Stereoselective preparation of functionalized unsaturated lactones and esters via functionalized magnesium carbenoids

Article abstract of DOI:10.1055/s-2003-41035

The reaction of β,β-dibromo or diiodo unsaturated esters with i-PrMgCl (1 equivalent) in diethyl ether allows the generation of functionalized alkenylmagnesium carbenoids which react with retention of configuration with various electrophiles providing polyfunctionalized unsaturated esters and lactones. By using two equivalents of i-PrMgCl, a 1,2-migration with retention of configuration occurs in diethyl ether allowing a new synthesis of tetrasubstituted esters and lactones.

Full text of DOI:10.1055/s-2003-41035

PAPER
1797
Stereoselective Preparation of Functionalized Unsaturated Lactones and
Esters via Functionalized Magnesium Carbenoids
Stereoselective
P
re
i
paratio
e
n
of Functi
t
onalized
L
act
A
one
s
and
E
ster
s
nh Vu,a Ilan Marek,b Paul Knochel*a
a
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
Fax +49(89)218077680 ; E-mail: paul.knochel@cup.uni-muenchen.de
b
Department of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
Fax +972(4)8295703; E-mail: chilanm@techunix.technion.ac.il
Received 3 June 2003; revised 1 July 2003
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday.
The reaction of 1a,b with i-PrMgCl in diethyl ether at
–50 °C for 15 minutes provided the expected magnesium
carbenoids 4a,b which can be quenched by several elec-
trophiles like iodine, benzaldehyde, benzophenone or cy-
Abstract: The reaction of , -dibromo or diiodo unsaturated esters
with i-PrMgCl (1 equivalent) in diethyl ether allows the generation
of functionalized alkenylmagnesium carbenoids which react with
retention of configuration with various electrophiles providing
polyfunctionalized unsaturated esters and lactones. By using two clopentanone providing the corresponding unsaturated
equivalents of i-PrMgCl, a 1,2-migration with retention of configu-
esters 5a,b (89% yield) or in the case of the reaction with
ration occurs in diethyl ether allowing a new synthesis of tetrasub-
stituted esters and lactones.
carbonyl compounds to the unsaturated bromolactones
6a,b, 7 and 8 in 56–79% yields (Scheme 2). Interestingly,
Key words: functionalized magnesium carbenoids, iodine–magne-
the bromolactone 8 can be further functionalized using a
Negishi reaction.6 Thus, the reaction of 8 with the func-
tionalized arylzinc bromide 9 prepared from methyl 4-io-
sium exchange, cross-coupling, lactone synthesis, palladium catal-
ysis
dobenzoate (10) via an iodine–magnesium exchange and
a transmetalation with zinc bromide furnished, in the pres-
Functionalized carbenoids are potentially important inter-
ence of catalytic amounts of palladium(0) bis(dibenz-
mediates for organic synthesis.1 In continuation of our
work on functionalized magnesium carbenoids2 using an
iodine– or bromine–magnesium exchange reaction,3 we
wish to report a new stereoselective synthesis of unsatur-
ated lactones and esters starting from dibromo esters 1a,b
and the diiodo ester 2 (Scheme 1). Thus, the reaction of
ethyl phenylglyoxylate (3a) or methyl pyruvate (3b) with
carbon tetrabromide and triphenylphosphine in CH2Cl2
(12 h, 25 °C) furnished the corresponding dibromo esters
1a and 1b in 58 and 69% yields, respectively.4 The diiodo
ester 2 was also prepared from ethyl phenylglyoxylate
(3a) using a method developed by Duhamel.5 Thus, the
treatment of 3a with an in situ generated lithiated di-
iodophosphate at –78 °C furnished the expected product 2
in 70% yield (Scheme 1).
ylideneacetone) (5 mol%)7 and tris(o-furyl)phosphine8
(10 mol%) at 30 °C after a reaction time of 10 hours, the
desired cross-coupling product 11 in 76% yield
(Scheme 3).
Br
Br
Br
MgCl
Br
E
i-PrMgCl (1 equiv)
E+
Et2O
-50 °C, 15 min
R1
CO2R2
R1
CO2R2
R1
CO2R2
4a: R1= Ph, R2= Et
4b: R1 = R2 = Me
5a,b, 6a,b
7, 8: 56-89 %
1a-b
Ph
Ph
Ph
Br
I
Br
Br
Br
R
O
O
O
O
O
R1
CO2R2
Ph
Ph
O
Br
Br
O
5a: R1= Ph, R2= Et: 89 %
5b: R1= R2 = Me: 89 %
CBr4 (2 equiv)
7: 79 %
8: 71 %
6a: R = Ph: 56 %
6b: R = Me: 56 %
R1
CO2R2
R1
CO2R2
Ph3P (4 equiv), CH2Cl2
25 °C, 4 h
Scheme 2 Generation and reaction of magnesium carbenoids 4a,b
1a: R1 = Ph, R2 = Et, 58 %
1b: R1 = R2 = Me, 69 %
3a: R1 = Ph, R2 = Et
3b: R1 = R2 = Me
MeO2C
Br
I
I
LiHMDS (2 equiv.)
ICH2P(O)(OEt)2, I2
O
Ph
I
ZnBr
O
1) i-PrMgCl, THF
-20 °C, 30 min
8
Ph
CO2Et
Ph
CO2Et
O
THF, -78 °C, 2 h
Ph
O
Pd(dba)2 (5 mol %)
2) ZnBr2
3a
2: 70 %
O
(10 mol %)
CO2Me
CO2Me
P
3
O
Scheme 1 Preparation of dibromo esters 1a,b and diiodo ester 2
11: 76 %
10
9
30 °C, 10 h
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1797,1802,ftx,en;T04803SS.pdf.
DOI: 10.1055/s-2003-41035
Scheme 3 Negishi cross-coupling reaction leading to the unsatura-
ted lactone 11
© Georg Thieme Verlag Stuttgart · New York

1798
V. A. Vu et al.
PAPER
We have also examined the electrophilic reactivity of nesium atom with the carbonyl group of the ester
magnesium carbenoids. It is well known in the literature function). Interestingly, by performing the reaction in
that a 1,2-migration occurs when carbenoid species of THF which is a stronger donor solvent compared to dieth-
type 12 bear a nucleophilic substituent (Nu), which leads yl ether, a mixture of diastereomers (E/Z = 1:9) was ob-
to products of type 13 with inversion of configuration at tained after an allylation reaction performed with allyl
the carbenoid center (Scheme 4).9
bromide (1.1 equiv) in the presence of catalytic amounts
of CuCN·2LiCl10 (Scheme 6).
Nu
R1
R2
Nu
CuCN 2LiCl
(10 mol %)
R1
R2
Mg
i-PrMgCl
(2 equiv)
inversion of configuration
i-Pr
I
I
i-Pr
MgCl
MgX
X
Br
-78 °C to -10 °C
2 h, THF
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
12: X = I, Br
13: X = I, Br
THF
Scheme 4 1,2-Migration of magnesium carbenoids
2
14a: 78 %
E:Z = 1:9
Scheme 6 Copper-catalyzed allylation in THF
We wish to report herein the related 1,2-migration reac-
tions proceeding formally with retention of configuration.
Thus, the reaction of the dibromo ester 1a with two equiv-
alents of an alkylmagnesium reagent like i-PrMgCl or i-
BuMgCl in diethyl ether provided after reaction with an
electrophile the products 14a,b, 15–17 in which formally
the 1,2-migration has occurred with retention of configu-
ration. The yields of the products are good (56–73%) and
the stereoselectivity of the resulting open-chain unsaturat-
ed esters is excellent. For the allylated product 14a,b, the
E/Z ratio is >1:99 (Scheme 5).
In summary, we have shown that the iodine– or bromine–
magnesium exchange reaction on -dibromo or -diiodo
ester of type 1 and 2 allows a stereoselective preparation
of functionalized unsaturated esters. In the presence of
two equivalents of an alkylmagnesium reagent, a 1,2-mi-
gration reaction occurs with an unusual retention of con-
figuration, which allows the elaboration of
steroselectively functionalized , -unsaturated ester and
lactones. In THF, less selective reactions are observed due
to a competitive complexation of THF.
RMgCl
(2 equiv)
Br
Br
ClMg
Ph
R
R
MgCl
Melting points were measured on a Büchi B 540 apparatus and are
uncorrected. NMR spectra were recorded in CDCl3 at 300 MHz for
1H NMR and 75 MHz for 13C NMR (Varian XL 300). Chemical
shifts are reported in ppm relative to TMS. IR spectra were recorded
on a Perkin-Elmer FT-IR Spectrum 1000 spectrophotometer. Low-
resolution mass spectra were recorded using a GC/MS-combination
of the type HP 6890/MSD 5973 fitted with a HP-5 column
(30m × 0.25 mm × 0.25 m). High-resolution mass spectra were re-
corded on a Finnigan-MAT 95Q spectrometer (electron impact, 70
eV). Microanalyses were performed using a Heraeus CHN Rapid
Elementaranalysator. Flash column chromatographical purifica-
tions were carried out using Merck Kieselgel 60 (230–400 mesh
ASTM).
Et2O
-78 °C to 0 °C
Ph
CO2Et
CO2Et
Ph
CO2Et
E-18
1a
Z-18
R
E
E+
Ph
CO2Et
14a,b, 15-17
O
Ph
O
R
i-Pr
I
i-Pr
i-Pr
Ph
CO2Et
16: 61 %
Ph
Ph
CO2Et
Ph
CO2Et
Ph
O
Commercially available starting materials with a purity >97% were
used without further purification. Solvents were distilled and dried
before use. Starting material 1a,b and 2 were prepared according to
known methods.4,5
14a: R = i-Pr: 75 %
14b: R= i-Bu: 73 %
15: 82 %
17: 56 %
Scheme 5 1,2-Migration of magnesium carbenoid with formal re-
tention of configuration
3,3-Dibromo-2-phenylacrylic Acid Ethyl Ester (1a)4
A solution of CBr4 (13.3 g, 40 mmol) in CH2Cl2 (15 mL) was added
to a solution of Ph3P (21.0 g, 80 mmol) in CH2Cl2 (20 mL) at 0 °C.
After 30 min at 0 °C, a solution of ethyl phenylglyoxylate (3a; 3.56
g, 20 mmol) in CH2Cl2 (10 mL) was added. The mixture was
warmed to 25 °C and stirred for 12 h, then added to pentane (70
mL), stirred for 30 min, filtered and concentrated. The crude residue
was purified by flash chromatography (pentane–Et2O, 3:1), yielding
the product 1a (3.94 g, 58%) as a yellow oil.
IR (film): 2982 (w), 1727 (s), 1204 cm–1 (s).
1H NMR (300 MHz, CDCl3): = 7.43–7.41 (m, 5 H), 4.29 (q,
J = 7.1 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 166.3, 142.0, 136.2, 129.4, 129.0,
128.5, 95.7, 62.6, 14.3.
The retention of configuration of the 1,2-migration is best
explained by a 1,2-migration occurring with an inversion
followed by an isomerization driven by a chelation stabil-
ization. Thus, the bromine–magnesium exchange of 1a
occurs like as shown in Scheme 2 leading to the corre-
sponding magnesium carbenoid 4a which transfers an
alkyl group (i-Pr or i-Bu) providing the E-magnesium re-
agent, (E)-18. Under the reaction conditions (–78 to
0 °C), the E-alkenylmagnesium compound, (E)-18
isomerizes to the more stable Z-alkenylmagnesium spe-
cies (Z)-18, which is stabilized by chelation (of the mag-
Synthesis 2003, No. 12, 1797–1802 © Thieme Stuttgart · New York

PAPER
Stereoselective Preparation of Functionalized Lactones and Esters
1799
MS: m/z (%) = 336 (6), 334 (12), 332 (5), 291 (5), 289 (12), 287 (5),
261 (15), 255 (33), 227 (21), 225 (23), 182 (49), 180 (51), 145
(100), 101 (54).
1H NMR (300 MHz, CDCl3): = 7.30 (s, 5 H), 4.19 (q, J = 7.1 Hz,
2 H), 1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 167.4, 147.9, 136.8, 129.3, 129.0,
128.4, 62.7, 57.9, 14.4.
HRMS: m/z calcd for C11H10Br2O2: 331.9048; found: 331.9076.
MS: m/z (%) = 382 (13), 380 (13), 255 (16), 227 (19), 225 (19), 182
(30), 180 (29), 145 (100), 101 (53).
3,3-Dibromo-2-methylacrylic Acid Methyl Ester (1b)4
A solution of CBr4 (6.7 g, 20.1 mmol) in CH2Cl2 (10 mL) was added
to a solution of Ph3P (10.5 g, 40.2 mmol) in CH2Cl2 (40 mL) at 0 °C.
After 30 min at 0 °C, a solution of methyl pyruvate (3b; 1.02 g, 10
mmol) in CH2Cl2 (5 mL) was added. The mixture was warmed to
r.t., stirred for 12 h, then added to pentane (70 mL), stirred for 30
min, filtered, and concentrated. The crude residue was purified by
flash chromatography (pentane–Et2O, 3:1) yielding the product 1b
(1.78 g, 69%) as a colorless oil.
IR (film): 2952 (w), 1732 (s), 1434 (m), 1285 (m), 1132 cm–1 (s).
1H NMR (300 MHz, CDCl3): = 3.83 (s, 3 H), 2.07 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 166.3, 134.9, 94.7, 51.9, 21.0.
HRMS: m/z calcd for C11H10BrIO2: 379.8909; found: 379.8910.
3-Bromo-3-iodo-2-methylacrylic Acid Methyl Ester (5b)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1b (252 mg, 0.98 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–50 °C and a 2 M solution of i-PrMgCl in Et2O (0.53 mL, 1.07
mmol) was added dropwise. After stirring for 15 min at –50 °C, io-
dine (357 mg, 1.4 mmol) dissolved in Et2O (4 mL) was added and
the mixture was allowed to warm up to r.t. After 4 h, the mixture
was quenched with brine (10 mL) and extracted with Et2O. The or-
ganic layer was washed with an aq solution of Na2S2O3, then brine,
dried (MgSO4) and concentrated under vacuum. The crude residue
was purified by flash chromatography (pentane–Et2O, 3:1), yielding
the product 5b (268 mg, 89%) as a yellow oil.
MS: m/z (%) = 260 (19), 258 (44), 255 (22), 229 (39), 227 (91), 225
(42), 201 (16), 199 (32), 197 (17), 179 (100), 177 (100), 119 (24),
117 (24).
IR (film): 2950 (w), 1728 (s), 1433 (m), 1252 (m), 1128 cm–1 (m).
1H NMR (300 MHz, CDCl3): = 3.74 (s, 3 H), 2.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 168.2, 141.7, 57.2, 53.0, 22.2.
HRMS: m/z calcd for C5H6Br2O2: 255.8735; found: 255.8752.
3,3-Diiodo-2-phenylacrylic Acid Ethyl Ester (2)5
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with 1,1,1,3,3,3-hexamethyldisilazane
(HMDS) (9.1 mL, 44 mmol) in THF (20 mL) under argon. The re-
action mixture was cooled to –10 °C and n-BuLi (29.3 mL, 44
mmol, 1.5 M in hexane) was added. The solution was stirred 30 min
at –10 °C and then cooled to –70 °C. A solution of iodine (5.58 g,
22 mmol) in THF (20 mL) was added and then after 10 min, a solu-
tion of diethyl iodomethylphosphonate (6.11 g, 22 mmol) in THF
(10 mL) was added. After 90 min at –70 °C, ethyl phenylglyoxylate
(3a; 3.56 g, 20 mmol) in THF (5 mL) was added. The mixture was
stirred 10 min at –70 °C then warmed up to r.t. After 2 h, H2O (80
mL) was added and the aqueous solution was extracted with Et2O.
The combined organic layers were dried (MgSO4) and concentrat-
ed. The crude residue was purified by flash chromatography (pen-
tane–Et2O, 9:1), yielding the product 2 (5.9 g, 70%) as a red oil.
MS: m/z (%) = 306 (45), 304 (48), 275 (19), 273 (19), 179 (93), 177
(100), 127 (11).
HRMS: m/z calcd for C5H6BrIO2: 303.8596; found: 303.8604.
Anal. Calcd for C5H6BrIO2: C, 19.70; H, 1.98. Found: C, 19.92; H,
2.00.
4-Bromo-3,5-diphenyl-5H-furan-2-one (6a)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (304 mg, 0.91
mmol) in Et2O (4 mL) under argon. The reaction mixture was
cooled to –50 °C and a 2 M solution of i-PrMgCl in Et2O (0.5 mL,
1.00 mmol) was added dropwise. After stirring for 15 min at
–50 °C, benzaldehyde (0.1 mL, 1.1 mmol) was added and the mix-
ture was allowed to warm up to r.t. After 4 h, the mixture was
quenched with brine (10 mL) and extracted with Et2O. The organic
layer was washed with brine, dried (MgSO4) and concentrated un-
der vacuum. The crude residue was purified by flash chromatogra-
phy (pentane–Et2O, 5:1), yielding the product 6a (158 mg, 55%) as
colorless crystals; mp 140 °C.
IR (film): 3435 (w), 2924 (m), 1727 (s), 1442 (m), 1260 (s), 1196
cm–1 (s).
1H NMR (300 MHz, CDCl3): = 7.26–7.17 (m, 5 H), 4.11 (q,
J = 7.1 Hz, 2 H), 1.16 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 167.0, 153.4, 140.3, 129.4, 129.1,
128.2, 62.7, 20.0, 14.4.
IR (film): 3487 (w), 1752 (s), 1634 (m), 1492 (m), 1294 (s), 1159
cm–1 (m).
MS: m/z (%) = 427 (30), 354 (10), 332 (100), 272 (48), 227 (62),
145 (80), 102 (61), 75 (40), 51 (44).
1H NMR (300 MHz, CDCl3): = 7.89–7.85 (m, 2 H), 7.55–7.35 (m,
8 H), 5.92 (s, 1 H).
HRMS: m/z calcd for C11H10I2O2: 427.8770; found: 427.8818.
13C NMR (75 MHz, CDCl3): = 169.9, 143.8, 133.7, 130.3, 129.9,
129.5, 129.1, 128.9, 127.9, 85.5.
3-Bromo-3-iodo-2-phenylacrylic Acid Ethyl Ester (5a)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (256 mg, 0.77 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–50 °C and a 2 M solution of i-PrMgCl in Et2O (0.42 mL, 0.84
mmol) was added dropwise. After stirring for 15 min at –50 °C, io-
dine (246 mg, 0.96 mmol) dissolved in Et2O (4 mL) was added and
the mixture was allowed to warm up to r.t. After 4 h, the mixture
was quenched with brine (10 mL) and extracted with Et2O. The or-
ganic layer was washed with an aq solution of Na2S2O3, then brine,
dried (MgSO4) and concentrated under vacuum. The crude residue
was purified by flash chromatography (pentane–Et2O, 3:1), yielding
the product 5a (261 mg, 89%) as a yellow oil.
MS: m/z (%) = 314 (4), 235 (100), 191 (23), 189 (22), 179 (33), 129
(13), 105 (100).
HRMS: m/z calcd for C16H11BrO2: 313.9942; found: 313.9922.
Anal. Calcd for C16H11BrO2: C, 60.98; H, 3.52; Br, 25.35. Found:
C, 60.87; H, 3.51; Br, 25.78.
4-Bromo-3-methyl-5-phenyl-5H-furan-2-one (6b)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1b (283 mg, 1.10 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–50 °C and a 2 M solution of i-PrMgCl in Et2O (0.6 mL, 1.20 mmol)
was added dropwise. After stirring for 15 min at –50 °C, benzalde-
hyde (0.16 mL, 1.6 mmol) was added and the mixture was allowed
IR (film): 2981 (w), 1723 (s), 1443 (m), 1200 (s), 1036 cm–1 (m).
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1800
V. A. Vu et al.
PAPER
HRMS: m/z calcd for C14H13BrO2: 292.0099; found: 292.0084.
to warm up to r.t. After 4 h, the mixture was quenched with brine
(10 mL) and extracted with Et2O. The organic layer was washed
with brine, dried (MgSO4) and concentrated under vacuum. The
crude residue was purified by flash chromatography (pentane–Et2O,
3:1), yielding the product 6b (157 mg, 56%) as a colorless oil.
4-(2-Oxo-3-phenyl-1-oxaspiro[4.4]non-3-en-4-yl)benzoic Acid
Methyl Ester (11)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with 4-iodobenzoic acid methyl ester (10; 200
mg, 0.76 mmol) in THF (4 mL) under argon. The reaction mixture
was cooled to –20 °C and a 1.6 M solution of i-PrMgCl in THF
(0.52 mL, 0.84 mmol) was added dropwise. After stirring for 30 min
at –20 °C, a 1.5 M solution of ZnBr2 in THF (0.56 mL, 0.84 mmol)
was added and the mixture was allowed to warm up to r.t. to give
the zinc reagent 9. Another dry two-necked flask equipped with a
magnetic stirring bar and a septum under argon was charged with
palladium(0) bis(dibenzylideneacetone) (14 mg, 5 mol%) and tris-
o-furylphosphine (11 mg, 10 mol%) followed by THF (1 mL). The
initial red color disappeared after 5 min leading to a yellow solution.
The bromolactone 8 (150 mg, 0.51 mmol) was added, followed by
the zinc reagent 9. The reaction mixture was warmed to 30 °C and
stirred for 10 h, worked up by pouring into aq sat. NaCl solution and
extracted with Et2O. The crude residue was purified by column
chromatography on silica gel (pentane–Et2O, 3:1) to give the spiro-
lactone 11 (135 mg, 76%) as a white solid; mp 135 °C.
IR (film): 3034 (w), 1766 (s), 1660 (m), 1456 (m), 1271 (m), 1088
cm–1 (m).
1H NMR (300 MHz, CDCl3): = 7.35–7.30 (m, 3 H), 7.21–7.16 (m,
2 H), 5.68 (s, 1 H), 1.91 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 171.5, 144.6, 133.6, 130.2, 129.3,
127.7, 85.6, 10.7.
MS: m/z (%) = 254 (20), 252 (21), 173 (100), 145 (10), 128 (22),
117 (14), 105 (48).
HRMS: m/z calcd for C11H9BrO2: 251.9786; found: 251.9806.
Anal. Calcd for C11H9BrO2: C, 52.20; H, 3.58. Found: C, 52.57; H,
3.62.
4-Bromo-3,5,5-triphenyl-5H-furan-2-one (7)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (238 mg, 0.71 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–50 °C and a 2 M solution of i-PrMgCl in Et2O (0.4 mL, 0.78 mmol)
was added dropwise. After stirring for 15 min at –50 °C, benzophe-
none (184 mg, 1.1 mmol) dissolved in Et2O (4 mL) was added and
the mixture was allowed to warm up to r.t. After 4 h, the mixture
was quenched with brine (10 mL) and extracted with Et2O. The or-
ganic layer was washed with brine, dried (MgSO4) and concentrated
under vacuum. The crude residue was purified by flash chromato-
graphy (pentane–Et2O, 9:1), yielding the product 7 (222 mg, 79%)
as a colorless oil.
IR (film): 3480 (w), 2948 (w), 1752 (s), 1728 (s), 1435 (w), 1273
cm–1 (m).
1H NMR (300 MHz, CDCl3): = 8.02–7.98 (m, 2 H), 7.36–7.12 (m,
7 H), 3.86 (s, 3 H), 2.05–1.60 (m, 8 H).
13C NMR (75 MHz, CDCl3): = 171.3, 166.7, 162.2, 137.7, 131.1,
130.5, 130.4, 130.1, 129.7, 129.4, 129.2, 129.0, 128.8, 128.6, 128.5,
96.3, 52.7, 36.7, 24.8.
MS: m/z (%) = 348 (46), 319 (11), 291 (11), 261 (14), 243 (14), 203
(35), 185 (100), 157 (20).
IR (film): 3436 (m), 1762 (s), 1446 (m), 1171 cm–1 (m).
HRMS: m/z calcd for C22H20O4: 348.1362; found: 348.1356.
1H NMR (300 MHz, CDCl3): = 7.76–7.72 (m, 2 H), 7.45–7.30 (m,
8 H).
13C NMR (75 MHz, CDCl3): = 167.8, 146.6, 136.7, 129.5, 128.8,
128.2, 127.4, 127.2, 91.1.
3-Isopropyl-2-phenylhexa-2,5-dienoic Acid Ethyl Ester (14a)
From Dibromo Ester 1a: A dry two-necked flask equipped with a
magnetic stirring bar and a septum was charged with the dibromo
ester 1a (230 mg, 0.68 mmol) in Et2O (4 mL) under argon. The re-
action mixture was cooled to –78 °C and a 2 M solution of i-PrMgCl
in Et2O (0.72 mL, 1.44 mmol) was added dropwise. After stirring
for 15 min at –78 °C, then 3 h at 0 °C, a 1 M solution of
CuCN·2LiCl in THF (0.01 mL, 0.01 mmol) was slowly added. After
5 min at 0 °C, allyl bromide (0.07 mL, 0.82 mmol) was added and
the mixture was allowed to stir at 0 °C overnight. The mixture was
quenched with brine (10 mL) and extracted with Et2O. The organic
layer was washed with brine, dried (MgSO4) and concentrated un-
der vacuum. The crude residue was purified by flash chromatogra-
phy (pentane–Et2O, 4:1), yielding the product 14a (133 mg, 75%)
as a colorless oil.
MS: m/z (%) = 392 (2), 312 (100), 265 (51), 178 (21), 165 (34), 129
(12), 106 (16).
HRMS: m/z calcd for C22H15BrO2: 390.0255; found: 390.0258.
Anal. Calcd for C22H15BrO2: C, 67.53; H, 3.86. Found: C, 67.48; H,
4.23.
4-Bromo-3-phenyl-1-oxaspiro[4.4]non-3-en-2-one (8)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (312 mg, 0.93 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–50 °C and a 2 M solution of i-PrMgCl in Et2O (0.51 mL, 1.03
mmol) was added dropwise. After stirring for 15 min at –50 °C, cy-
clopentanone (0.1 mL, 1.12 mmol) was added and the mixture was
allowed to warm up to r.t. After 4 h, the mixture was quenched with
brine (10 mL) and extracted with Et2O. The organic layer was
washed with brine, dried (MgSO4) and concentrated under vacuum.
The crude residue was purified by flash chromatography (pentane–
Et2O, 5:1), yielding the product 8 (195 mg, 71%) as a white solid;
mp 138 °C.
IR (film): 3417 (w), 2966 (m), 1715 (s), 1443 (m), 1236 cm–1 (m).
1H NMR (300 MHz, CDCl3): = 7.30–7.10 (m, 5 H), 5.91–5.76 (m,
1 H), 5.08–4.92 (m, 2 H), 4.03 (q, J = 7.1 Hz, 2 H), 3.12 (dt, J = 6.3
Hz, J = 1.7 Hz, 2 H), 2.60–2.49 (m, 1 H), 1.10 (t, J = 7.1 Hz, 3 H),
0.87 (d, J = 6.8 Hz, 6 H).
13C NMR (75 MHz, CDCl3): = 168.7, 151.9, 137.5, 129.2, 128.2,
127.1, 115.4, 60.5, 32.3, 20.8, 14.1.
MS: m/z (%) = 258 (8), 217 (22), 189 (13), 185 (82), 169 (25), 143
(100), 128 (54), 115 (38), 91 (34).
IR (film): 3470 (w), 1739 (s), 1643 cm–1 (w).
1H NMR (300 MHz, CDCl3): = 7.80–7.70 (m, 2 H), 7.51–7.42 (m,
3 H), 2.31–2.20 (m, 2 H), 2.11–1.90 (m, 6 H).
HRMS: m/z calcd for C17H22O2: 258.1620; found: 258.1604.
13C NMR (75 MHz, CDCl3): = 167.3, 145.9, 127.9, 127.1, 126.8,
94.8, 35.6, 23.6.
3-Isopropyl-2-phenylhexa-2,5-dienoic Acid Ethyl Ester (14a)
From Diodo Ester 2: A dry two-necked flask equipped with a mag-
netic stirring bar and a septum was charged with the diiodo ester 2
(191 mg, 0.44 mmol) in THF (4 mL) under argon. The reaction mix-
MS: m/z (%) = 294 (1), 292 (1), 213 (100), 186 (9), 157 (28), 129
(43), 115 (19).
Synthesis 2003, No. 12, 1797–1802 © Thieme Stuttgart · New York

PAPER
Stereoselective Preparation of Functionalized Lactones and Esters
HRMS: m/z calcd for C14H17IO2: 344.0273; found: 344.0341.
1801
ture was cooled to –78 °C and a 1.7 M solution of i-PrMgCl in THF
(0.55 mL, 0.93 mmol) was added dropwise. After stirring 5 min at
–78 °C, then 2 h at –10 °C, a 1 M solution of CuCN·2LiCl in THF
(0.04 mL, 0.04 mmol) was slowly added. After 5 min at –10 °C, al-
lyl bromide (0.04 mL, 0.5 mmol) was added and the mixture was al-
lowed to stir at –10 °C overnight. The mixture was quenched with
brine (10 mL) and extracted with Et2O. The organic layer was
washed with brine, dried (MgSO4) and concentrated under vacuum.
The crude residue was purified by flash chromatography (pentane–
Et2O, 4:1), yielding a E/Z mixture of 14 (determined by GC-MS and
NMR, (E/Z)-14a = 1:9, 89 mg, 78%) as a colorless oil.
3-Benzoyl-4-methyl-2-phenylpent-2-enoic Acid Ethyl Ester (16)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (210 mg, 0.63 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–78 °C and a 2 M solution of i-PrMgCl in Et2O (0.66 mL, 1.32
mmol) was added dropwise. After stirring for 15 min at –78 °C,
then 3 h at 0 °C, a 1 M solution of CuCN·2LiCl in THF (0.66 mL,
0.66 mmol) was slowly added. After 5 min at 0 °C, benzoyl chloride
(0.1 mL, 0.75 mmol) was added and the mixture was allowed to stir
at 0 °C overnight. The mixture was quenched with brine (10 mL)
and extracted with Et2O. The organic layer was washed with brine,
dried (MgSO4) and concentrated under vacuum. The crude residue
was purified by flash chromatography (pentane–Et2O, 3:1), yielding
the product 16 (124 mg, 61%) as a colorless oil.
3-Isobutyl-2-phenylhexa-2,5-dienoic Acid Ethyl Ester (14b)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (216 mg, 0.65 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–78 °C and a 2 M solution of i-BuMgCl in Et2O (0.68 mL, 1.35
mmol) was added dropwise. After stirring 15 min at –78 °C, then 4
h at 0 °C, a 1 M solution of CuCN·2LiCl in THF (0.06 mL, 0.06
mmol) was slowly added. After 5 min at 0 °C, allyl bromide (0.06
mL, 0.77 mmol) was added and the mixture was allowed to stir at
0 °C overnight. The mixture was quenched with brine (10 mL) and
extracted with Et2O. The organic layer was washed with brine, dried
(MgSO4) and concentrated under vacuum. The crude residue was
purified by flash chromatography (pentane–Et2O, 50:3), yielding
the product 14b (128 mg, 73%) as a colorless oil.
IR (film): 2972 (m), 1712 (s), 1670 (s), 1596 (m), 1448 (m), 1290
cm–1 (s).
1H NMR (300 MHz, CDCl3): = 7.97–7.92 (m, 2 H), 7.53–7.25 (m,
8 H), 3.78 (q, J = 7.1 Hz, 2 H), 2.78–2.64 (m, 1 H), 0.90 (d, J = 7.1
Hz, 6 H), 0.80 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 197.5, 166.5, 157.4, 137.8, 135.9,
133.4, 132.2, 129.7, 129.0, 128.9, 128.7, 128.2, 61.6, 32.1, 21.6,
13.9.
MS: m/z (%) = 322 (4), 276 (100), 217 (15), 143 (20), 105 (90), 77
(50).
IR (film): 3412 (w), 2957 (m), 1715 (s), 1464 (m), 1236 cm–1 (s).
1H NMR (400 MHz, CDCl3): = 7.34–7.24 (m, 3 H), 7.21–7.17 (m,
2 H), 5.96–5.85 (m, 1 H), 5.16–5.06 (m, 2 H), 4.14 (q, J = 7.1 Hz, 2
H), 3.18 (d, J = 6.7 Hz, 2 H), 1.91 (d, J = 7.0 Hz, 2 H), 1.88–1.76
(m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H), 0.75 (d, J = 6.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): = 168.8, 146.3, 137.7, 136.0, 132.6,
129.7, 128.0, 127.0, 116.2, 60.5, 41.2, 37.3, 26.4, 22.5, 14.1.
HRMS: m/z calcd for C21H22O3: 322.1569; found: 322.1581.
4-Isopropyl-3,5-diphenyl-5H-furan-2-one (17)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (214 mg, 0.64 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–78 °C and a 2 M solution of i-PrMgCl in Et2O (0.67 mL, 1.34
mmol) was added dropwise. After stirring for 15 min at –78 °C,
then 3 h at 0 °C, benzaldehyde (0.08 mL, 0.77 mmol) was added and
the mixture was allowed overnight to warm up to r.t. The mixture
was quenched with brine (10 mL) and extracted with Et2O. The or-
ganic layer was washed with brine, dried (MgSO4) and concentrated
under vacuum. The crude residue was purified by flash chromatog-
raphy (pentane–Et2O, 3:1), yielding the product 17 (100 mg, 56%)
as a colorless oil.
MS: m/z (%) = 272 (4), 227 (10), 211 (18), 199 (87), 169 (26), 155
(63), 143 (100), 129 (42), 115 (53), 91 (17).
HRMS: m/z calcd for C18H24O2: 272.1776; found: 272.1765.
3-Iodo-4-methyl-2-phenylpent-2-enoic Acid Ethyl Ester (15)
A dry two-necked flask equipped with a magnetic stirring bar and a
septum was charged with the dibromo ester 1a (205 mg, 0.61 mmol)
in Et2O (4 mL) under argon. The reaction mixture was cooled to
–78 °C and a 2 M solution of i-PrMgCl in Et2O (0.72 mL, 1.44
mmol) was added dropwise. After stirring for 15 min at –78 °C,
then 3 h at 0 °C, a solution of iodine (342 mg, 1.34 mmol) in Et2O
(4 mL) was added and the mixture was allowed to warm up to r.t.
overnight. The mixture was quenched with brine (10 mL) and ex-
tracted with Et2O. The organic layer was washed with aq sat. solu-
tion of Na2S2O3 and then brine, dried (MgSO4) and concentrated
under vacuum. The crude residue was purified by flash chromatog-
raphy (pentane–Et2O, 5:1), yielding the product 15 (172 mg, 82%)
as a colorless oil.
IR (film): 3491 (w), 2970 (m), 1755 (s), 1445 (m), 1132 cm–1 (m).
1H NMR (300 MHz, CDCl3): = 7.40–7.32 (m, 8 H), 7.27–7.19 (m,
2 H), 5.83 (s, 1 H), 2.99–2.96 (m, 1 H), 1.03 (d, J = 7.1 Hz, 3 H),
0.67 (d, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 173.5, 169.3, 135.8, 130.7, 129.9,
129.7, 129.3, 129.0, 128.9, 128.0, 127.0, 83.4, 28.5, 22.1, 21.3.
MS: m/z (%) = 278 (2), 235 (100), 179 (10), 129 (8), 105 (30), 77
(5).
HRMS: m/z calcd for C19H18O2: 278.1307; found: 278.1300.
IR (film): 3432 (w), 2966 (s), 1727 (s), 1614 (m), 1443 (m), 1266
(s), 1201 cm–1 (s).
1H NMR (300 MHz, CDCl3): = 7.30–7.19 (m, 5 H), 4.16 (q, Acknowledgments
J = 7.1 Hz, 2 H), 2.12–2.02 (m, 1 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.87
(d, J = 6.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): = 169.0, 141.3, 136.5, 129.1, 128.6,
128.5, 121.9, 89.1, 62.0, 34.7, 23.9, 14.4.
We thank the G.I.F. (German-Israeli Foundation for Scientific Re-
search and Development (I-535-083.05/97) for financial support.
We are grateful to the BASF AG (Ludwigshafen), Chemetall
GmbH (Frankfurt) and Degussa AG (Hanau) for generous gifts of
chemicals.
MS: m/z (%) = 344 (3), 217 (44), 189 (24), 171 (31), 143 (100), 128
(80), 115 (14), 77 (13).
Synthesis 2003, No. 12, 1797–1802 © Thieme Stuttgart · New York

1802
V. A. Vu et al.
PAPER
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Synthesis 2003, No. 12, 1797–1802 © Thieme Stuttgart · New York