Radical couplings as key steps for the preparation of derivatives of nonactic acid

Article abstract of DOI:10.1007/s00706-006-0578-x

Free radical couplings from furan, as cheap starting material, were studied in view of developing a rapid strategy en route to the synthesis of derivatives of nonactin. The chain containing the alcohol function was introduced in one or two steps in 86% yi

Full text of DOI:10.1007/s00706-006-0578-x

Monatshefte fu¨r Chemie 138, 121–129 (2007)
DOI 10.1007/s00706-006-0578-x
Printed in The Netherlands
Radical Couplings as Key Steps for the Preparation of Derivatives
of Nonactic Acid
ꢀ
Franc°ois Loiseau, Jean-Mary Simone, David Carcache, Pavel Bobal, and Reinhard Neier
^ ^
Institute of Chemistry, University of Neuchatel, Neuchatel, Switzerland
Received July 12, 2006; accepted (revised) July 21, 2006; published online January 19, 2007
# Springer-Verlag 2007
Summary. Free radical couplings from furan, as cheap start-
erty of this macrotetralide [3]. First reported in
1955 [4], 1 is isolated from Streptomyces cultures
and is the lowest homologue of the nactin family.
Structurally, nonactin (1) consist of four nonactic
acids (2) (Scheme 1) condensed in a (þ)(ꢁ)(þ)
(ꢁ) atypical fashion which confers S4 symmetry
(meso compound). To our knowledge, around 30
syntheses of nonactate derivatives and their 8-epimers
have been described so far [5]. These compounds
represent good candidates to test the stereospecificity
of modern synthesis methodology. In all the cases,
delicate chromatographies are required in the latter
stages of the syntheses. There are six total syntheses
of 1 in literature [6]. Difficulties to produce enan-
tiopure (þ) and (ꢁ)-nonactic acids (2) separately
and the problems associated with the assembly of
the enantiomers have prevented syntheses to com-
pete successfully with fermentation [7]. Consequent-
ly, 1 is expensive and not available in more than
gram quantities.
Analysing the particular structure of nonactin the
following question arises: Why did nature invests
such efforts to create 1, a 32-membered ring with
16 stereogenic centers if the result is an achiral
molecule? As part of our ongoing studies on the
macrocycle 1, we plan to develop a new, short, and
scalable route to generate 2,5-disubstituted furans
(Scheme 2). These 2,5-disubstituted furans are pre-
cursors of nonactic acid derivatives through cata-
lytic cis-hydrogenation of the furan rings.
ing material, were studied in view of developing a rapid strat-
egy en route to the synthesis of derivatives of nonactin. The
chain containing the alcohol function was introduced in one or
two steps in 86% yield. For the introduction of the second
chain with the ester function two different coupling methods
were tested. Starting from the advanced intermediates obtained
nonactin derivatives can be prepared by catalytic hydrogena-
tion of the furan ring.
Keywords. Heterocycles; Radical couplings; Natural pro-
ducts; Nonactic acid.
Introduction
Furan and tetrahydrofuran rings are present as
a significant structural element in many natural
products. They have been used as essential build-
ing blocks in the construction of important syn-
thetic targets. Furan (3) has attracted the interest
of chemists for well over a century [1], reflecting
the importance of this heterocycle in natural and
synthetic substances [2]. The stereoselective sub-
stitution of furans has been extensively studied.
Nonactin (1), an ionophore isolated from natural
sources, has raised interest as well as in its use as
antibiotic as in its use in ion selective electrodes.
The capacity of 1 to mediate selectively ammonium
and potassium transport is the predominant prop-
ꢀ
Corresponding author. E-mail: reinhard.neier@unine.ch

122
F. Loiseau et al.
Scheme 1
Scheme 2
Results and Discussion
[10] at 10ꢂC gave 6b in 86% yield (Table 1). Both
radical and anionic couplings are regioselective in
the 2-position of furan (3).
Since our synthetic strategy has to be scalable and
cheap, we chose furan (3) as starting material. We
first introduced one lateral chain leading to alcohols
6a and 6b (Scheme 3). Heavy-metal-free radical
coupling with an excess of 3 with ethyl 2-iodoethano-
ate (4a) according to Baciocchi conditions [8] led
to ethyl 2-(furan-2-yl)acetate (5) in almost quantita-
tive yield. Reduction of 5 gave 2-(furan-2-yl)ethanol
(6a) in 93% yield without further purification. Reac-
tion of 2-furyllithium with propylene oxide at 0ꢂC is
described in the literature to give 1-(furan-2-yl)pro-
pan-2-ol (6b) in good yield in THF [9] as solvent.
However, we obtained low yields under these re-
ported conditions but the reaction in diethyl ether
Before introducing the lateral chain in the fifth
position of our 2-subtituted furans 6a and 6b, we
have studied the protection of the alcohol function
(Table 2). Different protecting groups were intro-
duced, in 62–99% yields. The different protecting
groups of 6c–6h will give us a choice in order to
adapt the intermediates and their stabilities accord-
ing to the synthetic strategies used in the further
steps of our syntheses.
For the introduction of the second chain, we were
tempted to use the radical coupling with ethyl 2-
iodoethanoate (4a) according to Baciocchi condi-
Scheme 3

Radical Couplings
123
Table 1. Optimized reaction of 2-furyllithium with propylene
oxide
ethyl 2-iodopropanoate (4b), which is suitable to in-
troduce a methyl group in ꢀ-position as in nonactic
acid (2). We then started to decrease the excess of 7.
We could show that the excess of the heterocycle is
necessary to ensure total conversion of the iodoester.
Only 2 equivalents of 7 were required to obtain ac-
ceptable 53% yield on 2 g scale.
Less than 10% of unreacted iodoester 4a or 4b
remained. To remove the unreacted iodoesters the fol-
lowing procedure was applied. The mixture of the
furan derivatives and iodoester was refluxed in dry
n-hexane in the presence of activated zinc. Under
these conditions the Reformatsky enolate [11] of
the iodoester was created. Subsequent acidic hy-
drolysis led to the volatile ethyl acetate or ethyl pro-
pionate, which could be removed by evaporation
(Scheme 4). The heat-sensitivity of furans led to the
loss of about 20% of the product when applying
the conditions necessary for the formation of the
Reformatsky enolate.
Solvent
T1=ꢂC
t1=h
T2=ꢂC
t2=h
Yield=%
THF
THF
THF
THF
Et2O
0
2.5
1.5
1.25
1, 0.5
1, 3
ꢁ5, 12
0, 12
0, 12
0, 12
5–20
2
36
55
26
32
86
ꢁ2
1, 1
1, 1
1, 1
3
0
0, 20
10, 20
tions a second time. A large excess of 18 equivalents
is necessary to avoid dialkylation in the transforma-
tion of 3 to 5. The product 5 is isolated in almost
quantitative yield, in the presence of traces of DMSO.
Using sylvan (7) on 10 g scale, the yield in 8a is 65%
after filtration over silica gel with 19 equivalents of
7 as well as with 10 equivalents (Table 3). Using 7
on 100 g scale didn’t decrease much the yield in 8a,
which was 59%. The reaction is also efficient with
The Baciocchi reaction was then tried starting
from our previously synthesized 2-substituted furans.
To our delight, the radical coupling reaction works
with 2 equivalents of the benzyl protected furan 6e
Table 2. Protection of alcohol function
6
Prot1
R
Yield=%
c
d
e
f
g
h
Ac
THP
Bn
Bn
Me
TBDMS
H
H
H
Me
H
64
89
82
99
94
62
H
Scheme 4

124
F. Loiseau et al.
Table 3. Radical couplings under Baciocchi conditions
Reagent
mass=g; eq
R
t=h
Conversiona (Yield=%)b
3
7
7
7
7
7
6e
6e
6a
6b
6b
20; 18
10; 19
10; 10
100; 19
45; 10
2; 2
0.2; 2
0.1; 1
1.48; 2
0.38; 2
0.06; 1
H
H
H
H
Me
H
H
H
H
H
H
4
5
6
ꢁ(93)c 5
ꢁ(65)d 8a
ꢁ(65)d 8a
ꢁ(59)d 8a
ꢁ(54)d 8b
ꢁ(53)d 8a
ꢁ(53)d 9
7
16
19
30
14
21
22
2
ꢁ(14)d 9
50 (71)e 10
50 (64)d 11
100 (0)f–
a
b
Conversion based on the starting aromatic heterocycle, according to 1H NMR; isolated yield, based on ICHRCO2Et;
c
d
isolated without chromatography, with traces of DMSO; isolated by chromatography; e isolated without chromatography,
f
after distillation of the excess of 6a; the mixture was warmed to 70ꢂC
and the free alcohols 6a and 6b. Using stoechio-
metric quantities of our 2-substituted furan 6e we
did not obtain complete conversion to the correspond-
ing iodoesters. More dramatically the yield in 9 de-
creased to an unacceptable 14%. Attempts to push
the reaction to completion by heating the reaction
mixture to 70ꢂC led to the degradation of the furan
derivatives. We could show that the reaction works
with free iodoacids using DMSO as a solvent. The
isolation of the polar product was experimentally very
difficult.
To obtain better conversions, we tested a tin-free
radical coupling methodology developed few years
ago by Miranda [13], following Zard xanthate
(such as tert-butyl ethoxythiocarbonylsulfanylace-
tate (12)) based radical chemistry [14]. According
Table 4. Radical coupling with xanthate 12
13
R
addition t=h
Recovered material Yield=%
Yield=%
a
a
a
b
c
H
H
H
1.25
4.5
6a, 50
6a, 10
6a, 16
6h, 23
–
18
32
42
44
61
5.5a
5.5
TBDMS
Me
6.5
a
With only 0.87 equivalent of xanthate 12 and DLP

Radical Couplings
125
Scheme 5
to the reaction mechanism, one equivalent of initia-
tor dilauroyl peroxide (DLP) is necessary. In this
case, 6e is not suitable since the phenyl ring can
compete with the furan. Attempts to completely
remove DLP derivatives as their barium salts or
by filtration using basic alumina failed. Chromatog-
raphic purification was required accompanied by
a considerable loss of product. During chromatog-
raphy the non polar xanthate derivatives (mainly
dithiocarbonic acid O-ethyl-S-undecyl ester) are re-
moved first. The polar DLP derivatives are eluted
later. The use of the lighter benzoyl peroxide instead
of DLP allowed easier purification, but it gave
slightly lower conversions.
Experimental
All moisture-sensitive reactions were carried out under Ar and
N2 using oven-dried glassware. All reagents were of com-
mercial quality if not specifically mentioned. Solvents were
freshly distilled prior to use. Flash chromatography (FC):
Brunschwig silica gel 60, 0.032–0.063mm, under positive
pressure. TLC: Merck precoated silica gel thin-layer sheets
60 F 254, detection by UV and treatment with basic KMnO4
sol. Mp: Gallenkamp MFB-595. IR spectra: Perkin Elmer Spec-
trum One FT-IR, in cmꢁ1. NMR spectra: Bruker Avance-400
(400MHz (1H) and 100 MHz (13C)), at rt, chemical shifts ꢁ in
ppm rel. to CDCl3 (1H: 7.264ppm, 13C: 77.0ppm) as internal
reference, coupling constants J in Hz. ESI-MS: Finnigan LCQ.
HR-ESI-MS analyses of novel compounds agreed favourably
with calculated values.
The percentage of conversion can be increased by
slow portionwise addition of the peroxide while re-
fluxing the reaction mixture using 1,2-dichloroethane
(DCE) as solvent. The addition time reported is 12
hours. Miranda used 1.2 equivalents of the xanthate
12 and DLP. In our trials we used 1 equivalent of both
reagents to obtain easier purification and we opti-
mized the reaction time (see Table 4).
Following our proposed synthetic scheme, the
furan ring has to be reduced by a stereoselective cis
hydrogenation with 5% Rh over alumina [15] in order
to obtain a single diastereomer of our analogues of
nonactic acid (Scheme 5). In the case of substrate 14
prepared from xanthate 12, traces of impurities poi-
soned the rhodium catalyst. Therefore the furan de-
rivative 13a had to be subjected to the conditions of
the heterogenous reduction three times in order to
obtain complete conversion. Probably the impurities
had to be consumed first.
1-(Furan-2-yl)propan-2-ol (6b, C7H10O2)
Freshly distilled furan (3) (3.27 cm3, 45 mmol) stirred in 50cm3
dry diethyl ether was reacted at 10ꢂC with BuLi (1.6M in
n-hexane, 32cm3, 51.2mmol). After 1 h at 10ꢂC, the solution
was warmed at 20ꢂC for 2 h and then cooled at 5ꢂC, propylene
oxide (4cm3, 57mmol) was added other 15 min. The solution
was warmed to rt and stirred for 3 h, washed with saturated
NaHCO3 solution and extracted 3 times with diethyl ether.
The combined organic layers were washed with brine and
dried over MgSO4. Evaporation of the solvent in vacuo af-
forded 6b (4.89 g, 38.8mmol, 86%). Oil; Rf ¼ 0.26 (n-hexane=
AcOEt ¼ 75=25); 1H NMR (400 MHz, CDCl3): ꢁ ¼ 7.36
(dd, J ¼ 1.9, 0.8 Hz, H-6), 6.33 (dd, J ¼ 3.2, 1.9 Hz, H-5),
6.12 (dq, J ¼ 3.2, 0.8 Hz, H-4), 4.11 (dqd, J ¼ 7.6, 6.2,
4.7 Hz, H-1), 2.81 (dd, J ¼ 14.9, 4.7 Hz, H-2a), 2.76 (dd,
J ¼ 14.9, 7.6 Hz, H-2b), 2.06 (s, OH), 1.25 (d, J ¼ 6.2 Hz,
H-11) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 153.4, 142.0,
110.7, 107.4, 67.2 (C-1), 38.2 (C-2), 23.2 (C-11) ppm; EI-MS:
m=z ¼ 126 (25, [M]þ), 109 (11, [Mꢁ OH]þ), 83 (12, [Mþ
H ꢁ CO2]þ), 82 (100, [Mꢁ CO2]þ), 81 (95, [Mꢁ 45]þ), 54
(8, [Mþ H ꢁ CO2C2H5]þ), 53 (16, [Mꢁ CO2C2H5]þ).
2-(Furan-2-yl)ethanol (6a, C6H8O2)
Ester 5 (4.18 g, 27.13mmol) stirred in 160cm3 dry THF was
reacted at 0ꢂC with LiAlH4 (2.08 g, 58.55 mmol) added by
Conclusion
In conclusion, 2,5-disubstituted furans and tetrahy-
drofurans where prepared in few steps, with only one
chromatographic separation. The yields obtained for
the individual steps and the overall yield for the
transformation of 3 to 14 and 15 are satisfactory and
allowed us to continue our investigations.
Fig. 1. Labeling used for NMR assignment

126
F. Loiseau et al.
portions. The mixturewas heated to reflux for 1.5 h, cooled, and
hydrolysed with 90 cm3 brine. The salts were filtered off and
washed with AcOEt. The aqueous layer was extracted 3 times
with 90cm3 AcOEt and the combined organic layers were
washed with 90 cm3 brine and dried over MgSO4. Evaporation
of the solvents in vacuo provided 6a as a malodorous yellow
oil (2.86 g, 25.56 mmol, 93%). Oil; Rf ¼ 0.28 (n-hexane=
AcOEt¼ 95=5); IR (film): ꢂꢀ¼ 3368, 3118, 2956, 2928, 2079,
1736, 1598, 1507, 1469, 1422, 1374, 1341, 1241, 1210, 1146,
(400MHz, CDCl3): ꢁ ¼ 7.33 (dd, J ¼ 1.9, 0.8 Hz, H-6), 6.31
(dd, J ¼ 3.2, 1.9 Hz, H-5), 6.08 (dq, J ¼ 3.2, 0.8 Hz, H-4), 3.66
(t, J ¼ 6.8 Hz, H-1), 3.38 (s, OCH3), 2.93 (dt, J ¼ 6.8, 0.8Hz,
H-2) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 153.5 (C-3),
141.5 (C-6), 110.6 (C-5), 106.3 (C-4), 77.3 (C-1), 59.1
(OCH3), 29.3 (C-2) ppm; APCI-MS: m=z ¼ 127 (5, [M þ H]þ),
126 (38, [M]þ), 95 (18, [Mꢁ CH3O]þ), 94 (100), 81 (40),
53 (46).
1079, 1047, 1002, 731 cmꢁ1 1H NMR (400MHz, CDCl3):
;
tert-Butyl (2-(furan-2-yl)ethoxy)dimethylsilane
ꢁ ¼ 7.32 (dd, J ¼ 1.9, 0.8 Hz, H-6), 6.29 (ddt, J ¼ 3.1, 1.9,
0.3 Hz, H-5), 6.08 (dq, J ¼ 3.1, 0.8 Hz, H-4), 3.82 (t, J ¼ 6.5 Hz,
Hz, H-1), 2.86 (t, J ¼ 6.5Hz, H-2), 1.76 (s, OH) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 153.4 (C-3), 141.8 (C-6), 110.7 (C-5),
106.72 (C-4), 61.2 (C-1), 31.9 (C-2) ppm; APCI-MS:
m=z ¼ 113 (100, [Mþ H]þ), 95 (28, [Mþ H ꢁ H2O]þ).
(2h, C12H22O2Si)
Following the procedure of Ref. [18]: 2-(Furan-2-yl)ethanol
(6a) (4.5g, 40mmol), DMAP (489 mg, 4 cm3), and TEA (8.35,
4 cm3) stirred in 40cm3 dried CH2Cl2 were reacted at 5ꢂC
with a solution of TBDMSCl (6.63g, 44.0mmol) added drop-
wise in 10 cm3 of CH2Cl2. The solution was warmed to rt for
3 h and then diluted with CH2Cl2, and respectively washed
with saturated NaHCO3 solution and brine. The organic layer
was dried over MgSO4, and the CH2Cl2 was removed by
evaporation in vacuo. Purification by chromatography on a
silica gel column using n-hexane=AcOEt¼ 98=2 as an elu-
ent afforded 2h (5.6g, 24.7mmol, 62%). Oil; Rf ¼ 0.55
(n-hexane=AcOEt¼ 98=2); IR (film): ꢂꢀ¼ 2956, 2929, 2885,
2858, 1599, 1507, 1472, 1463, 1388, 1361, 1338, 1256, 1213,
1180, 1147, 1105, 1035, 1005, 969, 924, 904, 885, 837, 811,
General Procedure for the Protection of the Alcohol
Function [16]
A solution of 6a (1 eq) in dry THF was added dropwise at 0ꢂC
to a stirred suspension of NaH (1.2–1.7 eq) in dry THF. After
30min at 0ꢂC, the electrophile (1–2 eq) was added slowly and
the solution was warmed to rt for 6–16h. The mixture was
then slowly diluted with brine and extracted with diethyl
ether. The organic layers were washed with brine and dried
over MgSO4, and the volatiles were removed by evapora-
tion in vacuo.
776, 728, 680, 659, 599 cmꢁ1; H NMR (400MHz, CDCl3):
1
ꢁ ¼ 7.33 (dd, J ¼ 1.9, 0.8 Hz, H-6), 6.30 (dd, J ¼ 3.1, 1.9 Hz,
H-5), 6.08 (dd, J ¼ 3.2, 0.8 Hz, H-4), 3.88 (t, J ¼ 6.9 Hz, H-1),
2.88 (t, J ¼ 6.9 Hz, H-2), 0.90 (s, Si–C(CH3)3), 0.04 (s, Si–
(CH3)2) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 153.7 (C-3),
141.3 (C-6), 110.6 (C-5), 106.5 (C-4), 62.1 (C-1), 32.3 (C-2),
26.3 (Si–C(CH3)3), 18.7 (Si–C(CH3)), ꢁ5.0 (Si–(CH3)2) ppm.
2-(2-(Benzyloxy)ethyl)furan (2e, C13H14O2)
General procedure with 9.18 g (82 mmol) 6a, 3.31 g
(138 mmol) NaH, and 9.87cm3 (83 mmol) benzyl bromide.
Purification in reduced pressure yielded 2e (13.5 g, 67mmol,
82%). Oil; bp 60ꢂC (3.10ꢁ2 atm), 72–75ꢂC (5.10ꢁ2 atm) (Ref.
[17] 100ꢂC (4mm Hg)); Rf ¼ 0.53 (n-hexane=AcOEt¼ 95=5);
IR (film): ꢂꢀ¼ 3063, 3030, 2860, 2796, 1951, 1874, 1810, 1719,
1598, 1506, 1496, 1453, 1362, 1205, 1180, 1146, 1103, 1028,
1006, 734, 697 cmꢁ1; 1H NMR (400MHz, CDCl3): ꢁ ¼ 7.41–
7.33 (m, H-6, Ph), 6.34 (dd, J ¼ 3.1, 1.9Hz, H-5), 6.13 (ddt,
J ¼ 3.1, 1.7, 0.8 Hz, H-4), 4.59 (s, CH2–Ph)); 3.77 (t, J ¼
6.9 Hz, H-1), 3.01 (t, J ¼ 6.9 Hz, H-2) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 153.5 (C-3), 141.5 (C-6), 138.7,
128.8, 128.1 (Ph), 110.7 (C-5), 106.4 (C-4), 73.4 (CH2–Ph),
68.7 (C-1), 29.3 (C-2) ppm; APCI-MS: m=z ¼ 203 (100,
[Mþ H]þ), 185 (85), 92 (3), 91 (55), 65 (19).
2-Furan-2-ylethylacetate (2c, C8H10O3)
Following the procedure of Ref. [16]: 2-(Furan-2-yl)ethanol
(6a) (1g, 9 mmol) stirred in 40cm3 dried CH2Cl2, was reacted
at 0ꢂC with pyridine (0.81 cm3, 10mmol) and acetyl chlo-
ride (0.71 cm3, 10mmol). After 1 h at 0ꢂC, the solution was
warmed to rt for 6 h, then diluted with CH2Cl2, and washed
two times with 1 M HCl and with saturated NaHCO3 solution.
The organic layer was dried over MgSO4, and the CH2Cl2 was
removed by evaporation in vacuo. Purification by chromatog-
raphy on a silica gel column using n-hexane=AcOEt increas-
ing the AcOEt ratio afforded 2c (0.889 mg, 5.76mmol, 64%).
Oil; Rf ¼ 0.50 (n-hexane=AcOEt ¼ 75=25); IR (film): ꢂꢀ¼
2964, 2908, 1742, 1599, 1508, 1430, 1381, 1366, 1239, 1183,
2-(2-(Benzyloxy)propyl)furan (2f, C14H16O2)
1147, 1086, 1038, 1010, 737, 601 599 cmꢁ1 1H NMR
;
General procedure with 1.33 g (10.5 mmol) 6b, 0.87 g
(18.1mmol) NaH, and 1.3 cm3 (10.9 mmol) benzyl bromide.
Crude 2f was obtained (2.27 g, 10.5mmol, 99%). Oil;
Rf ¼ 0.50 (n-hexane=AcOEt¼ 75=25 þ 1% MeOH).
(400MHz, CDCl3): ꢁ ¼ 7.32 (dd, J ¼ 1.9, 0.9 Hz, H-6), 6.29
(ddt, J ¼ 3.1, 1.9, 0.4 Hz, H-5), 6.08 (dq, J ¼ 3.1, 0.9 Hz, H-4),
4.31 (t, J ¼ 6.8 Hz, H-1), 2.97 (td, J ¼ 6.9, 0.9 Hz, H-2), 2.04
(s, CH3) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 170.9
(C¼O), 151.8 (C-3), 141.4 (C-6), 110.2 (C-5), 106.3 (C-4),
62.3 (C-1), 27.7 (C-2), 20.9 (CH3) ppm.
2-(2-Methoxyethyl)furan (2g, C7H10O2)
General procedure with 2.71 g (24.2 mmol) 6a, 0.7 g
(29.2mmol) NaH, and 3 cm3 (48.3 mmol) methyl iodide.
Without further purification, 2g (2.86 g, 22.7mmol, 94%)
was obtained. Oil; Rf ¼ 0.43 (n-hexane=AcOEt¼ 95=5); IR
(film): ꢂꢀ¼ 2981, 2926, 2740, 1727, 1598, 1507, 1460, 1380,
2-(2-(Furan-2-yl)ethoxy)tetrahydro-2H-pyran (2d,
C11H16O3)
Following the procedure of Ref. [19]: A solution of 6a
(300mg, 2.7 mmol) and dihydropyrane (338mg, 4.0 mmol)
1340, 1270, 1146, 1118, 1047, 1008, 732 cmꢁ1 1H NMR
;

Radical Couplings
127
stirred in 50cm3 dried CH2Cl2 was reacted at rt with PPTS
(67 mg, 0.3 mmol) in 20 cm3 dried CH2Cl2 for 12 h. The solu-
tion was diluted with diethyl ether and washed with
brine=H2O ¼ 1=1. The organic layer was dried over MgSO4,
and the CH2Cl2 removed by evaporation in vacuo. Purification
by chromatography on a silica gel column using CH2Cl2=
diethyl ether ¼ 75=25 as an eluent afforded 2d (469mg,
2.39mmol, 89%). Oil; Rf ¼ 0.20 (CH2Cl2); IR (film): ꢂꢀ¼
2943, 2872, 1598, 1507, 1466, 1455, 1441, 1385, 1353,
1261, 1201, 1184, 1136, 1121, 1075, 1033, 1005, 973, 730,
492 cmꢁ1; 1H NMR (400MHz, CDCl3): ꢁ ¼ 7.30 (dd, J ¼ 1.9,
0.9 Hz, H-6), 6.28 (dd, J ¼ 3.2, 1.9 Hz, H-5), 6.07 (dq, J ¼ 3.2,
0.9 Hz, H-4), 4.61 (t, J ¼ 3.5 Hz, OCH–O), 3.97 (dt, J ¼ 9.7,
7.1 Hz, H-1a), 3.80 (m, 1H), 3.66 (dt, J ¼ 9.7, 7.1 Hz, H-1b),
3.48 (m, 1H), 2.94 (t, J ¼ 7.1 Hz, H-2), 1.85–1.46 (m, 6H)
ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 153.2 (C-3), 140.9
(C-6), 110.2 (C-5), 105.1 (C-4), 98.7 (OCH–O), 65.4 (C-1),
62.1 (CH2O), 30.6, 28.8, 25.4, 19.4ppm; DCI-MS: m=z ¼ 214
(38, [Mþ H2O]þ), 197 (30, [Mþ H]þ), 102 (100, [Mþ H2O ꢁ
CH2-furyl]þ), 94 (30), 85 (47).
CDCl3): ꢁ ¼ 169.4 (C-1), 147.7 (C-3), 142.0 (C-6), 110.5 (C-
5), 107.9 (C-4), 61.1 (C-11), 34.1 (C-2)), 14.1 (C-12) ppm; EI-
MS: m=z ¼ 154 (44, [M]þ), 153 (95), 125 (27, [Mꢁ C2H5]þ),
97 (61), 86 (30), 84 (55), 83 (61), 82 (28), 81 (100,
[Mꢁ CO2Et]þ), 69 (32), 55 (30), 49 (57).
Ethyl 2-(5-methylfuran-2-yl)acetate (8a, C9H12O3)
Oil; Rf ¼ 0.28 (n-hexane=AcOEt¼ 95=5); IR (film): ꢂꢀ¼ 2984,
2925, 1742, 1620, 1603, 1570, 1448, 1335, 1310, 1266, 1220,
1180, 1142, 1032, 1022, 998, 972, 956, 939, 913, 785, 700,
646, 573 cmꢁ1
;
1H NMR (400MHz, CDCl3): ꢁ ¼ 6.10 (m,
J ¼ 3.1Hz, H-4), 5.91 (m, J ¼ 3.1Hz, H-5), 4.17 (q, J ¼
7.1 Hz, H-11), 3.61 (s, H-2), 2.22 (s, H-7), 1.26 (t, J ¼ 7.1 Hz,
H-12) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 170.1 (C-1),
152.0 , 146.0 (C-3, C-6), 109.0 (C-5), 107.7 (C-4), 61.5
(C-11), 34.6 (C-2), 14.5 (C-12), 13.9 (C-7) ppm; ESI-MS:
m=z ¼ 191 (100, [Mþ Na]þ).
Ethyl 2-(5-methylfuran-2-yl)propanoate (8b, C10H14O3)
Reaction with freshly prepared or freshly distilled ethyl
2-iodopropanoate (4b). Oil; Rf ¼ 0.21 (n-hexane=AcOEt¼
95=5); IR (film): ꢂꢀ¼ 3108, 2985, 2941, 1739, 1614, 1566,
1455, 1377, 1322, 1250, 1202, 1160, 1073, 1023, 955, 940,
Ethyl 2-iodopropanoate (4b, C5H9IO2)
A solution of NaI (15.48g, 103.3 mmol.) and ethyl 2-bromo-
propanoate (17 g, 93.9 mmol) stirred in 300 cm3 acetone was
refluxed for 3 h. The mixture was cooled to rt, filtered, and
acetone was removed by evaporation in vacuo. 100cm3 n-
hexane and 100 cm3 H2O were added and the product was
extracted with 3ꢃ100 cm3 n-hexane. The combined organic
layers were washed with 100 cm3 brine, dried over Na2SO4,
and the volatiles were removed by evaporation in vacuo to
afford 4b (20.2g (86 mmol, 94%). Oil; Rf ¼ 0.06 (n-hexane=
AcOEt¼ 95=5); 1H NMR (400MHz, CDCl3): ꢁ ¼ 4.49 (q,
J ¼ 7.0 Hz, H-2), 4.26 (dq, J ¼ 11.5, 7.1 Hz, H-11a), 4.22
(dq, J ¼ 11.5, 7.1 Hz, H-11b), 1.98 (d, J ¼ 7.0Hz, H-3), 1.31
(t, J ¼ 7.1 Hz, H-12).
1
861, 784, 712 cmꢁ1; H NMR (400MHz, CDCl3): ꢁ ¼ 6.07
(dd, J ¼ 3.1, 0.3 Hz, H-4), 5.91 (dq, J ¼ 3.1, 1.0 Hz, H-5), 4.19
(q, J ¼ 7.1 Hz, H-11), 3.77 (q, J ¼ 7.3 Hz, H-2), 2.28 (d,
J ¼ 1.0 Hz; H-7), 1.24 (d, J ¼ 7.3 Hz, H-21), 1.28 (t, J ¼
7.1 Hz, H-12) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 170.3
(C-1), 152.0 , 151.7 (C-3, C-6), 106.9 (C-4), 106.5 (C-5), 61.4
(C-11), 39.9 (C-2), 16.2 (C-21), 14.5 (C-12), 13.9 (C-7) ppm;
ESI-MS: m=z ¼ 205 (100, [Mþ Na]þ), 101 [M-82 (sylvan)]þ).
Ethyl 2-(5-(2-hydroxypropyl)furan-2-yl)acetate
(11, C11H16O4)
Oil; Rf ¼ 0.13 (n-hexane=AcOEt ¼ 75=25); IR (film): ꢂꢀ¼
3444, 2977, 2932, 1739s, 1644, 1615, 1565, 1448, 1401,
1371, 1301, 1268, 1233, 1183, 1030, 1015, 975, 940, 878,
;
844, 788, 686, 624, 577, 471cmꢁ1 1H NMR (400 MHz,
General Procedure for the Radical Coupling in Baciocchi
Conditions
To a stirred mixture of the aromatic heterocycle (1–20 eq, see
Table 3, commercials furan (3) and sylvan (7) were freshly
distilled), the alkyl iodide (1 eq), and FeSO4 ꢄ 7H2O (0.5 eq) in
DMSO, 1.9 eq H2O2 (35% in H2O) were added dropwise,
while the solution was kept at rt with a H2O bath. The mixture
was then slowly diluted with brine and extracted with diethyl
ether. The organic layers were washed with brine, dried over
MgSO4, and the volatiles were removed by evaporation in
vacuo. If necessary, the residue was purified by chromatogra-
phy on a silica gel column using n-hexane=AcOEt or CH2Cl2
as an eluent.
CDCl3): ꢁ ¼ 6.15 (d, J ¼ 3.1 Hz, H-4), 6.07 (d, J ¼ 3.1 Hz,
H-5) 4.19 (q, J ¼ 7.2 Hz, H-11), 4.17 (dqd, J ¼ 7.6, 6.2Hz,
4.7 Hz, H-8), 3.66 (s, H-2), 2.98 (dd, J ¼ 14.9, 4.7 Hz,
H-7a), 2.71 (dd, J ¼ 14.9, 7.6 Hz, H-7b), 1.86 (br, OH), 1.29
(t, J ¼ 7.2 Hz, H-12), 1.25 (d, J ¼ 6.2 Hz, H-9) ppm; 13C NMR
(100MHz, CDCl3): ꢁ ¼ 169.9 (C-1), 157.2 (C-3), 152.8 (C-6),
109.0 (C-4), 108.4 (C-5), 67.2 (C-8), 61.6 (C-11), 38.3 (C-7),
34.6 (C-2), 23.0 (C-9), 14.6 (C-12) ppm; ESI-MS: m=z ¼ 235
(52, [Mþ Na]þ), 152 (32, [Mþ Na-83]þ), 150 (100, [Mþ
Na-85]þ).
Ethyl 2-(5-(2-(benzyloxy)ethyl)furan-2-yl)acetate
Ethyl 2-(furan-2-yl)acetate (5, C8H10O3)
(9, C17H20O4)
Oil; Rf ¼ 0.41 (CH2Cl2); IR (film): ꢂꢀ¼ 2984, 2940, 2908,
1741, 1603, 1507, 1478, 1466, 1448, 1392, 1369, 1338,
1301, 1272, 1229, 1185, 1157, 1097, 1075, 1031, 1013, 951,
Oil; Rf ¼ 0.20 (n-hexane=AcOEt ¼ 90=10); 1H NMR
(400MHz, CDCl3): ꢁ ¼ 7.40 ꢁ 7.28 (m, Ph), 6.15 (d, J ¼
3.1 Hz, H-4), 6.04 (d, J ¼ 3.1 Hz, H-5), 4.56 (s, CH2-Ph),
4.20 (q, J ¼ 7.1 Hz, H-11), 3.74 (t, J ¼ 6.9 Hz, H-8), 3.65
(s, H-2), 2.96 (t, J ¼ 6.9Hz, H-7), 1.29 (t, J ¼ 7.1 Hz, H-12)
ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 170.0 (C¼O), 153.0
(C-3), 146.6 (C-6), 138.7 (1C, Ph), 128.8, 128.1, 128.0, (5C,
1
737, 601 cmꢁ1; H NMR (400 MHz, CDCl3): ꢁ ¼ 7.37 (dd,
J ¼ 1.8, 0.9Hz, H-6), 6.35 (dd, J ¼ 3.2, 1.8Hz, H-5), 6.23
(dq, J ¼ 3.2, 0.8 Hz, H-4), 4.20 (q, J ¼ 7.1 Hz, H-11), 3.69 (s,
H-2), 1.28 (t, J ¼ 7.2 Hz, H-12) ppm; 13C NMR (100 MHz,

128
F. Loiseau et al.
Ph), 109.0 (C-4), 107.4 (C-5), 73.4 (CH2-Ph), 68.7 (C-8), 61.5
(C-11), 34.7 (C-2), 29.3 (C-7), 14.6 (C-12) ppm.
(C-8), 59.1 (OCH3), 35.8 (C-2), 29.2 (C-7), 28.4 (C(CH3)3)
ppm; ESI-MS: m=z ¼ 264 (23, [Mþ Naþ H]þ), 263 (100,
[Mþ Na]þ).
Ethyl 2-(5-(2-hydroxyethyl)furan-2-yl)acetate
(10, C10H14O4)
tert-Butyl 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)furan-
2-yl)acetate (13b, C18H32O4Si)
Oil; Rf ¼ 0.21 (n-hexane=AcOEt ¼ 75=25); IR (film): ꢂꢀ¼
3457, 2960, 2983, 2934, 1738, 1640, 1615, 1566, 1466,
1447, 1370, 1323, 1268, 1226, 1184, 1162, 1030, 971, 915,
General procedure with 5.5 g (24.3 mmol) 6h over a 6.5 h
period. 1.26g (5.58 mmol, 23%) unreacted 6h were recovered,
and 13b was yielded (3.85 g, 10.7mmol, 44%). Oil; Rf ¼ 0.56
(n-hexane=AcOEt¼ 95=5); IR (film): ꢂꢀ¼ 2957, 2930, 2858,
1714, 1651, 1473, 1463, 1367, 1258, 1198, 1134, 1096, 1035,
1
855, 791, 686 cmꢁ1; H NMR (400MHz, CDCl3): ꢁ ¼ 6.14
(d, J ¼ 3.1 Hz, H-4), 6.06 (d, J ¼ 3.1Hz, H-5) 4.19 (q,
J ¼ 7.1 Hz, H-11), 3.86 (t, J ¼ 6.2 Hz, H-8), 3.65 (s, H-2),
2.88 (t, J ¼ 6.2Hz, H-7), 1.83 (br, OH), 1.28 (t, J ¼ 7.1 Hz,
H-12) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 170.0 (C-1),
152.8 (C-3), 147.1 (C-6), 109.1 (C-4), 107.9 (C-5), 61.6
(C-11), 61.5 (C-8), 34.6 (C-2), 32.0 (C-7), 14.5 (C-12) ppm;
ESI-MS: m=z ¼ 221 (100, [Mþ Na]þ).
874, 836, 809, 775, 746, 662 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): ꢁ ¼ 6.08 (d, J ¼ 3.1 Hz, CH), 5.98 (d, J ¼ 3.1 Hz,
CH), 3.83 (t, J ¼ 7.0 Hz, H-8), 3.53 (s, H-2), 2.81 (t, J ¼
7.0 Hz, H-7), 1.46 (s, C(CH3)3), 0.88 (s, Si-C(CH3)3), 0.02
(s, 6H, Si-(CH3)2) ppm; 13C NMR (100MHz, CDCl3):
ꢁ ¼ 169.3 (C-1), 152.5 (C-3), 146.7 (C-6), 108.2 (C-4), 107.0
(C-5), 81.1 (C(CH3)3), 61.7 (C-8), 35.4 (C-2), 31.9 (C-7), 28.0
(C(CH3)3), 25.9 (Si–C(CH3)3), 18.3 (Si–C(CH3)3), ꢁ5.4 (Si–
(CH3)2) ppm.
General Procedure for the Radical Coupling
with Xanthate 12
A solution of xanthate 12 (1 eq) and the heteroatomic com-
pound (1 eq) in dry DCE (2cm3 ꢄ mmolꢁ1) was heated at reflux,
and a solution of DLP (1 eq) in DCE (0.5cm3 ꢄ mmolꢁ1) was
added dropwise over a period of several hours. After filtra-
tion, the solvent was removed by evaporation in vacuo and
the crude residue was purified by chromatography on a silica
gel column using n-hexane=AcOEt as an eluent.
tert-Butyl 2-(5-(2-hydroxyethyl)tetrahydrofuran-
2-yl)acetate (14, C12H22O4)
The furan 13a (358 mg, 1.58 mmol) and 5% Rh over alumina
(170mg, 0.082mmol) in 30cm3 MeOH were placed in a 3.8
atm pressure of hydrogen in a Parr apparatus. After 16h, the
mixture was filtered through a celite=silica ¼ 2=1 mixture. The
procedure was repeated 2 more times to complete the reaction.
14 (130mg, 0.56mmol, 35%) was yielded in presence of
traces of tert-butyl 2-(5-(2-hydroxyethyl)dihydrofuran-2(3H)-
ylidene)acetate. According to NMR, cis=trans ratio of 14 is
85=15. Oil; Rf ¼ 0.08 (n-hexane=AcOEt¼ 75=25); IR (film):
ꢂꢀ¼ 3437, 2974, 2935, 2930, 2876, 1729, 1458, 1393, 1368,
tert-Butyl 2-(5-(2-hydroxyethyl)furan-2-yl)acetate
(13a, C12H18O4)
General procedure with 0.5 g (4.5mmol) 6a over a 4.5 h
period. Unreacted 6a (0.34 mmol, 8%) was recovered, and
13a (357 mg, 1.43 mmol, 32%) was yielded. Oil; Rf ¼ 0.18
(n-hexane=AcOEt¼ 75=25); IR (film): ꢂꢀ¼ 3446, 3108, 2981,
2979, 2930, 1736, 1642, 1565, 1477, 1456, 1393, 1369, 1244,
1
1300, 1257, 1155, 1071, 950, 843cm1; H NMR (400 MHz,
CDCl3): ꢁ ¼ 4.32 (ꢅdq, J ¼ 7.4, 6.0 Hz, H-3 trans), 4.21
(ꢅquint, Jꢅ6.6Hz, H-3 cis), 4.08-4.02 (m, H-6 trans, H-6
cis), 3.76-3.73 (m, H-8 trans), 3.75 (ꢅdd, Jꢅ6.5, 4.5 Hz,
H-8 cis), 2.73 (br, OH cis, OH trans), 2.52 (dd, J ¼ 14.7,
7.2 Hz, H-2a cis), 2.48 (dd, J ¼ 14.9, 7.4Hz, H-2a trans),
2.39 (dd, J ¼ 14.7, 6.2 Hz, H-2b cis), 2.37 (dd, J ¼ 14.9,
6.0 Hz, H-2b trans), 2.17–1.99 (m, H-5a cis, H-5a trans,
H-4a cis, H-4a trans), 1.83–1.69 (m, H-7 cis, H-7 trans),
1.65–1.57 (m, H-5b cis, H-5b trans, H-4b cis, H-4b trans),
1.43 (s, C(CH3)3 cis, C(CH3)3 trans) ppm; 13C NMR
(100MHz, CDCl3): ꢁ ¼ 170.5 (C¼O cis), 170.4 (C¼O trans),
80.7 (C(CH3)3 cis), 80.6 (C(CH3)3 trans), 79.7 (C-6 cis), 79.1
(C-6 trans), 76.1 (C-3 cis), 75.2 (C-3 trans), 61.7 (C-8 cis),
61.4 (C-8 trans), 42.4 (C-2 cis), 42.0 (C-2 trans), 37.8 (C-7
cis), 37.3 (C-7 trans), 32.4, 31.4 (C-4 trans, C-5 trans), 31.1,
30.6 (C-4 cis, C-5 cis), 30.0 (C(CH3)3 cis, trans) ppm; APCI-
MS: m=z ¼ 253 (22, [Mþ Na]þ), 231 (28, [Mþ H]þ), 175
(100, [Mþ 2Hꢁ C(CH3)3]þ).
1
1147, 1048, 1011, 733 cmꢁ1; H NMR (400 MHz, CDCl3):
ꢁ ¼ 6.12 (d, J ¼ 3.1 Hz, CH), 6.06 (d, J ¼ 3.1 Hz, CH), 3.86
(t, J ¼ 6.4 Hz, H-8), 3.57 (s, H-2), 2.88 (t, J ¼ 6.4 Hz, H-7),
2.37 (s, OH), 1.48 (s, C(CH3)3) ppm; 13C NMR (100MHz,
CDCl3): ꢁ ¼ 169.3 (C-1), 152.6 (C-3), 147.7 (C-6), 108.8
(C-4), 107.8 (C-5), 81.8 (C(CH3)3), 61.5 (C-8), 35.8 (C-2),
28.4 (C-7), 27.9 (C(CH3)3) ppm; ESI-MS: m=z ¼ 227 (30,
[Mþ H]þ), 226 (90, [M]þ), 196 (59), 140 (50), 125 (49),
108 (100), 95 (60); ESI-HR-MS: m=z [Mþ Na]þ ¼ calcd
249.1097, found 249.1093.
tert-Butyl 2-(5-(2-methoxyethyl)furan-2-yl)acetate
(13c, C13H20O4)
General procedure with 0.5g (4.5 mmol) 6g over a 5.5 h pe-
riod. Product 13c was yielded (568 mg, 2.36mmol, 61%). Oil;
Rf ¼ 0.81 (n-hexane=AcOEt¼ 90=10); IR (film): ꢂꢀ¼ 2979,
2927, 2856, 2738, 1737, 1614, 1566, 1478, 1456, 1392,
1368, 1278, 1146, 1119, 1044, 1014, 733 cmꢁ1 1H NMR
;
Ethyl 2-(5-(2-hydroxyethyl)tetrahydrofuran-2-yl)acetate
(15, C10H18O4)
(400 MHz, CDCl3): ꢁ ¼ 6.10 (d, J ¼ 3.1 Hz, CH), 6.01 (d,
J ¼ 3.1 Hz, CH), 3.64 (t, J ¼ 6.9 Hz, H-8), 3.56 (s, H-2), 3.37
(s, OCH3), 2.89 (t, J ¼ 6.9Hz, H-7), 1.47 (s, C(CH3)3) ppm;
13C NMR (100MHz, CDCl3): ꢁ ¼ 169.3 (C-1), 152.7 (C-3),
147.3 (C-6), 108.7 (C-4), 107.2 (C-5), 81.6 (C(CH3)3), 71.1
Freshly purified by chromatography 10 (300mg, 1.51 mmol)
and 5% Rh over alumina (144 mg, 0.07mmol) in 20cm3
MeOH were placed in a 3.8 atm pressure of hydrogen in a

Radical Couplings
129
Parr apparatus. After 16 h, the mixture was filtered on a
celite=silica¼ 2=1 mixture. 15 (300mg, 1.48 mmol, 98%)
was yielded in presence of traces of ethyl 2-(5-(2-hy-
droxyethyl)dihydrofuran-2(3H)-ylidene)acetate. According to
NMR, cis=trans ratio of 15 is about 80=20. Oil; Rf ¼ 0.05
(n-hexane=AcOEt¼ 75=25); 1H NMR (400 MHz, CDCl3):
ꢁ ¼ 4.43–4.02 (m, H3, H-6, H-11 cis, trans), 3.78–3.75 (m,
H-8 cis, trans), 2.66 (br, OH cis, OH trans), 2.59 (dd, J ¼ 14.9,
7.2 Hz, H-2a cis), 2.48 (dd, J ¼ 14.9, 6.2 Hz, H-2b cis), 2.60–
2.44 (m, H-2 trans), 2.17–1.99 (m, H-4 trans, H-5 trans, H-4a
cis, H-5a cis), 1.86–1.59 (m, H-7 cis, H-7 trans), 1.68–1.29
(m, H-4b cis, H-5b cis), 1.26 (t, J ¼ 7.1 Hz, H-12 cis, H-12
trans) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 170.5 (C¼O
cis), 170.5 (C¼O trans), 80.1 (C-6 cis), 79.5 (C-6 trans),
76.3 (C-3 cis), 75.4 (C-3 trans), 62.0 (C-8 trans), 61.8 (C-8
cis), 60.9 (C-11 cis, C-11 trans), 41.6 (C-2 cis), 41.2 (C-2
trans), 38.2 (C-7 cis), 37.8 (C-7 trans), 32.5, 31.9 (C-4 trans,
C-5 trans), 31.6, 31.1 (C-4 cis, C-5 cis), 14.6 (C-12 cis, C-12
trans) ppm.
[4] Corbaz R, Ettinger L, Gaumann E, Keller-Schlierlein W,
Kradolfer F, Kyburz E, Neipp L, Prelog V, Zahner H
(1955) Helv Chim Acta 38: 1445
[5] Takatori K, Tanaka K, Matsuoka K, Morishita K,
Kajiwara M (1997) Synlett 2: 159
[6] a) Gerlach H, Oertle K, Thalmann A, Servi S (1975)
Helv Chim Acta 58: 2036; b) Schmidt U, Gombos J,
Haslinger E, Zak H (1976) Chem Ber 109: 2628; c)
Bartlett PA, Meadows JD, Ottow E (1984) J Am Chem
Soc 106: 5304; d) Kim BH, Lee JY (1996) Tetrahedron
52: 571; e) Fleming I, Ghosh SK (1998) J Chem Soc,
Perkin Trans 1 2733; f) Wu Y, Sun Y-P (2006) Org Lett
8: 2831
[7] Nikodinovic J, Dinges JM, Bergmeier SC, McMills MC,
Wright DL, Priestley ND (2006) Org Lett 8: 443
[8] Baciocchi E, Muraglia E, Sleiter G (1992) J Org Chem
57: 6817
[9] Fogagnolo M, Giovannini PP, Guerrini A, Medici A,
Pedrini P, Colombi N (1998) Tet Asym 9: 2317
[10] Jones TH, Highet RJ, Warwick Don A, Blum MS (1986)
J Org Chem 51: 2712
Acknowledgements
[11] a) Reformatsky S (1887) Chem Ber 20: 1210; b) Picotin
G, Miginiac P (1987) J Org Chem 52: 4796
[12] Schloemer GC, Greenhouse R, Muchowski JM (1994)
J Org Chem 59: 5230
[13] Osornio YM, Cruz-Almanza R, Jimenez-Montano V,
Miranda LD (2003) Chem Commun: 2316
[14] a) Cordero Vargas A, Quiclet-Sire B, Zard SZ (2003)
Org Lett 5: 3717; b) Zard SZ (1997) Angew Chem Intl
Ed 36: 673
NMR Spectra (400MHz) were measured by Heinz Bursian
and Dr. Claude Saturnin, mass spectra by Dr. Nicolas Mottier
and Dr. Bernard Jean-Denis, HR-MS analyses were made in
´
the Ecole d’ingenieurs et d’architectes de Fribourg. We thank
the University of Neuchatel and the Swiss National Science
^
Foundation for financial support.
[15] Schmidt U, Werner J (1986) Synthesis 986
[16] Annunziata R, Benaglia M, Cinquini M, Cozzi F,
Raimondi L (1995) J Org Chem 60: 4697
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[18] Bergmeier SC, Seth PP (1999) J Org Chem 64: 3237
[19] Miyashita N, Yoshikoshi A, Grieco PA, (1977) J Org
Chem 42: 3772
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