d, J = 11.8 Hz, 1H),
4.47 (d, J = 9.9 Hz, 1H), 4.87–4.98 (m, 2H), 5.47–5.59 (m,
1H), 7.17–7.45 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
33.22, 51.45, 53.07, 70.45, 82.58, 116.80, 127.43, 127.62,
127.75, 128.12, 128.40, 128.56, 134.43, 138.89, 137.97,
174.17; IR (neat) 2980, 1738, 1642, 1434, 1195 cm–1; MS
(FAB) 311 (MH, 100), 203 (22), 171 (25), 143 (87), 133
(83); HRMS calcd. for C20H23O3 (MH) 311.1647, found:
311.1659 (–3.7 ppm).
1
ether 26 as a white solid (1.64 g, 95%). Mp 38°C; H NMR
(400 MHz, CDCl3) δ –0.30 (s, 3H), 0.01 (s, 3H), 0.78 (s,
9H), 3.82 (s, 3H), 4.21 (d, J = 10.0 Hz, 1H), 4.98 (d, J =
10.0 Hz, 1H) 7.33–7.37 (m, 5H); 13C NMR (50.3 MHz,
CDCl3) δ –5.42, –4.75, 17.95, 25.49, 49.29, 52.85, 76.61,
127.62, 128.21, 128.63, 140.02, 169.53; IR (CDCl3) 2850,
1745, 1590, 1450, 1355, 1315, 1080, cm–1; MS (FAB) 373
(MH, 12), 317 (17), 221 (15), 131 (13), 73 (100); HRMS
calcd. for C16H2579BrO3Si (MH) 372.0756, found: 372.0746
© 2000 NRC Canada

864
Can. J. Chem. Vol. 78, 2000
Methyl (±)-2-[propen-3-yl]-3-[(trimethylsilyl)oxy]-3-phenyl-
propanoate (45 and 46): Compounds 45 and 46 were pre-
pared with iodoester 24 (63 mg, 0.17 mmol) following the
general procedure described above. A 1:4 ratio of anti:syn
Ethyl (±)-(2S*)-2-[(2S*,3R*)-3-((1,1-dimethylethyl)dimethyl-
silyl)oxytetrahydrofuran-2-yl]-2-[propen-3-yl]-2-methylpro-
panoate (61): Compound 61 was prepared with iodoester 34
(77 mg, 0.18 mmol) following the general procedure de-
scribed above. A 7:1 ratio of anti:syn products was deter-
mined by GC and H NMR analyses of the crude isolate.
Purification by flash chromatography (5% EtOAc in hex-
1
products was determined by GC and H NMR analyses of
1
the crude isolate. Purification by flash chromatography (4%
EtOAc in hexanes) afforded a mixture of allylated products
45 and 46 as a colorless oil (38 mg, 78%). 1H NMR
(300 MHz, CDCl3) δ 45 (2S*,3S*): –0.05 (s, 9H), 1.77–1.84
(m, 1H), 2.11–2.19 (m, 1H), 3.72 (s, 3H), 4.72 (d, J =
9.6 Hz, 1H), 4.92–5.00 (m, 2H), 5.54–5.60 (m, 1H), 7.20–
7.35 (m, 5H), 46 (2R*,3S*): 0.01 (s, 9H), 2.47–2.54 (m,
2H), 2.71–2.76 (m, 1H), 3.44 (s, 3H), 4.81 (d, J = 7.9 Hz,
1H), 5.01–5.08 (m, 2H), 5.68–5.82 (m, 1H), 7.20–7.35 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 45: 0.04, 33.11, 51.27,
55.10, 76.76, 116.52, 126.91, 127.44, 127.83, 128.18,
134.64, 141.92, 174.82, 46: 0.05, 32.76, 51.07, 55.19, 76.59,
116.30, 126.29, 127.44, 127.94, 135.59, 142.58, 173.31; IR
(neat) 3065, 2953, 1736, 1641, 1495, 1454, 1250, 1194,
1087, 995 cm–1; MS (FAB) 293.5 (MH, 58), 277.4 (30), 179
(100), 143 (55), 120 (12), 104 (20); HRMS calcd. for
C16H25SiO3 (MH) 293.1573, found: 293.1584 (–3.8 ppm).
anes) afforded allylated products 61 and 62 (43 mg, 70%).
1
61: Colorless oil; H NMR (400 MHz, CDCl3) δ 0.08 (s,
6H), 0.89 (s, 9H), 1.11 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H),
1.74–1.80 (m, 1H), 1.85–1.94 (m, 1H), 2.14 (dd, J = 7.9,
13.5 Hz, 1H), 2.60 (dd, J = 6.6, 13.5 Hz, 1H), 3.82–3.95 (m,
3H), 4.11–4.19 (m, 2H); 4.29–4.32 (m, 1H), 5.04–5.10 (m,
2H), 5.67–5.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ –
4.82, –4.61, 14.13, 16.73, 17.68, 25.59, 36.40, 40.37, 48.82,
60.45, 66.91, 72.85, 91.26, 118.04, 133.53, 174.76; IR (neat)
2980, 1735, 1460, 1110, 830 cm–1; MS (FAB) m/z 343
(MH+, 13), 327 (16), 285 (100), 211 (29), 201 (18), 171
(12); HRMS calcd. for C18H35O4Si (MH+) m/z 343.2305,
found: 343.2290 (4.3 ppm).
Ethyl (±)-(2S*)-2-[(2S*)-tetrahydropyran-2-yl]-2-[propen-3-yl]-2-
methylpropanoate (65): Compound 65 (59 mg, 54%) was
prepared with iodoester 30 (148 mg, 0.48 mmol) following
the general procedure described above. A 27:1 ratio of
Ethyl (±)-(2S*)-2-[(2S*,3R*)-3-((1,1-dimethylethyl)dimethyl-
silyl)oxytetrahydrofuran-2-yl]-2-[propen-3-yl]-propanoate (57):
Compound 57 was prepared with iodoester 33 (30 mg,
0.08 mmol) following the general procedure described
above. A 6:1 ratio of anti:syn products was determined by
1
anti:syn products was determined by GC and H NMR anal-
yses of the crude isolate. Purification by flash chromatogra-
phy (10% EtOAc in hexanes) afforded allylated product 65
1
1
GC and H NMR analyses of the crude isolate. Purification
as a colorless oil. H NMR (400 MHz, CDCl3) δ 1.11 (s,
by flash chromatography (5% EtOAc in hexanes) afforded
allylated products 57 and 58 (19 mg, 80%). 57: Colorless
oil; 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6H), 0.92 (s, 9H),
1.27 (t, J = 7.0 Hz, 3H), 1.72–1.87 (m, 1H), 2.00–2.08 (m,
1H), 2.26–2.31 (m, 2H), 2.92–2.96 (m, 1H), 3.80–3.85 (m,
2H), 3.95–4.00 (m, 1H), 4.15–4.22 (m, 2H), 4.32–4.38 (m,
1H), 4.99–5.10 (m, 2H), 5.70–5.82 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ –4.61, –4.82, 14.23, 17.79, 25.66,
33.24, 35.77, 45.62, 60.23, 66.18, 71.50, 83.63, 116.64,
134.47, 174.38; IR (neat) 2930, 2850, 1735, 1460, 1170,
1040 cm–1; MS (FAB) 329 (MH, 85), 283 (85), 169 (27).
Anal. calcd. for C17H32O4Si: C 62.15, H 9.82; found: C
61.72, H 9.61.
3H), 1.24 (t, J = 7.1 Hz, 3H), 1.27–1.57 (m, 5H), 1.85–1.89
(m, 1H), 2.07 (dd, J = 7.8, 13.5 Hz, 1H), 2.38 (dd, J = 7.2,
13.5 Hz, 1H), 3.33–3.41 (m, 1H), 3.48–3.52 (m, 1H), 3.93–
3.97 (m, 1H), 4.07–4.22 (m, 2H), 5.01–5.07 (m, 2H), 5.63–
5.69 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.11, 15.90,
23.58, 25.31, 25.97, 40.01, 50.29, 60.07, 68.86, 82.51,
117.76, 133.67, 176.03; IR (neat) 2930, 2870, 1725, 1640,
1435, 1080, 920 cm–1; MS (FAB) m/z 227 (MH+, 100), 199
(13), 185 (33), 151 (38), 135 (28); HRMS calcd. for
C13H23O3 (MH+) m/z 227.1647, found: 227.1654 (–3.0 ppm).
General procedure for the allylation of α-iodoesters in the
absence of Lewis acid (Conditions B)
To a solution of α-iodoester (1 equiv.) in hexanes (0.1 M)
at 23°C were added allyltributyltin (2 equiv) and AIBN (0.2
equiv). After being allowed to reflux, the mixture was stirred
until the reaction was judged complete by TLC.
Ethyl (±)-(2S*)-2-[(2S*)-tetrahydrofuran-2-yl]-2-[propen-3-
yl]-2-methylpropanoate (59): Compound 59 was prepared
with iodoester 28 (135 mg, 0.45 mmol) following the gen-
eral procedure described above. A 1:1 ratio of anti:syn prod-
1
ucts was determined by GC and H NMR analyses of the
Methyl (±)-(2R*,3S*)-2-[propen-3-yl]-3-benzyloxy-3-phenyl-
propanoate (44): To a solution of iodoester 13 (175 mg,
0.44 mmol) in CH2Cl2 (4.5 mL) at –78°C were added
allyltributyltin (275 FL, 0.88 mmol) and Et3B (90 µL of a
1.0 M solution in hexanes, 0.09 mmol). The reaction mixture
was stirred at –78°C with 0.2 equivalent of Et3B added each
30 min until the reaction was judged complete by TLC. A
1:10 ratio of anti:syn products was determined by GC and
1H NMR analyses of the crude isolate. Purification by flash
chromatography (5% EtOAc in hexanes) afforded allylated
crude isolate. Purification by flash chromatography (10%
EtOAc in hexanes) afforded allylated products 59 and 60
(79 mg, 82%). 59: Colorless oil; 1H NMR (400 MHz,
CDCl3) δ 1.12 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.69–1.92
(m, 4H), 2.08 (dd, J = 7.7, 13.5 Hz, 1H), 2.49 (dd, J = 7.1,
13.5 Hz, 1H), 3.75–3.86 (m, 2H), 4.07–4.11 (m, 1H), 4.17
(q, J = 7.1 Hz, 2H), 5.03–5.10 (m, 2H), 5.65–5.77 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 14.15, 15.97, 25.92, 26.28,
40.42, 49.96, 60.04, 68.47, 83.43, 117.84, 133.64, 175.09;
IR (neat) 2990, 1730, 1640, 1460, 1380, 1140, 1060 cm–1;
MS (FAB) m/z 213 (MH+, 100), 167 (22), 155 (26), 137
(74), 123 (30), 109 (40); HRMS calcd. for C12H21O3 m/z
(MH+) 213.1491, found: 213.1484 (3.1 ppm). Anal. calcd.
for C12H20O3: C 67.89, H 9.50; found: C 67.92, H 9.36.
1
products 43 and 44 (82 mg, 60%). 44: Colorless oil; H
NMR (400 MHz, CDCl3) δ 2.41–2.57 (m, 1H), 2.66–2.78
(m, 1H), 2.86–2.92 (m, 1H), 3.41 (s, 3H), 4.22 (d, J =
11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.47 (d, J = 8.8 Hz,
2H), 4.95–5.09 (m, 2H), 5.78–5.81 (m, 1H), 7.25–7.43 (m,
© 2000 NRC Canada

Guérin et al.
865
10H); 13C NMR (100 MHz, CDCl3) δ 33.31, 51.12, 53.71,
70.57, 81.30, 116.64, 127.36, 127.62, 127.84, 128.08,
128.31, 128.32, 135.33, 137.94, 139.50, 172.93; IR (neat)
3030, 2949, 1736, 1641, 1454, 1356, 1166, 1067, 920 cm–1;
MS (FAB) m/z 311 (MH+, 26), 233 (13), 143 (58), 133
(100), 121 (20), 105 (15), 91 (100). Anal. calcd. for
C20H22O3: C 77.39, H 7.14; found: C 77.19, H 7.30.
40.93, 48.90, 60.47, 67.03, 73.37, 91.81, 117.98, 133.93,
174.66; IR (neat) 2950, 1725, 1645, 1460, 1375, 1250, 1070,
910, 830, 770 cm–1; MS (CI, CH4) m/z 343 (MH+, 25), 327
(19), 285 (9), 269 (8), 257 (12), 210 (100), 169 (10).
Ethyl (±)-(2R*)-2-[(2S*)-tetrahydropyran-2-yl]-2-[propen-
3-yl]-2-methylpropanoate (66): Compound 66 was prepared
with iodoester 30 (187 mg, 0.60 mmol) following the gen-
eral procedure described above. A 1:18 ratio of anti:syn
Ethyl (±)-(2R*)-2-[(2S*,3R*)-3-((1,1-dimethylethyl)dimethyl-
silyl)oxytetrahydrofuran-2-yl]-2-[propen-3-yl]-propanoate (58):
Compound 58 was prepared with iodoester 33 (52.5 mg,
0.13 mmol) following the general procedure described
above. A 1:51 ratio of anti:syn products was determined by
1
products was determined by GC and H NMR analyses of
the crude isolate. Purification by flash chromatography (10%
EtOAc in hexanes) afforded allylated product 66 as a color-
1
less oil (105 mg, 77%). H NMR (400 MHz, CDCl3) δ 1.01
1
GC and H NMR analyses of the crude isolate. Purification
(s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.36–1.53 (m, 5H), 1.82–
1.86 (m, 1H), 2.30 (dd, J = 7.9, 13.6 Hz, 1H), 2.50 (dd, J =
6.9, 13.6 Hz, 1H), 3.36–3.46 (m, 2H), 3.97–4.02 (m, 1H),
4.13 (q, J = 7.1 Hz, 2H), 5.01–5.08 (m, 2H), 5.65–5.79 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 14.12, 15.98, 23.60,
26.01, 26.32, 40.88, 50.26, 60.12, 68.99, 81.77, 117.50,
134.33, 174.98; IR (neat) 2920, 1725, 1450, 1300, 1210,
1085, 910 cm–1; MS (FAB) m/z 227 (MH+, 100), 199 (13),
185 (27), 151 (31), 143 (15), 135 (25); HRMS cacld for
C13H23O3 m/z (MH+) 227.1647, found: 227.1656 (–3.9 ppm).
Anal. calcd. for C13H22O3: C 68.99, H 9.80; found: C 68.58,
H 10.17.
by flash chromatography (5% EtOAc in hexanes) afforded
allylated product 58 as a colorless oil (30.5 mg, 74%). H
1
NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.06 (s, 3H), 0.88
(s, 9H), 1.25 (t, J = 7.1 Hz, 3H), 1.78–1.91 (m, 1H), 2.00–
2.18 (m, 1H), 2.44–2.52 (m, 1H), 2.60–2.67 (m, 1H), 2.81–
2.92 (m, 1H), 3.73–4.25 (m, 5H), 4.38–4.43 (m, 1H), 4.97–
5.11 (m, 2H), 5.69–5.90 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ –5.40, –4.49, 14.19, 17.87, 25.62, 34.26, 36.14,
44.33, 59.82, 65.82, 72.27, 81.66, 116.74, 134.83, 173.38;
IR (neat) 2910, 1730, 1645, 1460, 1370, 1240, 1175, 1070,
820 cm–1; MS (FAB) m/z 329 (MH+, 12), 283 (16), 271 (82),
149 (100); HRMS calcd. for C17H33O4Si m/z (MH+)
329.2148, found: 329.2130 (5.5 ppm).
Determination of magnesium concentrations in allylation
reaction mixtures by filtration and EDTA titration
Preparation of the sample: To a stirred solution of α-
iodoester (0.5 mmol) in dry CH2Cl2 (5 mL) at –78°C was
added MgBr2·OEt2. The mixture was stirred for 15 min at
this temperature before allyltributyltin (1.0 mmol) was
added. A 3 mL aliquot of the solution was removed from the
flask using a syringe equipped with a filter (Millex HV
0.45 mm). This 3 mL aliquot was then concentrated under
reduced pressure.
Titration of magnesium by EDTA: Deionized water
(5 mL) and CH2Cl2 (5 mL) were added to the sample. The
mixture was then shaken and poured into a 125 mL erlen-
meyer flask. Deionized water (10 mL), NH3–NH4Cl buffer
solution at pH = 10 (4 mL), and six drops of Calmagite indi-
cator were added successively to the stirred solution, which
was then titrated with a standardized EDTA solution (0.099
M, Aldrich) until the color changed completely from red to
blue. The amount of Mg (mmol) in the total sample =
0.099 mmol/mL × VEDTA added (mL) × (5/3).
Ethyl (±)-(2R*)-2-[(2S*)-tetrahydrofuran-2-yl]-2-[propen-3-
yl]-2-methylpropanoate (60): Compound 60 was prepared
with iodoester 28 (163 mg, 0.55 mmol) following the gen-
eral procedure described above. A 1:10 ratio of anti:syn
products was determined by GC and H NMR analyses of
the crude isolate. Purification by flash chromatography
1
(10% EtOAc in hexanes) afforded allylated products 59 and
1
60 (94 mg, 81%). 60: Colorless oil; H NMR (400 MHz,
CDCl3) δ 1.11 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.68–1.91
(m, 4H), 2.32 (dd, J = 7.9, 13.6 Hz, 1H), 2.54 (dd, J = 6.8,
13.6 Hz, 1H), 3.73–3.85 (m, 2H), 4.02–4.07 (m, 1H), 4.14
(q, J = 7.1 Hz, 2H), 5.03–5.10 (m, 2H), 5.67–5.79 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 14.12, 15.86, 26.01, 26.87,
41.59, 49.83, 60.17, 68.49, 82.85, 117.62, 134.05, 174.94;
IR (neat) 2990, 1730, 1645, 1465, 1380, 1140, 1065 cm–1;
MS (EI) m/z 213 (MH+, 14), 171 (10), 142 (21), 69.5 (100);
HRMS cacld for C12H21O3 m/z (MH+) 213.1491, found:
213.1499 (–3.9 ppm). Anal. calcd. for C12H20O3: C 67.89,
H 9.50; found: C 67.96, H 9.35.
The buffer pH = 10 was prepared from concentrated
NH4OH solution (57 mL) and 7 g of NH4Cl in sufficient
deionized water to give 100 mL of solution.
The calmagite indicator solution was prepared by adding
0.05 g of calmagite to 50 mL of deionized water.
Ethyl (±)-(2R*)-2-[(2S*,3R*)-3-((1,1-dimethylethyl)dimethyl-
silyl)oxytetrahydrofuran-2-yl]-2-[propen-3-yl]-2-methylpro-
panoate (62): Compound 62 was prepared with iodoester 34
(33.5 mg, 0.08 mmol) following the general procedure de-
scribed above. A 1:16 ratio of anti:syn products was deter-
1
mined by GC and H NMR analyses of the crude isolate.
13C observations of β-alkoxyesters in the presence of a
saturating amount of MgBr2·OEt2 in CD2Cl2 at –23°C.
To a stirred solution of α-iodoester (1 equiv) in CD2Cl2
(0.1 M) at –23°C was added MgBr2·OEt2 (3 equiv). The so-
lution was then stirred for 15 min at the same temperature.
A 1.5 mL aliquot of solution was removed from the flask us-
ing a syringe equipped with a filter (Millex HV 0.45 mm).
The aliquot was placed in an NMR tube and kept at –23°C
Purification by flash chromatography (5% EtOAc in hexanes)
afforded allylated products 61 and 62 (17.5 mg, 65%). 62:
1
Colorless oil; H NMR (200 MHz, CDCl3) δ 0.05 (s, 6H),
0.86 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H), 1.67–1.97 (m, 2H), 2.19
(dd, J = 7.7, 13.6 Hz, 1H), 2.57 (dd, J = 6.9, 13.6 Hz, 1H),
3.77–3.98 (m, 3H), 4.02–4.22 (m, 2H), 4.30–4.36 (m, 1H),
5.01–5.09 (m, 2H), 5.60–5.78 (m, 1H); 13C NMR (50.3 MHz,
CDCl3) δ –4.86, –4.33, 14.19, 17.43, 17.75, 25.68, 36.59,
© 2000 NRC Canada

866
Can. J. Chem. Vol. 78, 2000
until the 13C NMR spectrum was recorded on a Bruker
ARX400 spectrometer at that temperature.
(1990); (b) Y. Guindon, J.-F. Lavallée, L. Boisvert, C. Chabot,
D. Delorme, C. Yoakim, D. Hall, R. Lemieux, and B.
Simoneau. Tetrahedron Lett. 32, 27 (1991); (c) K. Durkin, D.
Liotta, J. Rancourt, J.-F. Lavallée, L. Boisvert, and Y.
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Guindon, C. Yoakim, V. Gorys, W.W. Ogilvie, D. Delorme, J.
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Competition experiments
Substrates A (0.5 equiv) and B (0.5 equiv) were dissolved
in CDCl3 and the mixture was analyzed by NMR 1H integra-
tion to determine the exact A:B ratio before the allylation re-
action. The solution was concentrated and redissolved in dry
CH2Cl2 (0.1 M) at –78°C before MgBr2·OEt2 (3 equiv) was
added. The mixture was then stirred for 15 min at the
same temperature, and allyltributyltin (0.5 equiv) as well as
Et3B (0.2 equiv of a 1.0 M solution in hexanes) were subse-
quently added. The resulting suspension was stirred at
–78°C, and 0.2 equivalent of Et3B was added each 30 min
until the reaction was judged complete by TLC. The reaction
mixture was then poured into a saturated NaHCO3 solution
and extracted with CH2Cl2. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. Another 1H NMR
analysis was done on the crude mixture to determine the ex-
act A:B ratio after the allylation reaction.
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We would like to thank Ms. LaVonne Dlouhy for her as-
sistance in the preparation of this manuscript.
11. Supplementary material available
13C NMR spectra for compounds 23, 43, 45–46, 58, 61,
62, and 65. Tables of NMR chemical shift correlations for
allylated products (11 pages) have been deposited as supple-
mentary material and may be purchased from: The Deposi-
tory of Unpublished Data, Document Delivery, CISTI,
National Research Council Canada, Ottawa, Ontario, Can-
ada, K1A 0S2.
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© 2000 NRC Canada