The Use of Lewis Acids in Radical Chemistry. Chelation-Controlled Radical Reductions of Substituted α-Bromo-β-alkoxy Esters and Chelation-Controlled Radical Addition Reactions

Article abstract of DOI:10.1021/jo980636x

The radical reduction of a series of α-bromo-β-alkoxy esters under chelation-controlled conditions is reported. Proceeding with high stereoselectivity in the presence of MgBr₂middot;OEt₂, reductions give access to syn products. Syste

Full text of DOI:10.1021/jo980636x

6554
J . Org. Chem. 1998, 63, 6554-6565
Th e Use of Lew is Acid s in Ra d ica l Ch em istr y.
Ch ela tion -Con tr olled Ra d ica l Red u ction s of Su bstitu ted
r-Br om o-â-a lk oxy Ester s a n d Ch ela tion -Con tr olled Ra d ica l
Ad d ition Rea ction s
Yvan Guindon*,† and J . Rancourt‡
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry Laboratory, 110 avenue des
Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, Department of Chemistry and Department of
Biochemistry, Universite´ de Montre´al, C.P. 6128, succursale Centre-ville,
Montre´al, Que´bec, Canada H3C 3J 7, and Bio-Me´ga Research Division,
Boehringer Ingelheim (Canada) Ltd., 2100 rue Cunard, Laval, Que´bec, Canada H7S 2G5
Received April 6, 1998
The radical reduction of a series of R-bromo-â-alkoxy esters under chelation-controlled conditions
is reported. Proceeding with high stereoselectivity in the presence of MgBr2‚OEt2, reductions give
access to syn products. Systematic variations in substrate substituents show that these reactions
tolerate a wide variety of alkyl functionalities at positions 2 and 3 and are relatively unaffected by
the nature of the ester group. Changes to the alkoxy function indicate that a bidentate chelate is
involved in the reaction and that an excess of MgBr2‚OEt2 is required for optimum selectivity by
favoring this species in preference to the anti-selective monodentate or nonchelated pathways.
Competition experiments suggest that the monodentate pathway is kinetically favored over the
bidentate one. The suppressibility of the reaction by radical chain inhibitors and the need for
initiation indicate the intermediacy of radicals. Further support for this mechanism includes both
radical addition to R,â-unsaturated esters and reduction of bromides conducted in the presence of
a Lewis acid.
In tr od u ction
stereogenic center in three types of reactions: (1) ally-
lation, (2) atom transfer, and (3) hydrogen transfer
reactions.4,7 These radicals can be obtained via the
homolytic cleavage of a halide or phenyl selenide. As
shown by Scheme 1, the reaction of iodides such as 1 with
The problem of controlling the stereochemical outcome
of reactions involving acyclic radicals is receiving con-
siderable attention.1 Significant levels of diastereoselec-
tivity have already been achieved in strategies involving
chiral auxiliaries2 or a preexisting vicinal chiral center
(1,2-induction).3,4 The scope of these reactions has been
expanded by using mono-5 or bidentate6,7 Lewis acids,
solvent complexation,8 and intramolecular hydrogen
bonding.9 New developments in this research include
reagent control approaches that employ chiral Lewis
acids.10
(4) (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.; Delorme,
D.; Lavalle´e, J .-F. Tetrahedron Lett. 1990, 31, 2845. (b) Guindon, Y.;
Lavalle´e, J .-F.; Boisvert, L.; Chabot, C.; Delorme, D.; Yoakim, C.; Hall,
D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett. 1991, 32, 27. (c)
Durkin, K.; Liotta, D.; Rancourt, J .; Lavalle´e, J .-F.; Boisvert, L.;
Guindon, Y. J . Am. Chem. Soc. 1992, 114, 4912. (d) Guindon, Y.;
Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme, D.; Renaud, J .;
Robinson, G.; Lavalle´e, J .-F.; Slassi, A.; J ung, G.; Rancourt, J .; Durkin,
K.; Liotta, D. J . Org. Chem. 1994, 59, 1166. (e) Guindon, Y.; Slassi,
A.; Rancourt, J .; Bantle, G.; Bencheqroun, M.; Murtagh, L.; Ghiro, E.;
J ung, G. J . Org. Chem. 1995, 60, 288.
Our group has been particularly interested in the
reactivity of radicals flanked by both an ester and a
(5) (a) Renaud, P.; Ribezzo, M. J . Am. Chem. Soc. 1991, 113, 7803.
(b) Renaud, P.; Moufid, N.; Kuo, L. H.; Curran, D. P. J . Org. Chem.
1994, 59, 3547. (c) Curran, D. P.; Kuo, L. H. J . Org. Chem. 1994, 59,
3259. (d) Nishida, M.; Ueyama, E.; Hayashi, H.; Ohtake, Y.; Yamaura,
Y.; Yanaginuma, E.; Yonemitsu, O.; Nishida, A.; Kawahara, N. J . Am.
Chem. Soc. 1994, 116, 6455. (e) Renaud, P.; Bourquard, T.; Gerster,
M.; Moufid, N. Angew. Chem., Int. Ed. Engl. 1994, 33, 1601. (f) Nishida,
M.; Hayashi, H.; Yamaura, Y.; Yanaginuma, E.; Yonemitsu, O.
Tetrahedron Lett. 1995, 36, 269. (g) Murakata, M.; Tsutsui, H.;
Hoshino, O. J . Chem. Soc., Chem. Commun. 1995, 481. (h) Urabe, H.;
Kobayashi, K.; Sato, F. J . Chem. Soc., Chem. Commun. 1995, 1043.
(i) Moufid, N.; Renaud, P.; Hassler, C.; Giese, B. Helv. Chim. Acta 1995,
78, 1006.
(6) (a) Toru, T.; Watanabe, Y.; Tsusaka, M.; Ueno, Y. J . Am. Chem.
Soc. 1993, 115, 10464. (b) Ru¨ck, K.; Kunz, H. Synthesis 1993, 1018.
(c) Nagano, H.; Kuno, Y. J . Chem. Soc., Chem. Commun. 1994, 987.
(d) Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N. J . Am. Chem. Soc.
1994, 116, 421. (e) Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi,
K.; Sato, F. J . Org. Chem. 1995, 60, 3576. (f) Gerster, M.; Audergon,
L.; Moufid, N.; Renaud, P. Tetrahedron Lett. 1996, 37, 6335. (g) Sibi,
M. P.; Shay, J . J .; J i, J . Tetrahedron Lett. 1997, 38, 5955.
† Institut de recherches cliniques de Montre´al (IRCM).
‡ Bio-Me´ga Research Division/Boehringer Ingelheim (Canada) Ltd.
(1) (a) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991,
24, 296. (b) Liotta, D. C.; Durkin, K. A.; Soria, J . J . Chemtracts 1992,
5, 197. (c) Miracle, G. S.; Cannizzaro, S. M.; Porter, N. A. Chemtracts
1993, 6, 147. (d) Smadja, W. Synlett 1994, 1. (e) Giese, B.; Damm, W.;
Batra, R. Chemtracts 1994, 7, 355. (f) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions - Concepts, Guidelines
and Synthetic Applications; VCH: New York, 1996.
(2) Selected examples: (a) Crich, D.; Davies, J . W. Tetrahedron Lett.
1987, 28, 4205. (b) Porter, N. A.; Scott, D. M.; Lacher, B.; Giese, B.;
Zeitz, H. G.; Lindner, H. J . J . Am. Chem. Soc. 1989, 111, 8311. (c)
Curran, D. P.; Qi, H.; Geib, S. J .; DeMello, N. C. J . Am. Chem. Soc.
1994, 116, 3131. (d) Porter, N. A.; Carter, R. L.; Mero, C. L.; Roepel,
M. G.; Curran, D. P. Tetrahedron 1996, 52, 4181 and references
therein. (e) Andre´s, C.; Duque-Soladana, J . P.; Iglesias, J . M.; Pedrosa,
R. Tetrahedron Lett. 1996, 37, 9085.
(3) (a) Bartlett, P. A.; Adams, J . L. J . Am. Chem. Soc. 1980, 102,
337. (b) Hart, D. J .; Huang, H.-C. Tetrahedron Lett. 1985, 26, 3749.
(c) Hart, D. J .; Krishnamurthy, R. J . Org. Chem. 1992, 57, 4457. (d)
Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron Lett.
1992, 33, 1863. (e) Curran, D. P.; Ramamoorthy, P. S. Tetrahedron
1993, 49, 4841. (f) Morikawa, T.; Washio, Y.; Harada, S.; Hanai, R.;
Kayashita, T.; Nemoto, H.; Shiro, M.; Taguchi, T. J . Chem. Soc., Perkin
Trans. 1. 1995, 271. (f) Easton, C. J .; Merrett, M. C. Tetrahedron 1997,
53, 1151. (g) Suzuki, H.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1995,
60, 6114.
(7) (a) Guindon, Y.; Lavalle´e, J .-F.; Llinas-Brunet, M.; Horner, G.;
Rancourt, J . J . Am. Chem. Soc. 1991, 113, 9701. (b) Guindon, Y.;
Gue´rin, B.; Chabot, C.; Mackintosh, N.; Ogilvie, W. W. Synlett 1995,
449. (c) Guindon, Y.; Gue´rin, B.; Rancourt, J .; Chabot, C.; Mackintosh,
N.; Ogilvie, W. W. Pure Appl. Chem. 1996, 68, 89. (d) Guindon, Y.;
Gue´rin, B.; Chabot, C.; Ogilvie, W. W. J . Am. Chem. Soc. 1996, 118,
12528.
S0022-3263(98)00636-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/28/1998

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6555
Ta ble 1. P r ep a r a tion of Su bstr a tes 10-16 by
Sch em e 1
Meth oxy-br om in a tion 13
yield
entry
olefin
R1
R2
R3
R4
bromide
(%)
1
2
3
4
5
6
4
5
6
7
8
9
H
tBu
iPr
Me
H
Me
Me
Me
Me
Me
Me
tBu
Me
H
H
H
H
H
H
10
11,12
13
14
15
84
80
93
89
62
69
Ph
Ph
Ph
Ph
Me
16
Sch em e 2
tributyltin hydride give primarily products such as 2
which have an anti relative configuration.4a This ster-
eochemical outcome is best rationalized by transition
state A,1-4 which takes into account allylic 1,3-strain,1a,3c
dipole-dipole repulsion,4 and hyperconjugative stabili-
zation.4e
Inspired by this model, we postulated that facial
selectivity could be reversed by the use of a bidentate
Lewis acid to promote the intermediacy of transition state
B.7a Thus, the reaction of iodide 1 with tributyltin
hydride in the presence of 0.25 equiv of MgBr2‚OEt2
afforded syn product 3 with excellent diastereoselectivity
(>25:1)7a and in good yield (81%). Interestingly, neither
a full equivalent of Lewis acid nor an initiator11 was
needed to achieve maximal selectivity. However, this
reaction was also highly dependent on the relative
configuration of the iodide substrates; anti iodides gave
better selectivity than their syn counterparts in the
presence of MgI2. The limited availability of substituted
R-iodo-â-alkoxy esters12 precluded an extensive study of
C-2 and C-3 substituent effects on the stereochemical
outcome.
Subsequently, we have found that the limitations
inherent to the iodide substrates do not exist in the
corresponding bromide series. Reported herein are our
studies on the chelation-controlled radical reductions of
R-bromoesters, including experimental evidence for the
involvement of a chelated intermediate in the free radical
chain reaction. Preliminary findings also indicate that
chelation control could regulate the addition of radicals
to R,â-unsaturated esters.
(8) (a) Waldner, A.; De Mesmaeker, A.; Hoffmann, P.; Mindt, T.;
Winkler, T. Synlett 1991, 101. (b) De Mesmaeker, A.; Waldner, A.;
Hoffmann, P.; Mindt, T. Synlett 1993, 871.
(9) (a) Curran, D. P.; Abraham, A. C.; Liu, H.-T. J . Org. Chem. 1991,
56, 4335. (b) Ku¨ndig, E. P.; Xu, L.-H.; Romanens, P. Tetrahedron Lett.
1995, 36, 4047. (c) Hanessian, S.; Yang, H.; Schaum, R. J . Am. Chem.
Soc. 1996, 118, 2507.
(10) (a) Sibi, M. P.; J asperse, C. P.; J i, J . G. J . Am. Chem. Soc. 1995,
117, 10779. (b) Wu, J . H.; Radinov, R.; Porter, N. A. J . Am. Chem.
Soc. 1995, 117, 11029. (c) Sibi, M. P.; J i, J . G. J . Am. Chem. Soc. 1996,
118, 3063. (d) Sibi, M. P.; J i, J . G. Angew. Chem., Int. Ed. Engl. 1996,
35, 190. (e) Sibi, M. P.; J i, J . G.; Wu, J . H.; Gurtler, S.; Porter, N. A.
J . Am. Chem. Soc. 1996, 118, 9200. (f) Fhal, A. R.; Renaud, P.
Tetrahedron Lett. 1997, 38, 2661. (g) Sibi, M. P.; J i, J . J . Org. Chem.
1997, 62, 3800.
Ch ela tion -Con tr olled Red u ction s of r-Br om o Es-
ter s. The substituted R-bromo-â-alkoxy ester substrates
used in this study were prepared in a variety of ways.
Substrates 10-16 were prepared by methoxy-bromina-
tion of the corresponding unsaturated esters 4-9 as
shown in Table 1.13,14 Substrates 19 and 20 were
prepared from the readily available3c alcohol 17 (Scheme
2). Thus, reaction of 17 with benzyl 2,2,2-trichloroace-
timidate15 gave the benzyl ether 19, whereas TBS ether
20 was smoothly obtained from the treatment of 17 with
tert-butyldimethylsilyl trifluoromethanesulfonate.16 Iso-
(11) For an example of the use of zinc chloride as an initiator, see
ref 6d.
(12) The R-iodo-â-alkoxy esters can be prepared by the silver nitrate-
mediated alkoxy iodination reaction of an R,â-unsaturated ester; see
ref 13. This reaction works well only for substituted cinnamates and
crotonates. The presence of a secondary or tertiary alkyl substituent
at the â position of the unsaturated ester will preclude formation of
the desired regioisomer. A Mukaiyama reaction between the silyl
ketene acetal derived from methyl 2-iodopropanoate and a dimethyl
acetal could not be used due to the propensity of the intermediate
enolate to form a carbene. See Maryanoff, C. A.; Sorgi, K. L.; Zientek,
A. M. J . Org. Chem. 1994, 59, 237.
(13) Vishwakarma, L. C.; Walia, J . S. J . Indian Chem. 1976, 53,
156.
(14) The unsaturated esters were either purchased or prepared from
the corresponding acids, which were commercially available. Unsatur-
ated esters 4 and 5 were prepared from an aldol condensation (LDA,
THF, -78 °C then PhCHO) followed by dehydration (MsCl, pyridine
then DBU, toluene).
(15) Iversen, T.; Bundle, K. R. J . Chem. Soc., Chem. Commun. 1981,
25, 1240.

6556 J . Org. Chem., Vol. 63, No. 19, 1998
Guindon and Rancourt
Ta ble 2. Effect of C-2 a n d C-3 Su bstitu tion s in r-Br om oester Su bstr a tes on Ra d ica l Red u ction s
products
entry
substrate
R
R1
syn
anti
conditions,a A or B
temp (°C)
ratiob syn:anti
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
16
16
26
26
28
28
30
30
13
13
13
13
11
11
10e
14
14
Me
Me
iPr
iPr
c-C6H11
c-C6H11
tBu
tBu
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
iPr
tBu
H
33
33
35
35
37
37
39
39
3
3
3
3
41
41
43
45
45
34
34
36
36
38
38
40
40
2
2
2
2
42
42
44
46
46
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
A f
0
0
0
0
0
0
0
0
0
27:1
1:1.8
32:1
1:8
27:1
1:8
33:1
1:21
8:1
d
-
75
75
74
93
91
75
78
91
70
70
71
83
71
70
88
0
1:9
-78
-78
-78
-78
-78
-78
-78
28:1
1:20
84:1
1:13
64:1
3:1
Ph
Ph
Ph
Ph
f
H
B
1:4
a
Conditions A: 5 equiv of MgBr2‚OEt2, 2 equiv of Bu3SnH, 0.2 equiv of Et3B, CH2Cl2; B: 2 equiv of Bu3SnH, 0.2 equiv of Et3B, CH2Cl2.
Determined by GC analysis of crude reaction isolates. c Isolated yields. Volatile products. e Relative configuration between OMe and
b
d
Br is syn. f Bu3SnD was used.
propyl ethers 21 and 22 were obtained in good yield when
dibromide 18 (afforded by bromination of methyl R-me-
thylcinnamate) reacted with silver tetrafluoroborate in
2-propanol at 60 °C. Bromoesters 23 and 24 were
prepared by using standard enolate chemistry. Sub-
strates bearing a secondary or tertiary alkyl substituent
at the 3-position could not be prepared efficiently by the
methoxy-bromination reaction. Instead, these com-
pounds were obtained from a Mukaiyama reaction17
between silyl ketene acetal 25 and the appropriate
dimethylacetal, and the resultant diastereomeric bro-
mides were separated after flash chromatography on
silica gel.18 Finally, diethylamide 32 was derived in a
straightforward manner from R-methylcinnamic acid.
reduction of the R-bromoesters, we were able to conduct
a systematic analysis of the scope and limitations of the
reaction.
As shown in Table 2, the reduction of the R-bro-
moesters in the presence of MgBr2‚OEt2 completely
reversed the stereoselection of the reaction7 (cf. conditions
A versus B), affording the syn isomer with excellent
diastereofacial selectivity (entries 1, 3, 5, 7, 9).22,23
Similar to the nonchelation reaction in exhibiting a
sensitivity to temperature,4a the chelation-controlled
reduction proceeded with greater diastereoselectivity at
lower reaction temperatures, as exemplified by the 3-fold
enhancement in syn selectivity when the reaction was
conducted at -78 °C (28:1, entry 11) instead of 0 °C (8:1,
entry 9).
With the R-haloester substrates in hand, we were
poised to study their reaction with tributyltin hydride
under various conditions. Initial experiments employing
conditions optimized for R-iodoesters (2.0 equiv of Bu3-
SnH, 0.25 equiv of MgBr2‚OEt2)7a gave results that
deviated significantly from our earlier findings. If either
MgBr2‚OEt2, MgI2, or AlCl3 was used, the reduction of
R-iodoesters did not require an initiator. However, the
chelation-controlled reduction of R-bromoesters would
proceed only if Et3B19 was added to the reaction medium.
Another important difference between these reductions
was the necessity to use an excess (5 equiv) of MgBr2‚
OEt2 to achieve optimal results for the bromide series
(vide infra),20 while only catalytic amounts were required
for the reduction of the R-iodoesters. Having ascertained
the optimal conditions (2 equiv of Bu3SnH, 5 equiv of
MgBr2‚OEt2, 0.2-0.6 equiv of Et3B, CH2Cl2)21 for the
Interestingly, the nature of the substituent (R) at
position-3 had little effect on the reduction since primary,
secondary, and tertiary alkyl groups all gave ratios of
∼30:1 (Table 2; entries 1, 3, 5, 7). This finding contrasts
4
with the results obtained in the absence of MgBr2‚OEt2
which show that larger R substituents at position-3
confer greater selectivity in the nonchelated reduction
pathway (entries 2, 4, 6, 8). Table 2 also shows that
primary, secondary, and tertiary alkyl substituents at
position-2 were well tolerated (entries 11, 13, 15), and
that slightly higher ratios were observed with greater R1
substitution. The reduction of secondary bromides (entry
(21) To ensure that the radical process was quenched at the same
temperature at which the reaction was conducted, a radical inhibitor,
m-dinitrobenzene (m-DNB), was added to the reaction mixture prior
to workup.
(22) The relative configuration of the reduced products was estab-
lished by correlation of NMR chemical shifts. In all cases, the methyl
group adjacent to the ester function resonated slightly downfield for
the syn compounds relative to the corresponding resonance of the anti
isomers. The original NMR reference assignments were verified by
X-ray crystallographic structures; see ref 4d.
(23) For purposes of comparison, these reactions were all performed
at 0 °C since the tert-butyl substrate 31 was insoluble at lower
temperatures. Substrates 16, 26, and 28 gave higher ratios at -78
°C.
(16) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1984, 25, 5953.
(17) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043.
(18) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(19) (a) Brown, H. C.; Midland, M. M.; Kabalka, G. W. J . Am. Chem.
Soc. 1971, 93, 1024. (b) Nozaki, K.; Oshima, K.; Utimoto, K. Bull.
Chem. Soc. J pn. 1991, 64, 403.
(20) A similar observation has been made in the chelation-controlled
allylation of secondary R-iodoesters; see ref 7b.

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6557
Ta ble 3. Effect of Rela tive Con figu r a tion of
r-Br om oester Su bstr a tes on Ch ela tion -Con tr olled
Ra d ica l Red u ction s
addition of tin hydride; only starting material was
recovered under these circumstances.
Scheme 3 illustrates a set of experiments designed to
show whether the chelation-controlled reaction proceeds
through an intermediate that can be generated through
a different approach. More specifically, we wanted to
compare the reaction outcomes for 48 and for 49 in the
presence of MgBr2‚OEt2. If both reactions were to
proceed through the same radical intermediate, the
mechanism for its formation would involve halogen
abstraction for 48 and a radical transfer (addition) for
49, but more importantly, the method used to generate
the intermediate species should have little bearing on the
hydrogen transfer step dictating the outcome of the
reaction. As shown in Scheme 4, both the requisite
substrates 48 and 49 were prepared from alcohol 52.25
In control experiments, these compounds were subjected
to radical conditions in the absence of Lewis acid. The
treatment of 49 with ICH2Cl and Bu3SnH in the presence
of Et3B furnished a 1:4 mixture of 50 and 51 (Scheme 3),
demonstrating the expected anti-preference, while the
reduction of 48 (Bu3SnH, Et3B) gave similar results. In
the absence of MgBr2‚OEt2, both reactions would there-
fore seem to proceed through the same radical intermedi-
ate. In the presence of MgBr2‚OEt2 (2.0 equiv), reaction
of 49 with ICH2Cl, Bu3SnH, and Et3B led to a reversal
in facial selection (i.e. syn), as anticipated for a hydrogen
transfer reaction under chelation control, affording a 6:1
mixture of 50 and 51.26 The significance of this experi-
ment lies in the fact that 50 and 51 could arise from 49
only through a radical process. In the crucial experiment
where bromide 48 was subjected to Bu3SnH, Et3B, and
MgBr2‚OEt2, a similar outcome was observed, which
strongly suggests a common radical intermediate in both
chelation-controlled reactions.
Lending further support to radical involvement in the
chelation-controlled reduction is another set of similar
experiments based on a radical addition as the initial
step. In this study, tert-butyl radical was added to the
R,â-unsaturated ester 55 in the presence and absence of
Lewis acid (Scheme 5). Although the levels of selectivity
were modest (1:3), the reaction in the absence of MgBr2‚
OEt2 predictably favored the anti-isomer 57, while syn-
product (56) formation was prevalent in the presence of
the Lewis acid, presumably through the intermediacy of
a bidentate radical.
An interesting observation made from these experi-
ments was the apparent kinetic enhancement of the
radical addition in the presence of MgBr2‚OEt2. In a
typical experiment, Bu3SnH was introduced slowly by
syringe pump to a solution of olefin and alkyl halide to
minimize reduction of the radical prior to its addition to
the olefin. With an alkyl halide that is very bulky, such
as tert-butyl iodide, the slow addition of Bu3SnH was
unnecessary in the absence of MgBr2‚OEt2, but the
addition to the olefin (55) took place very slowly (50% of
unreacted substrate was recovered after a reaction time
of 20 h). By contrast, an acceleration of the reaction was
observed in the presence of MgBr2‚OEt2 since the addi-
tion products (56 and 57) were obtained in fair yield
(68%) after a total reaction time of only 2.5 h (no starting
products
ratioa
yieldb
entry substrate
R
R1 R2 syn anti syn:anti (%)
1
2
3
4
5
6
7
8
13
47
28
29
30
31
11
12
Ph
Ph
Me Br
Br Me
3
3
2
2
28:1
20:1
42:1
33:1
33:1
3:1
70
-
c-C6H11 Me Br 37
c-C6H11 Br Me 37
tBu
tBu
Ph
38
38
40
40
42
42
-
74
91
-
71
70
Me Br 39
Br Me 39
iPr Br 41
Br iPr 41
84:1
81:1
Ph
a
b
Determined by GC analysis of crude reaction isolates. Iso-
lated yields.
F igu r e 1.
17) proceeded, however, with considerably reduced syn
selectivity (vide infra).
Table 3 addresses the impact of the relative configu-
ration at C-2 and C-3 on the reduction. In most cases,
the chelation-controlled reductions of syn and anti bro-
mides (entries 1-4) had similar outcomes. Replacement
of the R1 methyl with an isopropyl group led to a similar
conclusion (entries 7 and 8). In other words, excellent
diastereoselectivity was observed irrespective of the
relative (C-2)-(C-3) configuration of the bromide sub-
strates, except when the R group at C-3 was tert-butyl
(cf. entries 5 and 6). In this case, the syn bromide 31
was reduced with little facial discrimination (3:1) com-
pared to its anti counterpart 30 (33:1) under the same
reaction conditions.24 To confirm these results, the
relative configuration of the syn bromide 31 was verified
by X-ray analysis (Figure 1). A rationale based on a
mechanistic model of chelation control is proposed for this
seemingly discordant result (vide infra).
In volvem en t of F r ee Ra d ica ls. Do these chelation-
controlled reductions actually proceed through the in-
termediacy of free radicals? The essentiality of an
initiator such as Et3B for the reduction of bromide 13 in
the presence of MgBr2‚OEt2 would suggest that radicals
do play a key role. Other evidence in support of this
includes the complete inhibition of the reaction of 13
when the radical chain inhibitor m-dinitrobenzene (m-
DNB) was added to the reaction mixture prior to the
(25) Poly, W.; Schomburg, D.; Hoffmann, H. M. R. J . Org. Chem.
1988, 53, 3701.
(24) The difference in reactivity between these two diastereomeric
bromides was similar to that observed for the corresponding iodides;
see ref 7a.
(26) In the Lewis acid mediated reaction of 49, a competitive process
leading to the formation of methyl R-methylcinnamate (45%) was
operative.

6558 J . Org. Chem., Vol. 63, No. 19, 1998
Guindon and Rancourt
Sch em e 3
Sch em e 4
hydrogen transfer step. Based on the assumption that
an electron-withdrawing group (i.e. ester) R to the incipi-
ent radical center would enhance the rate of radical
addition or halogen atom abstraction (by the electropos-
itive tin radical),29-31 these reactions should accelerate
when the ester becomes even more electrophilic upon
coordination with a Lewis acid. Similarly, hydrogen
transfer between the radical and the incoming tin hydride
should accelerate since the radical would be more elec-
trophilic when the ester carbonyl is complexed to the
Lewis acid. In fact, the work of Lusztyk and Dolbier
supports this argument; in reaction with tin hydride, the
more electrophilic perfluoro-n-alkyl radicals have been
found to be ∼100 times more reactive than n-alkyl
radicals at 20 °C.31a
In volvem en t of Lew is a cid Ch ela tes. We envi-
sioned the coordination of the bidentate Lewis acid with
the R-bromo-â-alkoxy ester as the initial step of the
reductive process. Subsequently, homolytic cleavage of
the C-Br bond would afford the chelated radical (B),
which would react with Bu3SnH from the face opposite
to that shielded by the phenyl or alkyl R group at C-3
(Scheme 1). Since the MgBr2‚OEt2 mediated reduction
does favor syn product formation, the results presented
in Tables 2 and 3 would seem to support this model.
However, we had yet to garner experimental evidence
for the involvement of the Lewis acid in a bidentate
chelate.
Sch em e 5
One approach to verify the existence of a bidentate
chelate between the carbonyl and the â-alkoxyl group of
the substrate would entail alteration of the substrate’s
ability to chelate with the Lewis acid and observation of
its effect on the selectivity of the reduction. The modi-
fications of the â-alkoxyl (X) group and its effects on the
hydrogen transfer reaction are shown in Table 4. Re-
material was recovered).27,28 The enhanced electrophi-
licity of the R,â-unsaturated ester due to activation by
the Lewis acid may have enhanced the rate of addition
of the nucleophilic alkyl radical and/or the subsequent
(29) (a) Kuvila, H. G.; Menapace, L. W. J . Org. Chem. 1963, 28, 2165.
(b) Kuvila, H. G. Adv. Organomet. Chem. 1964, 1, 47. (c) Menapace,
L. W.; Kuvila, H. G. J . Org. Chem. 1964, 29, 3047. (d) Kuvila, H. G.
Synthesis 1970, 499.
(30) (a) Coates, D. A.; Tedder, J . M. J . Chem. Soc., Perkin Trans. 2
1973, 1570. (b) Blackburn, E. V.; Tanner, D. D. J . Am. Chem. Soc.
1980, 102, 692. See also refs 3a-d.
(31) (a) Avila, D. V.; Ingold, K. U.; Lusztyk, J .; Dolbier, W. R., J r.;
Pan, H.-Q.; Muir, M. J . Am. Chem. Soc. 1994, 116, 99. (b) Xiao, X.;
Pan, H.-Q.; Dolbier, W. R., J r. J . Am. Chem. Soc. 1994, 116, 4521.
(27) An increase in the radical based polymerization rate has been
observed in the presence of a Lewis acid: (a) Imoto, M.; Otsu, T.;
Harada, Y. Makromol. Chem. 1963, 65, 180. (b) Yabumoto, S.; Ishii,
K.; Arita, K. J . Polym. Sci. A-1, 1969, 7, 1577. (c) Inoue, H.; Otsu, T.
Die Makromol. Chem. 1972, 153, 21. See also ref 29.
(28) A similar observation has been made by Sato in
a
study
involving radical additions in the presence of diethylaluminum
chloride.6e.

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6559
Ta ble 4. Effect of Su bstr a te Mod ifica tion s on MgBr 2‚OEt2 Ch ela tion in Ra d ica l Red u ction s
products
entry
substrate
X
R
syn
anti
conditions,a A or B
ratiob syn:anti
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
13
13
19
19
22
22
20
20
23,24
23,24
15
15
32
OMe
OMe
OBn
OBn
OiPr
OiPr
OTBS
OTBS
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OtBu
OtBu
NEt2
NEt2
3
3
2
2
A
B
A
B
A
B
A
B
A
B
A
B
A
B
28:1
1:20
12:1
1:13
1:7
1:9
1:4.8
1:4
1:2.5
1:3.3
57:1
1:22
6:1
70
81
80
72
76
97
91
99
81
90
62
89
70
83
58
58
60
60
62
62
64
64
66
66
68
68
59
59
61
61
63
63
65
65
67
67
69
69
Me
OMe
OMe
OMe
OMe
32
1:13
a
Conditions A: 5 equiv of MgBr2‚OEt2, 2 equiv of Bu3SnH, 0.2 equiv of Et3B, CH2Cl2, -78 °C; B: 2 equiv of Bu3SnH, 0.2 equiv of Et3B,
CH2Cl2, -78 °C. Determined by GC analysis of crude reaction isolates. c Isolated yields.
b
placement of the OMe by an OBn group led to an erosion
of syn diastereoselectivity under chelation-controlled
conditions (cf. entries 1 and 3). When the OMe was
replaced by an OiPr (cf. entries 1 and 5), the Lewis acid
lost its influence in controlling the stereochemical out-
come (cf. entries 5-6). Presumably, the steric congestion
furnished by the larger iPr group (relative to Me)
precluded chelation of the oxygen with MgBr2‚OEt2.
Similar observations were made for the radical reduction
of silyl ether 20;32 indeed, in the presence or absence of
MgBr2‚OEt2, the reaction favored anti-product formation
(entries 7-8). The inability of the X group to chelate due
to steric and/or electronic factors therefore produced the
same effect as the absence of a coordinating oxygen at
the â-position (entries 9-10). From these results, it is
clear that the bidentate Lewis acid chelate in these
hydrogen transfer reactions is essential for facial dis-
crimination favoring syn product.
The effect of modifying the ester R group is also shown
in Table 4. While replacement of the ester OMe by OtBu
led to a 2-fold enhancement in facial selectivity (cf. entries
1 and 11) under chelation controlled conditions, this
change had little impact on the nonchelation pathway
(cf. entries 2 and 12). On the other hand, replacement
of the ester by a N,N-diethylamide had a deleterious
effect on the reduction mediated by MgBr2‚OEt2 (cf.
entries 1 and 13); the bidentate chelate in this case may
be destabilized by a 1,3-allylic interaction between an
amide ethyl group and the R-methyl group. Interest-
ingly, the effect of the N,N-diethylamide on the reduction
was less severe in the absence of MgBr2‚OEt2 (cf. entries
2 and 14).
level of facial discrimination, more than 3 equiv of MgBr2‚
OEt2 was required. These observations suggest that the
bidentate chelate may be in fact less reactive than the
nonchelated and/or monodentate species giving rise to
anti-product, and that an excess of MgBr2‚OEt2 would
then be needed to ensure a maximal concentration of the
substrate in its bidentate chelate form for optimal syn-
selectivity.
Under the conditions of excess MgBr2‚OEt2, at least
three reactive species may play a role in determining the
product distribution. One of these would be the bidentate
(71, Scheme 6) giving rise to the syn product. While anti-
product could arise from the radical reduction of R-bro-
moesters via a nonchelation pathway, it is more likely
that this isomer also arises from an intermediate com-
plexed to MgBr2‚OEt2, which is present in excess, and
that Lewis acid complexation of the ester would enhance
the rate of reaction relative to that of the uncomplexed
ester. Nevertheless, reduction of a monodentate Lewis
acid complex (70) involving the ester carbonyl should
proceed through an anti-predictive transition state (A)
analogous to the nonchelation pathway. Therefore,
depending on the nature and amount of Lewis acid
present, an interplay between the uncomplexed, mono-
dentate, and bidentate pathways and their respective
reaction rates probably determine the stereochemical
outcome of the radical reduction.
To distinguish between the reactivity of the monoden-
tate and bidentate species, we designed the following
competition experiment. A mixture consisting of silyl
ether 20 (1 equiv) and methyl ether 13 (1 equiv) was
treated with tributyltin hydride (1 equiv) under normal
reaction conditions in the presence of MgBr2‚OEt2. The
NMR spectrum of the crude reaction isolate revealed a
∼1:10 mixture of unreacted 20 to 13, indicating that the
silyl ether 20, reacting through the monodentate species,
was consumed ∼10 times faster than the methyl ether
13, which is expected to react as a bidentate species. In
a control experiment to verify that the differential
reactivity is attributed to interaction with the Lewis
acid and is not inherent to the substrates, the reaction
rates of 20 and 13 under radical reduction conditions
An observation noted earlier was the necessity for an
excess of MgBr2‚OEt2 to be present prior to the addition
of Bu3SnH to achieve good selectivity in the hydrogen
transfer reactions. When less than 1 equiv of MgBr2‚
OEt2 was used, no significant preference for the syn
product was observed. Indeed, to attain an optimum
(32) Oxygen atoms of hindered silyl ethers are known to be less
efficient in complexation with Lewis acids; see Chen, X.; Hortelano,
E. R.; Eliel, E. L.; Frye, S. V. J . Am. Chem. Soc. 1992, 114, 1778 and
references therein.

6560 J . Org. Chem., Vol. 63, No. 19, 1998
Guindon and Rancourt
Sch em e 6
Sch em e 8
the SOMO energy of the bidentate radical may actually
be greater than that of the monodentate, and the slower
reaction rate of the bidentate may be due to a SOMO-
(bidentate)-HOMO(Bu3SnH) interaction that is weaker
than that of the SOMO(monodentate)-HOMO(Bu3SnH).
The greater reactivity of the monodentate (compared
to the bidentate) may in fact provide a rationale for the
anomaly noted earlier, in which the stereochemical
outcome appeared to rely on the relative configuration
of the substrates 30 and 31 (cf. entries 5-6, Table 3). In
a competition experiment in which a mixture of anti
bromide 30 (1 equiv) and syn bromide 31 (1 equiv) was
subjected to Bu3SnH (1 equiv) in the presence of MgBr2‚
OEt2, it was found that 31, which reacted less selectively
(3:1, entry 6), was consumed ∼8 times faster than 30.
By contrast, no difference in rates of reaction was found
between the anti bromide 13 and its syn counterpart 47
(nor between any other pair of diastereomeric bromides
shown in Table 3) under similar conditions. The resem-
blance between the kinetic behavior of syn bromide 31
and that of silyl ether 20 in terms of high reactivity and
poor selectivity (albeit with opposite stereoselection)
would suggest that the bidentate pathway is also disfa-
Sch em e 7
vored in the Lewis acid mediated reduction of 31.
A
comparison of the bidentate chelates 78 and 79 (Scheme
8), which arise from bromides 30 and 31, respectively,
may provide a rationale for the differential reactivity of
these diastereomeric substrates. In both syn-predictive
chelates (78 and 79), the bromine would presumably
occupy a pseudoaxial position for the maximum overlap
with the carbonyl π system to facilitate C-Br bond
cleavage. While chelate 78 appears relatively free of
destabilizing interactions, the steric compression between
the pseudoequatorial tert-butyl and R-methyl groups in
the bidentate complex 79 may be sufficiently severe to
permit the anti-selective monodentate pathway to become
more competitive.
were found in fact to be similar in the absence of MgBr2‚
OEt2. Therefore, it would appear that the monodentate
reacts more rapidly than the bidentate species in the
chelation-controlled reduction.
Taking into account the observations made above,
Scheme 6 provides a rationale for the stereochemical
outcome of the chelation-controlled hydrogen transfer
reaction. At low concentrations (<1 equiv) of MgBr2‚
OEt2, it appears that reaction through the monodentate
pathway (70 f 73 f 2) is favored to afford anti product.
Since this pathway is kinetically favored, an excess of
MgBr2‚OEt2 is required to favor bidentate chelate forma-
tion prior to homolytic cleavage of the C-Br bond and
during the hydrogen transfer step.33 Although there are
two possible bidentate conformers (71 and 72) after initial
complexation with 13, chelate 71 should be more reactive
Why is there such a difference between the monoden-
tate and bidentate reaction rates? Assuming that the
hydrogen transfer is the rate-determining step, one could
attribute the lower reactivity of the bidentate (compared
to the monodentate) to destabilization of the bidentate
transition state by the developing steric compression
between the pseudoaxial Ph and a ligand on the magne-
sium (i.e. Br or Et2O) during rehybridization (Scheme 7).
An electronic factor contributing to the diminished
reactivity of the bidentate may involve the less optimal
alignment between the magnesium, ester carbonyl, and
the radical p orbital in the bidentate. In such a scenario,

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6561
(1.25 equiv) in anhydrous THF (1.5 M) at 0 °C. After being
stirred for 20 min at 0 °C, the solution was cooled to -78 °C,
and a solution of an appropriate acetate (1 equiv) in THF (1.5
M solution) was added. The reaction mixture was stirred at
this temperature for 45 min before benzaldehyde (1 equiv) was
added. The mixture was then quenched by adding a saturated
aqueous NH4Cl solution and extracted with Et2O (3×). The
organic extracts were combined and washed with a saturated
aqueous NaHCO3 solution. The organic layer was dried
(MgSO4), filtered, and concentrated. To a cold (0 °C) solution
of this residue in dry pyridine (1.5 M) was added mesyl chloride
(4.8 equiv). The reaction mixture was stirred overnight at 25
°C, diluted with Et2O (200 mL), and successively washed with
a cold 10% aqueous HCl solution (2 × 50 mL), water, a
saturated aqueous NaHCO3 solution, and brine. The organic
layer was dried (MgSO4), filtered, and concentrated. To a
solution of the residue in dry toluene (2 M) was added DBU
(5.5 equiv), and the resultant solution was refluxed for 1.5 h.
The reaction mixture was then diluted with Et2O (150 mL)
and successively washed with a 10% aqueous HCl solution (3
× 50 mL), water, and brine. The organic layer was dried
(MgSO4), filtered, and concentrated. To a solution of the
residue in absolute MeOH was added sodium carbonate (1.1
equiv). The reaction mixture was refluxed for 2.5 days, diluted
with water (10 mL), and extracted with Et2O (4×). The
organic extracts were combined, dried (MgSO4), filtered, and
concentrated. The residue was flash chromatographed on
silica gel (2% EtOAc-hexane) to afford the desired olefins.
Meth yl r-ter t-Bu tylcin n a m a te (4). The olefin 4 was
prepared from methyl tert-butylacetate (without the transes-
terification step) and was isolated as a colorless oil (mixture
of isomers E/Z ) 1/1.5, 54% overall yield); IR (neat) νmax 1720,
1640 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.11 (s, 9H (minor)),
1.24 (s, 9H (major)), 3.63 (s, 3H (major)), 3.79 (s, 3H (minor)),
6.55 (s, 1H (major)), 7.14 (s, 1H (minor)), 7.16-7.36 (m, 10H
(minor + major)); 13C NMR (50.3 MHz, CDCl3) δ 29.0, 30.5,
34.9, 35.1, 50.9, 51.0, 126.0, 126.6, 127.1, 127.3, 127.5, 127.7,
127.9, 133.7, 136.1, 137.5, 144.4, 144.5, 170.4 (CdO), 170.5
(CdO); MS (CI, CH4) m/e (relative intensity) 219 (MH+, 100),
187 (52); HRMS calcd for C14H18O2 (M+) 218.1307, found
218.1301 (2.5 ppm). Anal. Calcd for C14H18O2: C, 77.03; H,
8.31. Found: C, 77.14; H, 8.53.
in the homolytic cleavage due to the better overlap of the
C-Br bond with the carbonyl π system. This electronic
interaction should permit a more facile conversion of 71
to 74 than that of 72 to 75. Once formed, the radical
may exist in the two conformers 74 and 75, which lead,
respectively, to transition states B and C for the hydro-
gen transfer step. One would expect a preference for the
syn-predictive transition state B over anti-predictive C
on both electronic and steric grounds. Electronically, the
electron-poor radical should be better stabilized by
overlap with the C-Ph bond in B than with the C-H
bond in C.34 From a steric standpoint, C appears to
suffer from a 1,2-allylic interaction between the phenyl
and methyl groups. In the absence of this steric interac-
tion, such as in the case of secondary bromide substrates,
the decrease in energy difference between B and C may
well account for the observed erosion in syn preference
(Table 2, entry 16). Thus the high level of diastereose-
lectivity exhibited by the chelation-controlled process may
be attributed to the prevalence of the syn-selective
bidentate pathway during both radical formation and the
subsequent hydrogen transfer. These hypotheses await
verification through kinetic analyses and theoretical
evaluation.
Con clu sion s
Our study of substituent effects clearly establishes the
scope and limitations of the chelation-controlled radical
reduction of R-bromo-â-alkoxy esters. This reaction
tolerates a wide variety of substitutions and, except for
large groups at position 3, is generally unaffected by the
relative configuration of the substrate. In the presence
of MgBr2‚OEt2, the reduction requires initiation and is
inhibited by m-DNB, thereby demonstrating behavior
typical of radical chain reactions. Other testimony to the
intermediacy of radicals are the tandem addition/
hydrogen transfer reactions involving R,â-unsaturated
esters, performed in the presence of a Lewis acid. We
are presently evaluating other types of acyclic radical-
based reactions that may be subject to kinetic enhance-
ment through chelation.
Gen er a l P r oced u r e for th e P r ep a r a tion of Su bstr a tes
10-16 by Meth oxy-br om in a tion .13 To a cold (0 °C) solution
of the appropriate methyl cinnamate 4-9 (1 equiv) in absolute
MeOH (3.5 M) were successively added AgNO3 (1.2 equiv) and
Br2 (1.2 equiv). The reaction mixture was stirred at 25 °C for
1 h and then filtered and concentrated. The residue was
purified by flash chromatography on silica gel to afford the
desired bromides.
Exp er im en ta l Section
Meth yl (()-(2R*,3S*)-2-Br om o-2-ter t-bu tyl-3-m eth oxy-
3-p h en ylp r op ion a te (10). After flash chromatography on
silica gel (8% Et2O-hexane), the bromide 10 was obtained as
a white solid (84% yield); mp ) 58-59 °C; IR (neat) νmax 1720
Gen er a l Meth od s. All reactions requiring anhydrous
conditions were conducted under a positive nitrogen atmo-
sphere in oven-dried glassware using standard syringe tech-
niques. The anhydrous solvents purchased from Aldrich were
used as received. i-Pr2NH and Et3N were freshly distilled from
CaH2 under N2 atmosphere. n-BuLi (1.6 M solution in hexane)
purchased from Aldrich was titrated prior to use (diphenyl-
acetic acid end-point in dry THF). Bu3SnH and Et3B (1 M
solution in hexane), also purchased from Aldrich, were 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. Melting
points were determined on an electrothermal melting point
apparatus and are uncorrected.
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.00 (s, 9H), 3.11 (s, 3H),
3.83 (s, 3H), 4.82 (s, 1H), 7.34-7.37 (m, 3H), 7.68-7.71 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ 27.6, 38.4, 52.7, 55.9, 84.4,
86.0, 127.4, 128.5, 130.0, 136.7, 169.6 (CdO); MS (CI, NH3)
m/e (relative intensity) 348 (MNH4+, 98), 346 (MNH4+, 100),
331 (MH+, 12), 329 (MH+, 12).
Meth yl (()-(2S*,3S*)-2-Br om o-2-m eth yl-3-h yd r oxy-3-
p h en ylp r op ion a te (17). To a solution of methyl R-methyl-
cinnamate 6 (1.46 g, 8.3 mmol) in a mixture of acetone (19.4
mL) and water (29 mL) were successively added NBS (2.95 g,
16.6 mmol) and H2SO4 (144 µL).3c The reaction mixture was
stirred overnight at 25 °C and then poured into brine and
extracted with Et2O (3×). The organic extracts were combined,
dried (MgSO4), filtered, and concentrated. The residue was
flash chromatographed on silica gel (15% EtOAc-hexane) to
afford the alcohol 17 (1.28 g, 56% yield). White solid (mp )
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth yl
Cin n a m a tes 4 a n d 5. A solution of LDA was prepared by
the addition of n-BuLi (1.25 equiv) to a solution of i-Pr2NH
50-51 °C); IR (neat) νmax 1730 cm-1 1H NMR (400 MHz,
;
(33) In the same manner that oxygen-containing solvents (e.g. THF)
can stabilize Grignard reagents through coordination with magnesium,
the bidentate chelate may be more stable than the monodentate form
when MgBr2‚OEt2 is present in excess relative to the substrate.
(34) (a) See refs 4c and 4e. (b) Curran, D. P.; Balas, L. Synlett 1995,
119.
CDCl3) δ 1.80 (s, 3H), 3.16 (d, 1H, J ) 5.1 Hz), 3.84 (s, 3H),
5.32 (d, 1H, J ) 5.1 Hz), 7.31-7.38 (m, 3H), 7.44-7.48 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ 21.4, 52.8, 61.4, 77.0,
127.1, 127.8, 128.1, 137.1, 171.2 (CdO); HRMS calcd for C11H13
-

6562 J . Org. Chem., Vol. 63, No. 19, 1998
Guindon and Rancourt
BrO3 (M+) 272.0055, found 272.0048 (-2.5 ppm). Anal. Calcd
for C11H13BrO3: C, 48.37; H, 4.80. Found: C, 48.41; H, 4.73.
Meth yl (()-(2S*,3S*)-2-Br om o-2-m eth yl-3-br om o-3-ph e-
n ylp r op ion a te (18). To a solution of methyl R-methylcin-
namate 6 (5.04 g, 28.6 mmol) in CCl4 (in the dark) was added
Br2 (3.0 mL, 57.3 mmol). The reaction mixture was stirred
overnight at 25 °C and then concentrated. The residue was
flash chromatographed on silica gel (3% EtOAc-hexane) to
afford the desired dibromoester 18 (8.28 g, 86% yield). White
solid (mp ) 49-50 °C); IR (neat) νmax 1740 cm-1; 1H NMR (200
MHz, CDCl3) δ 2.06 (s, 3H), 3.90 (s, 3H), 5.76 (s, 1H), 7.35-
7.38 (m, 3H), 7.50-7.60 (m, 2H); 13C NMR (50.3 MHz, CDCl3)
δ 22.0, 53.4, 57.2, 61.3, 127.6, 128.9, 130.7, 135.1, 169.6 (Cd
O); HRMS calcd for C12H12Br2O2 (M+) 333.9205, found 333.9205
(0.1 ppm).
Meth yl (()-2-Br om o-2-m eth yl-3-p h en ylbu ta n oa tes (23
a n d 24). A solution of LDA was prepared by the addition of
a 1.6 M solution of n-BuLi in hexane (16.7 mL, 26.7 mmol) to
a cold (0 °C) solution of i-Pr2NH (3.75 mL, 26.7 mmol) in dry
THF (20 mL). After being stirred for 20 min at 0 °C, the
solution was cooled to -78 °C, and a solution of methyl
3-phenylbutanoate (4.00 g, 22.3 mmol) in THF (15 mL) was
added. The reaction mixture was stirred at this temperature
for 1 h before MeI (1.67 mL, 26.8 mmol) was added. The
mixture was then slowly allowed to warm to 25 °C, diluted
with ether, and successively washed with 10% aqueous HCl,
10% aqueous Na2S2O3, water, and brine. The residue was then
dried (MgSO4) and purified by flash chromatography on silica
gel (4% Et2O-hexane) to afford methyl 2-methyl-3-phenylbu-
tanoates 64 and 65 (3.86 g, 90% yield) as a mixture of
diastereomers. The diastereomers can be separated using the
above conditions. Less polar isomer: colorless oil; IR (neat)
Meth yl (()-(2S*,3S*)-2-Br om o-2-m eth yl-3-(ben zyloxy)-
3-p h en ylp r op ion a te (19). To a solution of alcohol 17 (509
mg, 1.9 mmol) in a mixture of cyclohexane (13 mL) and CH2-
Cl2 (7 µL) were successively added benzyl 2,2,2-trichloroace-
timidate (694 mL, 3.7 mmol) and trifluoromethanesulfonic acid
(98 µL).15 The reaction mixture was stirred for 2.5 h at 25
°C and then filtered and successively washed with a saturated
aqueous NaHCO3 solution, water, and brine. The organic
layer was dried (MgSO4), filtered, and concentrated. The
residue was flash chromatographed on silica gel (5% Et2O-
hexane) to afford the benzyl ether 19 (505 mg, 74% yield).
ν
max 1730 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.93 (d, 3H, J )
6.7 Hz), 1.24 (d, 3H, J ) 7.0 Hz), 2.56-2.64 (m, 1H), 2.86-
2.94 (m, 1H), 3.70 (s, 3H), 7.14-7.21 (m, 3H), 7.24-7.30 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ 16.1, 20.6, 43.4, 46.7, 51.3,
126.4, 127.4, 128.4, 144.2, 176.6 (CdO); HRMS calcd for
C
12H16O2 (M+) 192.1150, found 192.1147 (1.6 ppm). Anal.
Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.87; H,
8.59. More polar isomer: colorless oil; IR (neat) νmax 1730
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.17 (d, 3H, J ) 7.0 Hz),
Colorless oil; IR (neat) νmax 1735 cm-1 1H NMR (400 MHz,
;
1.27 (d, 3H, J ) 7.3 Hz), 2.63-2.70 (m, 1H), 3.02-3.10 (m,
1H), 3.47 (s, 3H), 7.16-7.20 (m, 3H), 7.22-7.29 (m, 2H); 13C
NMR (100.6 MHz, CDCl3) δ 13.5, 16.9, 41.8, 46.1, 50.5, 125.8,
126.8, 127.7, 144.4, 175.1 (CdO); HRMS calcd for C12H16O2
(M+) 192.1150, found 192.1146 (4.4 ppm). A solution of LDA
was prepared by the addition of a 1.6 M solution of n-BuLi in
hexane (3.9 mL, 6.2 mmol) to a cold (0 °C) solution of i-Pr2NH
(875 µL, 6.2 mmol) in dry THF (5 mL). After being stirred
for 20 min at 0 °C, the solution was cooled to -78 °C and a
solution of methyl 2-methyl-3-phenylbutanoates 64 and 65
(1.00 g, 5.2 mmol) in THF (3.5 mL) was added. The reaction
mixture was stirred at this temperature for 1 h before a
solution of CBr4 (1.90 g, 5.7 mmol) in THF (4 mL) was added.
The mixture was then slowly allowed to warm to 25 °C, diluted
with Et2O, and successively washed with 10% aqueous HCl,
water, and brine. The residue was then filtered through a pad
of silica gel (200 mL, 15% EtOAc-hexane) and flash chro-
matographed on silica gel (5% Et2O-hexane) to afford methyl
2-bromo-2-methyl-3-phenylbutanoates 23 and 24 (1.06 g, 75%
yield) as a pale red oil (5:1 mixture of diastereomers). Color-
CDCl3) δ 1.79 (s, 3H), 3.75 (s, 3H), 4.30 (d, 1H, J ) 11.4 Hz),
4.45 (d, 1H, J ) 11.4 Hz), 5.13 (s, 1H), 7.15-7.53 (m, 10 H);
13C NMR (100.6 MHz, CDCl3) δ 21.5, 52.9, 60.3, 71.7, 83.9,
127.6, 127.7, 128.2, 128.5, 129.6, 134.9, 137.4, 171.0 (CdO);
MS (CI, NH3) m/e (relative intensity) 382 (MNH4+, 98), 380
(MNH4+, 100); HRMS calcd for C14H13O (M+ - C4H6BrO3)
197.0966, found 197.0970 (-2.0 ppm).
Meth yl (()-(2S*,3S*)-2-Br om o-2-m eth yl-3-(ter t-bu tyld i-
m eth ylsilyloxy)-3-p h en ylp r op ion a te (20). To a cold (0 °C)
stirred solution of alcohol 17 (1.51 g, 5.5 mmol) in dry CH2Cl2
were successively added Et3N (1.2 mL, 8.3 mmol) and t-BuMe2-
SiOTf (1.5 mL, 6.6 mmol).16 The reaction mixture was stirred
at 25 °C for 2 h and then diluted with Et2O and successively
washed with a 10% aqueous K2CO3, water, and brine. The
organic layer was dried (MgSO4), filtered, and concentrated.
The residue was flash chromatographed on silica gel (1.5%
EtOAc-hexane) to afford the silyl ether 20 (1.63 g, 76% yield).
Colorless oil; IR (neat) νmax 1740 cm-1 1H NMR (400 MHz,
;
CDCl3) δ -0.35 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.80 (s, 3H),
3.82 (s, 3H), 5.37 (s, 1H), 7.29-7.36 (m, 3H), 7.43-7.47 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ -5.9, -4.7, 17.7, 20.8,
25.4, 52.6, 61.7, 78.1, 127.1, 128.1, 129.2, 137.8, 170.9 (CdO);
MS (CI, isobutane) m/e (relative intensity) 389 (MH+, 10), 387
(MH+, 9), 257 (100), 255 (100). Anal. Calcd for C17H27BrO3-
Si: C, 52.71; H, 7.03. Found: C, 52.55; H, 7.28.
1
less oil; IR (neat) νmax 1735 cm-1; H NMR (400 MHz, CDCl3)
δ 1.38 (d, 3H, J ) 7.3 Hz (minor)), 1.55 (d, 3H, J ) 7.3 Hz
(major)), 1.82 (s, 3H (major)), 1.85 (s, 3H (minor)), 3.61 (q, 1H,
J ) 7.0 Hz (minor)), 3.66 (q, 1H, J ) 7.0 Hz (major)), 3.70 (s,
3H (major)), 3.78 (s, 3H (minor)), 7.22-7.32 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) (major diastereomer) δ 17.2, 24.6, 47.8,
52.7, 67.0, 127.3, 128.0, 129.1, 139.6, 171.5 (CdO); 13C NMR
(100.6 MHz, CDCl3) (minor diastereomer) δ 16.9, 24.6, 48.3,
52.9, 65.8, 127.2, 127.7, 129.5, 140.2, 171.5 (CdO); HRMS calcd
for C12H15BrO2 (M+) 270.0255, found 270.0262 (-2.5 ppm).
1-Meth oxy-1-(tr im eth ylsilyloxy)-2-br om op r op en e (25).
A solution of LDA was prepared by the addition of a 1.6 M
solution of n-BuLi in hexane (44.8 mL, 71.7 mmol) to a cold (0
°C) solution of i-Pr2NH (10 mL, 71.4 mmol) in dry THF (54
mL). After being stirred for 20 min at 0 °C, the solution was
cooled to -78 °C, and a solution of methyl 2-bromopropionate
(8 mL, 71.7 mmol) was added. The reaction mixture was
stirred for 15 min before Me3SiCl (20 mL, 157.6 mmol) was
added. The mixture was then slowly allowed to warm to 25
°C, stirred at this temperature for 1 h and then filtered and
concentrated. The residue was taken up in hexane, and the
resultant solution was filtered twice. After concentration, the
residue was distilled under reduced pressure (10 mmHg, 85
°C) to afford the desired silyl ketene acetal 25 (12.61 g, 74%
yield) as a colorless liquid (mixture of E and Z isomers, and
∼30% of C-silylated material) that was used without further
purification.
Meth yl (()-2-Br om o-2-m eth yl-3-(isop r op yloxy)-3-p h e-
n ylp r op ion a tes (21 a n d 22). To a solution of dibromoester
18 (1.52 g, 4.5 mmol) in i-PrOH (14 mL) was added AgBF4
(1.06 g, 5.4 mmol). The reaction mixture was stirred at 60 °C
for 1 h and then filtered and concentrated. The residue was
flash chromatographed on silica gel (3% Et2O-hexane) to
afford a mixture of isopropyl ethers 21 and 22 (1.18 g, 82%
yield). The two diastereomers can be separated using the
above conditions. Compound 21 (less polar isomer): colorless
oil; 1H NMR (400 MHz, CDCl3) δ 0.99 (d, 3H, J ) 6.0 Hz),
1.07 (d, 3H, J ) 6.0 Hz), 1.74 (s, 3H), 3.50 (h, 1H, J ) 6.0 Hz),
3.84 (s, 3H), 5.10 (s, 1H), 7.31-7.40 (m, 3H), 7.47-7.50 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ 20.9, 21.4, 23.0, 52.6, 60.7,
71.0, 82.0, 127.3, 128.1, 129.4, 136.3, 170.9 (CdO). Compound
22 (more polar isomer): colorless oil; IR (neat) νmax 1740 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.08 (d, 3H, J ) 6.0 Hz), 1.22 (d,
3H, J ) 6.0 Hz), 1.77 (s, 3H), 3.58 (h, 1H, J ) 6.0 Hz), 3.73 (s,
3H), 4.94 (s, 1H), 7.29-7.37 (m, 5H); 13C NMR (100.6 MHz,
CDCl3) δ 21.0, 22.6, 23.0, 52.6, 65.3, 71.0, 82.2, 127.8, 128.2,
128.4, 137.3, 170.4 (CdO); Mixture of isomers; colorless oil;
MS (CI, isobutane) m/e (relative intensity) 317 (MH+, 100),
315 (MH+, 100). Anal. Calcd for C14H19BrO3: C, 53.35; H,
6.08. Found: C, 53.19; H, 6.01.
Gen er a l P r oced u r e for th e P r ep a r a tion of Su bstr a tes
26-31 a n d 47 Usin g Mu k a iya m a ’s P r otocol.17 To a cold

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6563
(-78 °C) solution of the appropriate dimethylacetal (1 equiv)
in dry CH2Cl2 (2 M) were successively added a 1.0 M solution
of TiCl4 in CH2Cl2 (1 equiv) and a solution of the silyl ketene
acetal 25 (2 equiv) in CH2Cl2. The reaction mixture was
stirred for 4 h at -78 °C and 15 min at 0 °C and was poured
into a 10% aqueous K2CO3. After the aqueous layer was
extracted with CH2Cl2 (3×), the organic extracts were com-
bined, successively washed with water and brine, dried
(MgSO4), filtered through a pad of silica gel, and concentrated.
Met h yl (()-2-Br om o-2,4-d im et h yl-3-m et h oxyp en t a n -
oa tes (26 a n d 27). Each diastereomer, prepared from isobu-
tyraldehyde dimethylacetal, can be obtained in pure form by
flash chromatography on silica gel (3% Et2O-hexane, 75%
yield). Compound 26 (less polar isomer): colorless oil; IR
°C, the mixture was filtered through a short pad of silica gel
(100 mL, 15% EtOAc-hexane) and concentrated.
Meth yl (()-2-(2-Ch lor oeth yl)-3-h yd r oxy-3-p h en ylp r o-
p ion a te 53. To a warmed (80 °C) solution of alcohol 5225 (1.00
g, 5.2 mmol) and ICH2Cl (1.9 mL, 26.1 mmol) in dry toluene
(19 mL) was slowly added, over a period of 2 h, a solution of
Bu3SnH (2.80 mL, 10.4 mmol) and AIBN (128 mg, 0.8 mmol)
in toluene (8 mL). The reaction mixture was then stirred
overnight at 25 °C, concentrated, diluted with hexane, and
treated with a 1.0 M solution of n-Bu4NF in THF (12.5 mL,
12.5 mmol). The mixture was filtered through a short pad of
silica gel (200 mL, 40% EtOAc-hexane) and concentrated. The
residue was flash chromatographed on silica gel (20% EtOAc-
hexane) to afford a mixture of alcohols 53a and 53b (1.03 g,
82% yield). Less polar alcohol; colorless oil; IR (neat) νmax 3470,
1
(neat) νmax 1735 cm-1; H NMR (400 MHz, CDCl3) δ 0.89 (d,
1
1730 cm-1; H NMR (200 MHz, CDCl3) δ 1.96-2.32 (m, 2H),
3H, J ) 7.0 Hz), 1.02 (d, 3H, J ) 6.7 Hz), 1.65-1.75 (m, 1H),
1.85 (s, 3H), 3.62 (d, 1H, J ) 5.7 Hz), 3.65 (s, 3H), 3.79 (s,
3H); 13C NMR (100.6 MHz, CDCl3) δ 19.0, 21.4, 22.1, 32.2, 52.7,
62.9, 65.6, 89.3, 171.1 (CdO); MS (CI, NH3) m/e (relative
intensity) 270 (MNH4+, 100); HRMS calcd for C6H10O3Br (M+
- C3H7) 208.9813, found 208.9822 (-4.4 ppm). Compound 27
2.76 (d, 1H, J ) 3.3 Hz), 2.93-3.04 (m, 1H), 3.37-3.65 (m,
2H), 3.66 (s, 3H), 5.08 (dd, 1H, J ) 3.3, J ) 4.8 Hz), 7.28-
7.37 (m, 5H); 13C NMR (50.3 MHz, CDCl3) δ 29.6, 42.7, 50.2,
51.5, 73.6, 125.6, 127.4, 128.0, 141.1, 173.7 (CdO). More polar
1
isomer; colorless oil; IR (neat) νmax 3460 (br), 1735 cm-1; H
(more polar isomer): colorless oil; IR (neat) νmax 1740 cm-1
;
NMR (400 MHz, CDCl3) δ 1.72-1.89 (m, 1H), 2.01-2.19 (m,
1H), 2.88 (d, 1H, J ) 5.5 Hz), 2.99-3.10 (m, 1H), 3.34-3.56
(m, 2H), 3.71 (s, 3H), 4.83 (dd, 1H, J ) 5.5, J ) 7.5 Hz), 7.28-
7.44 (m, 5H); 13C NMR (50.3 MHz, CDCl3) δ 31.2, 41.8, 50.2,
51.3, 74.4, 126.1, 127.6, 127.9, 141.0, 174.0 (CdO); HRMS calcd
for C12H16ClO3 (MH+) 243.0788, found 243.0795 (-2.9 ppm).
Anal. Calcd for C12H15ClO3: C, 59.39; H, 6.23. Found: C,
59.03; H, 6.13.
1H NMR (400 MHz, CDCl3) δ 1.01 (d, 3H, J ) 7.0 Hz), 1.14 (d,
3H, J ) 7.0 Hz), 1.84 (s, 3H), 2.21-2.32 (m, 1H), 3.45 (s, 3H),
3.69 (d, 1H, J ) 3.2 Hz), 3.80 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 17.7, 22.5, 24.3, 29.2, 52.7, 61.3, 62.5, 88.5, 171.2
+
(CdO); MS (CI, NH3) m/e (relative intensity) 270 (MNH4
,
100).
N,N-Dieth yl-(()-(2S*,3S*)-2-br om o-2-m eth yl-3-m eth oxy-
3-p h en ylp r op ion a m id e (32). To a solution of R-methylcin-
namic acid (1.03 g, 6.3 mmol) and Br2 (390 µL, 7.6 mmol) in
absolute MeOH (36 mL) was added AgNO3 (1.29 g, 7.6 mmol).
After being stirred for 45 min at 25 °C, the reaction mixture
was filtered and concentrated. The residue was diluted with
Et2O and successively washed with 10% aqueous Na2S2O3,
water, and brine. The organic layer was dried (MgSO4),
filtered, and concentrated to afford the desired R-bromoacid
(1.72 g, 99% yield). To a solution of the crude acid (1.50 g, 5.5
mmol) in dry toluene (2 mL) were successively added oxalyl
chloride (1.44 mL, 16.5 mmol) and a catalytic amount of DMF
(100 µL). After being stirred for 1 h at 25 °C, the reaction
mixture was concentrated, and the residue was dissolved in
dry CH2Cl2 (8 mL). To the cold (-78 °C) solution of crude acyl
chloride was added Et2NH (1.25 mL, 12.1 mmol). The reaction
mixture was slowly allowed to warm to 25 °C and then diluted
with Et2O and successively washed with saturated aqueous
NaHCO3, 10% aqueous HCl, water, and brine. The organic
layer was dried (MgSO4), filtered, and concentrated. The
residue was flash chromatographed on silica gel (10% EtOAc-
hexane) to afford the R-bromoamide 32 (1.31 g, 72% yield).
White solid (mp ) 68-69 °C); IR (CHCl3) νmax 2990, 2930, 1620,
Meth yl r-(2-Ch lor oeth yl)cin n a m a te 54. To a cold (0 °C)
solution of the Martin sulfurane dehydrating agent35 (1.07 g,
1.6 mmol) in dry CH2Cl2 (4 mL) was added a solution
containing a mixture of the alcohols 53a and 53b (320 mg,
1.3 mmol) in CH2Cl2 (2 mL). The reaction mixture was slowly
allowed to warm to 25 °C, stirred for 1 h and then diluted with
Et2O and successively washed with aqueous 10% NaOH,
water, and brine. The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was flash chromato-
graphed on silica gel (4% EtOAc-hexane) to afford the olefin
54 (237 mg, 1.1 mmol, 84% yield). Colorless oil; IR (neat) νmax
1
1710 cm-1; H NMR (400 MHz, CDCl3) δ 3.03 (t, 2H, J ) 7.5
Hz), 3.73 (t, 2H, J ) 7.5 Hz), 3.85 (s, 3H), 7.37-7.45 (m, 5H),
7.85 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 30.8, 42.5, 52.0,
128.5, 128.6, 128.7, 129.0, 134.8, 142.1, 167.8 (CdO); HRMS
calcd for C12H14O2Cl (MH+) 225.0682, found 225.0678 (1.9
ppm). Anal. Calcd for
Found: C, 64.03; H, 5.75.
C12H13ClO2: C, 64.34; H, 5.85.
Meth yl (()-(2S*,3S*)-2-Br om o-2-(2-ch lor oeth yl)-3-m eth -
oxy-3-p h en ylp r op ion a te 48. To a solution of olefin 54 (174
mg, 0.8 mmol) in absolute MeOH (1 mL) were successively
added Br2 (48 µL, 0.9 mmol) and AgNO3 (158 mg, 0.9 mmol).
The reaction mixture was stirred for 5 h at 25 °C, filtered,
and concentrated. The residue was diluted with Et2O, suc-
cessively washed with 10% aqueous Na2S2O3, water, and brine,
and dried (MgSO4). After filtration and concentration, the
residue was flash chromatographed on silica gel (3% EtOAc-
hexane) to afford the R-bromoester 48 (158 mg, 62% yield).
1450, 1370, 1270, 1090 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.22 (t, 6H, J ) 7.0 Hz), 1.85 (s, 3H), 3.26 (s, 3H), 3.30-3.48
(m, 2H), 3.70-3.88 (m, 2H), 4.85 (s, 1H), 7.34-7.39 (m, 3H),
7.43-7.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ 26.1, 42.5,
57.7, 62.5, 86.8, 127.6, 128.3, 129.4, 135.8, 168.0 (CdO); MS
(CI, NH3) m/e (relative intensity) 328 (MH+, 100), 248 (82);
HRMS calcd for C15H23NO2Br (M+) 328.0912, found 328.0900
(3.7 ppm).
Gen er a l P r oced u r e for Ra d ica l Red u ction u n d er Ch e-
la tion -Con tr olled Con d ition s (Con d ition s A). To a stirred
suspension of MgBr2‚OEt2 (5 equiv) in dry CH2Cl2 was added
R-bromoester in CH2Cl2 (0.1 M). After being stirred for 5 min
at 25 °C, the reaction mixture was cooled to 0 °C, and Bu3-
SnH was then added. Triethylborane (1 M solution in hexane)
was subsequently added in three equal portions during the
first 15 min of the reaction (3 × 0.2 equiv, total of 0.6 equiv).
After 2 h at 0 °C, m-dinitrobenzene (0.5 equiv) was added, and
the mixture was poured into a saturated aqueous NaHCO3.
The aqueous layer was extracted (3×) with CH2Cl2, and the
organic extracts were combined, successively washed with
water and brine, and dried (MgSO4). GC analysis was
performed on the crude reaction isolate. After filtration and
concentration, the residue was taken up in hexane and n-Bu4-
NF was added (2.5 equiv). After being stirred for 5 min at 25
Colorless oil; IR (neat) νmax 1740 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.27-2.35 (m, 1H), 2.65-2.73 (m, 1H), 3.26 (s, 3H),
3.59-3.66 (m, 1H), 3.83 (s, 3H), 3.84-3.92 (m, 1H), 4.85 (s,
1H), 7.36-7.47 (m, 5H); 13C NMR (50.3 MHz, CDCl3) δ 38.2,
41.6, 53.2, 57.9, 64.8, 87.1, 127.9, 128.8, 129.1, 134.2, 169.6
(CdO); HRMS calcd for C13H17BrClO3 (MH+) 335.0050, found
335.0065 (-4.6 ppm).
Meth yl (()-2-(1-Meth oxy-1-p h en ylm eth yl)p r op en oa te
49. To a solution of alcohol 5225 (500 mg, 2.6 mmol) in dry
CH2Cl2 (3 mL) were successively added proton sponge (2.80 g,
13.0 mmol) and MeOTf (1.5 mL, 13.0 mmol). The reaction
mixture was stirred overnight at 25 °C, diluted with Et2O, and
successively washed with 10% aqueous HCl (2×), water, and
brine. The organic layer was dried (MgSO4), filtered, and
concentrated. The residue was flash chromatographed on
(35) Martin, J . C.; Arhart, R. J . J . Am. Chem. Soc. 1971, 93, 4327.

6564 J . Org. Chem., Vol. 63, No. 19, 1998
Guindon and Rancourt
silica gel (5% EtOAc-hexane) to afford the methyl ether 49
(460 mg, 86% yield). 1H NMR (400 MHz, CDCl3) δ 3.33 (s,
3H), 3.71 (s, 3H), 5.14 (s, 1H), 5.94 (s, 1H), 6.34 (s, 1H), 7.27-
7.38 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 50.9, 56.1, 80.4,
123.8, 127.0, 127.7, 139.1, 140.9, 165.4 (CdO); IR (neat) νmax
1720, 1630 cm-1. Anal. Calcd for C12H14O3: C, 69.89; H, 6.84.
Found: C, 69.90; H, 7.05.
reduction of 30 or 31. The compounds were separated by flash
chromatography on silica gel by using 2% Et2O-hexane.
Meth yl (()-2-Isopr opyl-3-m eth oxy-3-ph en ylpr opan oates
(41 a n d 42). The ratio of 41 and 42 was determined by GC
analysis of the crude reaction isolate arising from the radical
reduction of 11. The compounds were purified by flash
chromatography on silica gel by using 6% Et2O-hexane.
Meth yl (()-2-ter t-Bu tyl-3-m eth oxy-3-ph en ylpr opan oates
(43 a n d 44). The ratio of 43 and 44 was determined by GC
analysis of the crude reaction isolate arising from the radical
reduction of 10. The compounds were separated by flash
chromatography on silica gel by using 5% Et2O-hexane.
Meth yl (()-2-Deu ter o-3-m eth oxy-3-p h en ylp r op a n oa te
(45 a n d 46). The ratio of 45 and 46 was determined by 1H
NMR analysis of the crude reaction isolate arising from the
radical reduction of 14. The compounds were purified by flash
chromatography on silica gel (4% EtOAc-hexane).
Met h yl (()-2-Met h yl-3-(b en zyloxy)-3-p h en ylp r op a n -
oa tes (58 a n d 59). The ratio of 58 and 59 was determined
by 1H NMR analysis of the crude reaction isolate arising from
the radical reduction of 19. The compounds were separated
by flash chromatography on silica gel by using 7% Et2O-
hexane.
Meth yl (()-2-(1-Meth oxyeth yl)p r op en oa te 55. To a
solution of methyl 2-(1-hydroxyethyl)propenoate36 (2.01 g, 15.5
mmol) in dry CH2Cl2 (19 mL) were successively added proton
sponge (16.6 g, 77.5 mmol) and MeOTf (8.7 mL, 77.5 mmol).
The reaction mixture was stirred overnight at 25 °C, diluted
with Et2O, and successively washed with 10% aqueous HCl
(2×), water, and brine. The organic layer was dried (MgSO4),
filtered, and concentrated to afford the methyl ether 55 (1.55
1
g, 70% yield). IR (neat) νmax 1720, 1630 cm-1; H NMR (400
MHz, CDCl3) δ 1.32 (d, 3H, J ) 6.4 Hz), 3.31 (s, 3H), 3.78 (s,
3H), 4.22 (q, 1H, J ) 6.4 Hz), 5.86 (s, 1H), 6.29 (s, 1H); 13C
NMR (50.3 MHz, CDCl3) δ 20.7, 51.2, 55.9, 75.0, 123.8, 141.4,
166.0 (CdO).
Gen er a l P r oced u r e for Ra d ica l Red u ction in th e
Absen ce of a Lew is Acid (Con d ition s B). To a cold (0 °C)
stirred solution of the R-bromoester in dry CH2Cl2 (0.1 M) were
added Bu3SnH (2 equiv) and Et3B (3 × 0.2 equiv during the
first 15 min of reaction). After the reaction mixture was
stirred at 0 °C for 2 h, m-dinitrobenzene (0.5 equiv) was added,
and the mixture was concentrated. GC analysis was per-
formed on the crude reaction isolate. The residue was taken
up in hexane, and the resultant solution was treated with
n-Bu4NF (2.5 equiv). After being stirred for 5 min at 25 °C,
the mixture was filtered through a short pad of silica gel (100
mL, 15% EtOAc-hexane) and concentrated.
Meth yl (()-2-Meth yl-3-(isopr op yloxy)-3-ph en ylp r op a n -
oa tes (60 a n d 61). The ratio of 60 and 61 was determined
by 1H NMR and GC analyses of the crude reaction isolate
arising from the radical reduction of 22. The compounds were
separated by flash chromatography on silica gel by using 4%
EtOAc-hexane.
Meth yl (()-2-Meth yl-3-(ter t-bu tyld im eth ylsilyloxy)-3-
p h en ylp r op a n oa tes (62 a n d 63). The ratio of 62 and 63
was determined by 1H NMR analysis of the crude reaction
isolate arising from the reduction of 20. The compounds were
purified by flash chromatography on silica gel by using 2%
EtOAc-hexane.
Meth yl (()-2-Meth yl-3-m eth oxy-3-p h en ylp r op a n oa tes
(2 a n d 3). The ratio of 2 and 3 was determined by GC analysis
of the crude isolate arising from the radical reduction of 13 or
47. They were purified by flash chromatography on silica gel
by using 5% EtOAc-hexane. Compound 237 (2S*,3S*) was
Meth yl (()-2-Meth yl-3-p h en ylbu ta n oa tes (64 a n d 65).
1
The ratio of 64 and 65 was determined by H NMR analysis
1
isolated as a colorless oil; IR (neat) νmax 1740 cm-1; H NMR
of the crude reaction isolate arising from the radical reduction
of a 5:1 mixture of 23 and 24. The compounds were separated
by flash chromatography on silica gel by using 4% Et2O-
hexane.
(200 MHz, CDCl3) δ 0.87 (d, 3H, J ) 7.1 Hz), 2.77 (dq, 1H, J
) 9.8, J ) 7.1 Hz), 3.15 (s, 3H), 3.76 (s, 3H), 4.24 (d, 1H, J )
9.8 Hz), 7.25-7.42 (m, 5H); 13C NMR (50.3 MHz, CDCl3) δ 13.9,
46.9, 51.7, 56.7, 85.9, 127.6, 128.2, 128.4, 138.9, 175.7 (CdO);
HRMS calcd for C12H16O3 (M+) 208.1099, found 208.1094 (-2.3
ppm).
ter t-Bu tyl (()-2-Meth yl-3-m eth oxy-3-ph en ylpr opan oates
(66 a n d 67). The ratio of 66 and 67 was determined by GC
analysis of the crude reaction isolate arising from the radical
reduction of 15. The compounds were separated by flash
chromatography on silica gel by using 4% Et2O-hexane.
N,N-Diet h yl (()-2-Met h yl-3-m et h oxy-3-p h en ylp r op i-
on a m id es (68 a n d 69). The ratio of 68 and 69 was deter-
mined by 1H NMR analysis of the crude reaction isolate arising
from the radical reduction of 32. The compounds were
separated by flash chromatography on silica gel by using 25%
EtOAc-hexane.
Meth yl (()-2-(2-Ch lor oeth yl)-3-m eth oxy-3-p h en ylp r o-
p ion a tes 50 a n d 51. The ratio of 50 and 51 was determined
by GC analysis of the crude reaction isolate arising from the
radical reduction of 48 or from the addition reaction on 49 as
described below.
Un d er Ch ela tion Con tr ol. To a cold (0 °C), stirred
suspension of MgBr2‚OEt2 (735 mg, 2.8 mmol) in dry CH2Cl2
(33 mL) were successively added a solution of ester 49 (293
mg, 1.4 mmol) in CH2Cl2 (6 mL), ICH2Cl (518 µL, 7.0 mmol),
a 1.0 M solution of Et3B in hexane (280 µL, 0.28 mmol), and
Bu3SnH (765 µL, 2.84 mmol). After being stirred for 2 h at 0
°C, the mixture was poured into a saturated aqueous NaHCO3,
and the aqueous layer was extracted (3×) with CH2Cl2. The
organic extracts were combined, successively washed with
water and brine, and dried (MgSO4). 1H NMR analysis of the
crude reaction isolate, performed to determine the ratio of 50
and 51, revealed also the presence of methyl R-methylcin-
namate 6 (ca. 45%) and unreacted substrate 49 (ca. 13%).
In th e Absen ce of Lew is Acid . To a cold (0 °C), stirred
solution of olefin 49 (207 mg, 1.0 mmol) and ICH2Cl (366 µL,
5.0 mmol) in dry CH2Cl2 (23 mL) was slowly added over 2.5 h
a solution of Bu3SnH (541 µL, 2.0 mmol) in CH2Cl2 (5 mL).
During the addition of Bu3SnH, a 1.0 M solution of Et3B in
Com p ou n d 336 (2R*,3S*). Colorless oil; IR (CDCl3) νmax
1
1735 cm-1; H NMR (200 MHz, CDCl3) δ 1.22 (d, 3H, J ) 7.1
Hz), 2.74 (dq, 1H, J ) 7.1, J ) 6.7 Hz), 3.24 (s, 3H), 3.55 (s,
3H), 4.44 (d, 1H, J ) 6.7 Hz), 7.19-7.41 (m, 5H); 13C NMR
(50.3 MHz, CDCl3) δ 12.2, 47.3, 51.3, 57.0, 84.2, 126.9, 127.7,
128.1, 139.6, 174.3 (CdO); HRMS calcd for C12H16O3 (M+)
208.1099, found 208.1105 (-3.0 ppm).
Met h yl (()-2-Met h yl-3-m et h oxyb u t a n oa t es (33 a n d
34).38,39 The ratio of 33 (2R*,3S*) and 34 (2S*,3S*) was
1
determined by GC and H NMR analyses of the crude isolate
arising from the radical reduction of 16.
Meth yl (()-2,4-Dim eth yl-3-m eth oxyp en ta n oa tes (35
a n d 36). The ratio of 35 and 36 was determined by GC
analysis of the crude reaction isolate arising from the radical
reduction of 26 (conditions A and B). The residue was purified
by flash chromatography on silica gel by using 5% Et2O-
hexane.
Meth yl (()-2-Meth yl-3-cycloh exyl-3-m eth oxyp r op a n -
oa tes (37 a n d 38). The ratio of 37 and 38 was determined
by GC analysis of the crude reaction isolate arising from the
radical reduction of 28 or 29. They were separated by flash
chromatography on silica gel by using 4% EtOAc-hexane.
Meth yl (()-3-Meth oxy-2,4,4-tr im eth ylp en ta n oa tes (39
a n d 40). The ratio of 39 and 40 was determined by GC
analysis of the crude reaction isolate arising from the radical
(36) Drewes, S. E.; Hode, R. F. A. Synth. Commun. 1985, 15, 1067.
(37) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259.
(38) Gouzoules, F. H.; Whitney, R. A. J . Org. Chem. 1986, 51, 2024.
(39) Maskens, K.; Polgar, N. J . Chem. Soc., Perkin Trans. 1 1973,
1, 109.

The Use of Lewis Acids in Radical Chemistry
J . Org. Chem., Vol. 63, No. 19, 1998 6565
hexane was added in three equal portions (3 × 67 µL, 0.2
mmol). The reaction mixture was stirred for an additional 30
min at 0 °C and then concentrated. 1H NMR analysis of the
crude reaction isolate was performed to determine the ratio
of 50 and 51. The residue was taken up in hexane, and to the
resultant solution was added a 1.0 M solution of n-Bu4NF in
THF (2.4 mL, 2.4 mmol). After being stirred for 5 min at 25
°C, the mixture was filtered through a short pad of silica gel
(200 mL, 20% EtOAc-hexane) and concentrated. The residue
was flash chromatographed on silica gel (4% EtOAc-hexane)
to afford a mixture of ester 50 and 51 (125 mg, 49% yield).
The two diastereomers can be separated by performing a
second flash column chromatography using the above condi-
being stirred for 5 min at 25 °C, the mixture was filtered
through a short pad of silica gel (100 mL, 20% EtOAc-hexane)
and concentrated. The residue was flash chromatographed on
silica gel (4% EtOAc-hexane) to afford a mixture of esters 56
and 57 (203 mg, 68% yield).
In th e Absen ce of Lew is Acid . To a cold (0 °C), stirred
solution of olefin 55 (214 mg, 1.5 mmol) and t-BuI (885 µL,
7.4 mmol) in dry CH2Cl2 (41 mL) were successively added a
1.0 M solution of Et3B in hexane (300 µL, 0.297 mmol) and
Bu3SnH (800 µL, 2.97 mmol). The reaction mixture was
stirred at 0 °C for 7 h, slowly allowed to warm to 25 °C, and
stirred at this temperature overnight. 1H NMR analysis of
the concentrated crude reaction isolate, conducted to determine
the ratio of 56 and 57, revealed substrate 55 (∼50%). A 4:1
mixture of 56 and 57 was recovered as a colorless oil; major
tions. Ester 50 (syn): colorless oil; IR (neat) νmax 1730 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.18-2.29 (m, 2H), 2.88-2.93
(m, 1H), 3.22 (s, 3H), 3.45-3.61 (m, 2H), 3.50 (s, 3H), 4.40 (d,
1H, J ) 7.3 Hz), 7.24-7.37 (m, 5H); 13C NMR (100.6 MHz,
CDCl3) δ 31.0, 42.9, 50.9, 51.5, 57.0, 83.9, 126.9, 128.0, 128.3,
138.9, 172.8 (CdO).
1
diastereomer: IR (neat) νmax 1735 cm-1; H NMR (400 MHz,
CDCl3) δ 0.87 (s, 9H), 1.14 (d, 3H, J ) 6.0 Hz), 1.26 (dd, 1H,
J ) 1.6, J ) 14.0 Hz), 1.77 (dd, 1H, J ) 10.8, J ) 14.0 Hz),
2.55-2.60 (m, 1H), 3.30 (s, 3H), 3.38-3.41 (m, 1H), 3.68 (s,
3H); 13C NMR (100.6 MHz, CDCl3) δ 16.3, 29.2, 30.3, 41.1, 47.9,
51.4, 56.6, 78.7, 175.9 (CdO); MS (CI, isobutane) m/e (relative
intensity) 203 (MH+, 20), 171 (100); HRMS calcd for C10H19O3
(M+ - CH3) 187.1334, found 187.1335 (-0.5 ppm).
Ester 51 (anti): colorless oil; IR (neat) νmax 1730 cm-1; H
1
NMR (400 MHz, CDCl3) δ 1.50-1.58 (m, 1H), 1.90-2.00 (m,
1H), 2.92-2.98 (m, 1H), 3.13 (s, 3H), 3.20-3.38 (m, 2H), 3.75
(s, 3H), 4.29 (d, 1H, J ) 9.5 Hz), 7.27-7.39 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) δ 31.6, 42.0, 50.4, 51.8, 56.7, 84.7, 127.4,
128.4, 128.5, 138.3, 174.0 (CdO); MS (CI, isobutane) m/e
(relative intensity) 257 (MH+, 1.5), 225 (100). Anal. Calcd
for C13H17ClO3: C, 60.82; H, 6.67. Found: C, 60.73; H, 6.72.
Ack n ow led gm en ts. We thank Professor N. A. Por-
ter for bringing reference 27 to our attention. We also
thank Drs. William Ogilvie, Grace J ung, and Brigitte
Gue´rin, and Ms. LaVonne Dlouhy for their assistance
in the preparation of this manuscript. The experimental
part of this work was financed by and performed at Bio-
Me´ga Research Division/Boehringer Ingelheim (Canada)
Ltd.
Meth yl (()-2-Neop en tyl-3-m eth oxybu ta n oa tes (56 a n d
57). Un d er Ch ela tion Con tr ol. To a cold (0 °C), stirred
suspension of MgBr2‚OEt2 (760 mg, 2.9 mmol) in dry CH2Cl2
(34 mL) were successively added a solution of ester 55 (212
mg, 1.5 mmol) in CH2Cl2 (6.4 mL), t-BuI (877 µL, 7.4 mmol),
a 1.0 M solution of Et3B in hexane (295 µL, 0.295 mmol), and
Bu3SnH (792 µL, 2.9 mmol). After being stirred for 2.5 h,
the mixture was poured into a saturated aqueous NaHCO3,
and the aqueous layer was extracted (3×) with CH2Cl2. The
organic extracts were combined, successively washed with
water and brine, and dried (MgSO4). GC analysis of the crude
reaction isolate was performed to determine the ratio of 56
and 57. After filtration and concentration, the residue was
taken up in hexane, and to the resultant solution was added
a 1.0 M solution of n-Bu4NF in THF (3.5 mL, 3.5 mmol). After
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 5, 11-16, 28-31, 47, 35-46, 58-69; 13
C
NMR spectra for compounds 10, 12, 15, 16, 18, 19, 23, 24, 26,
27, 30, 32, 37-42, 44, 47, 48, 50, 55-57, 59, 66-69 (39 pages).
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