Stereocontrolled synthesis of carbon-carbon double bond locked analogues of strobilurins which are characterized by a trans-1,2-disubstituted cyclopropane ring

Article abstract of DOI:10.1016/S0040-4020(01)00136-3

The racemic forms of four new carbon-carbon double bond locked analogues of strobilurins, which are characterized by a trans-1,2-disubstituted cyclopropane ring, have been synthesized according to a strategy which involves palladium-catalyzed cross-coupli

Full text of DOI:10.1016/S0040-4020(01)00136-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2847±2856
Stereocontrolled synthesis of carbon±carbon double bond locked
analogues of strobilurins which are characterized
by a trans-1,2-disubstituted cyclopropane ring
a,p
Renzo Rossi, Adriano Carpita, Arianna Ribecai and Luisa Mannina
a,p
a
b
a
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
b
Corso di Laurea in Scienze Ambientali, Universit aÁ del Molise, Via Mazzini 8, I-86170 Isernia, Italy
Received 30 October 2000; revised 3 January 2001; accepted 25 January 2001
AbstractÐThe racemic forms of four new carbon±carbon double bond locked analogues of strobilurins, which are characterized by a trans-
,2-disubstituted cyclopropane ring, have been synthesized according to a strategy which involves palladium-catalyzed cross-coupling
reactions between methyl (Z)-2-iodo-3-methoxypropenoate and organometallic derivatives such as (1R ,2R )-2-phenylcyclopropylboronic
1
p
p
p
acid and (1R ,2R)-1-(2-bromozinciophenyl)-2-arylcyclopropanes. The boronic acid has been prepared via cyclopropanation of (E)-2-phenyl-
ethenyl-1,3,2-dioxaborinane and the organozinc compounds have been synthesized from easily available (E)-2-bromostilbenes. q 2001
Elsevier Science Ltd. All rights reserved.
Strobilurins (1) are metabolites isolated from basidiomy-
cetes which inhibit mitochondrial respiration in fungi by1
broad-spectrum agricultural fungicides such as azoxystrobin
(formerly ICI A 5504) (3), kresoxim-methyl (BAS 490 F)
3
4
5
(4), tri¯oxystrobin (CGA 279202)(5) and metominostrobin
interfering with the function of cytochrome bc complex.
1
6
As a result, strobilurins exhibit good broad-spectrum fungi-
cidal activity in vitro. However, they can not be used
(SSF 126)(6).
1
directly as fungicides because of insuf®cient levels of
activity in vivo, photolytic instability and volatility.
2
Owing to their novel mode of action, low toxicity towards
mammalian cells and favourable pro®les to human safety,
these natural products have been used as leads for the design
and development of photostable structural analogues able to
1
c,2
control the major classes of fungi which affect crops.
Thus, several types of variations of the lead structures as
regards their pharmacophore, i.e. the methyl (E)-3-methoxy-
propenoate unit (2), or their lipophilic moiety have been
performed and, quite recently, the intense research activity
performed in this ®eld by more than 20 companies and
research institutes allowed the development of some
These fungicides, similarly to several other analogues of
7
,8
1, are characterized by direct attachment of a suitably
ortho-substituted aromatic ring to a pharmacophore, which
in the case of 3 is unit 2, in the case of compounds 4 and 5 is
the methyl (E)-O-methyloximinoacetate group (7), and in
compound 6 is the (E)-O-methyloximino-N-methylaceta-
Keywords: strobilurins; palladium; cyclopropanation; cross-coupling;
organozinc derivatives.
p
Corresponding authors. Tel.: 139-50-918214; fax: 139-50-918260;
e-mail: rosse@dcci.unipi.it
9
mide group (8).
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00136-3

2
848
R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
Scheme 1. (a) Catecholborane (1 equiv.), 708C, 8 h, rt; (b) H
1
2
O, 5 h, rt; (c) 1,3-propanediol (1.1 equiv.), pentane, 1.5 h, rt; (d) distillation (71% yield based on
7); (e) catecholborane (1 equiv.), 708C, 15 h; (f) 1,3-propanediol (1.1 equiv.), hexane, 20 h, rt; (g) distillation (48% yield based on 17); (h) CH (5 equiv.),
(4 mol%), 0±58C, 50 min (96% yield); (i) 1.5N KOH (3 equiv.), 80 min, rt; (j) 2N HCl, 08C (93% yield based on (1R ,2R )-18); (k) 11
2 2
N
p
p
2 2
Et O, Pd(OAc)
p
p
(
3 4 2
0.87 equiv.), Pd(PPh ) ´3H O (3 equiv.), toluene, 1108C, 20 h; (l) MPLC on silica gel (90% yield based on (1R ,2R )-13).
Attention has also been paid to the synthesis of photostable
carbon±carbon double bond locked analogues of 1 in which
unit 2 is linked to a a-substituted cyclopentenyl ring.
catalyzed cross-coupling reaction of easily available methyl
7
a,e
(Z)-2-iodo-3-methoxypropenoate (11)
propylboronic acid (1R ,2R )-13 and the 2-{2-[2-(aryl)-
with the cyclo-
7
d,e
p
p
p
(1R ,2R )-16a±c,
p
However, to our knowledge, structural analogues of 1,
which do not contain ole®nic carbon±carbon double
bonds in their lipophilic subunit and in which the Z or E
double bond present in the lipophilic subunit of naturally-
occurring strobilurins is locked in a cis- or trans-1,2-disub-
stituted cyclopropane ring, have not been described so far.
Now, we wish to report a concise synthesis of some of these
cyclopropyl]phenyl}zinc
respectively.
bromides
p
p
p
p
analogues, i.e. compounds (1R ,2R )-9, (1R ,2R )-10a,
(
p
1R ,2R )-10b and (1R ,2R )-10c.
p
p
p
All these substances do not contain ole®nic carbon±carbon
double bonds in their lipophilic backbone and are character-
ized by a trans-1,2-disubstituted cyclopropane ring.
This strategy was similar to that we previously employed to
prepare analogues of 1 in which the key unit 2 is linked to a
1
0
7b
substituted (hetero)aromatic ring and, in the case of
p
p
compound (1R ,2R )-9 involved the stereocontrolled cyclo-
propanation reaction of the (E)-b-phenylethenylboron
derivative 12. On the other hand, the synthetic plan
followed to prepare the trans-1,2-disubstituted cyclopropane
ring present in 1-(2-bromophenyl)-2-arylcyclopropanes
p
p
p
p
For the synthesis of compounds (1R ,2R )-9 and (1R ,2R )-
0a±c, we followed a synthetic plan in which a key step was
1
the direct introduction of pharmacophore 2 into the lipo-
philic moieties of these analogues of 1 by palladium(0)-
1
Scheme 2. (a) CF
(
3 2 2 2 3 2 3 4
COOZnCH I (3.5±5 equiv.), CH Cl , rt, 6±98 h; (b) H O ; (c) Mg, THF, 658C; (d) ZnBr , THF, 08C; (e) 11 (0.83 equiv.), Pd(PPh )
5 mol%), THF, rt, 70±96 h.

R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
2849
p
1R ,2R )-15a±c, which we used as precursors to
compounds (1R ,2R )-10a±c, involved the stereospeci®c
cyclopropanation reaction of (E)-2-bromostilbenes [(E)-
p
(
However, we observed that when a similar molar excess of
CF COOZnCH I and a long reaction time (20 h) were used
for the cyclopropanation reaction of (E)-14b, a complex
reaction mixture which contained (1R ,2R )-15b as the
major product (36%) was obtained. The main byproduct
p
p
3
2
p
p
14a±c].
(
and to characterize, had a molecular ion peak higher for
7%), which we did not succeed to isolate in pure form
1
. Results and discussion
p
4 mass units than that of (1R ,2R )-15b. Puri®cation of
p
1
this reaction mixture by MPLC on silica gel allowed to
p
The synthesis of methyl (E)-(1R ,2R)-2-[2-(phenyl)cyclo-
p
propyl]-3-methoxypropenoate [(1R ,2R )-9] was carried
p
p
p
isolate (1R ,2R )-15b in 24% yield. Nevertheless, we
found that when the cyclopropanation reaction of (E)-14b
was carried out for 6 h at rt using 3.5 equiv. of
out using the reaction sequence illustrated in Scheme 1.
Thus, crude (E)-b-phenylethenylcatecholborane, which was
obtained by hydroboration of phenylethyne (17) with
catecholborane, was stirred with water and the boronic
acid so obtained was converted in 48% yield to 98%
isomerically pure (E)-2-phenylethenyl-1,3,2-dioxaborinane
(12a) by reaction with 1,3-propanediol in pentane at rt
followed by distillation of the resulting hexane solution.
Alternatively, 95% isomerically pure 12a was prepared in
71% overall yield by reaction of 17 with catecholborane
CF COOZnCH I, the reaction was not complete but the
3 2
amount of the above-mentioned byproduct was minimized
(ca. 1%). Puri®cation of the reaction mixture provided
(1R ,2R )-15b in 48% yield. It must also be noted that in
1
1
p
p
our hands, the cyclopropanation reaction of compounds
(E)-14a±c by treatment with CF COOZnCH I proved to
3 2
be superior to the procedure involving the reaction of
these alkenes with diazomethane in the presence of
1
2
Pd(OAc)
.
In fact, the cyclopropanation of (E)-14a
according to this last protocol proved to be a very sluggish
2
followed by treatment of the resulting crude (E)-1-alkenyl-
catecholborane with 1,3-propanediol in hexane and distil-
lation of the hexane solution so obtained. Compound 12a
was then treated with a large molar excess of an ethereal
solution of diazomethane at 0±58C in the presence of a
p
reaction which provided (1R ,2R )-15a in ca. 20% GLC
p
yield.
p
p
p
p
p
p
Compounds (1R ,2R )-15a, (1R ,2R )-15b and (1R ,2R )-
15c were then converted to the corresponding Grignard
reagents by the standard procedure and these organometal-
lics were transmetallated by treatment with a molar excess
1
2
p
p
catalytic amount of Pd(OAc)2 to give (1R ,2R )-18 in
9
1
6% yield. This boronic acid ester was saponi®ed with
.5N KOH at 08C and the potassium salt so obtained was
p
p
p
p
acidi®ed with 2N HCl at 08C to give (1R ,2R )-13 in 93%
yield. Interestingly, an attempt to prepare this compound by
cyclopropanation of (E)-2-phenylethenylboronic acid using
of dry ZnBr in THF at 08C to give the (1R ,2R )-16a,
2
p p
p
p
(1R ,2R )-16b and (1R ,2R )-16c, respectively. Finally, the
cross-coupling reaction of these organozinc derivatives with
0.83 equiv. of 11 at rt for 70±96 h, in the presence of
1
3
the Simmons±Smith reaction failed. Finally, the cross-
p
p
p
p
coupling reaction between (1R ,2R )-13 and 0.87 equiv. of
1 in the presence of 3 equiv. of K PO ´3H O and 4 mol%
Pd(PPh ) in toluene at 1108C gave (1R ,2R )-9 in 90%
5 mol% Pd(PPh ) , provided compounds (1R ,2R )-10a,
3 4
p
p
p
p
1
(1R ,2R )-10b and (1R ,2R )-10c in 80, 68 and 76% yield,
respectively. The trans-stereochemistry of the 1,2-disubsti-
tuted cyclopropane moiety of these analogues of 1 was
con®rmed by NOESY experiments. In fact, the NOESY
2D maps of these compounds showed cross-peaks between
3
4
2
p
p
3
4
1
4
yield. The trans-stereochemistry of the cyclopropane
moiety of this compound was con®rmed by a NOESY
experiment. In fact, the NOESY 2D map showed the
presence of cross-peaks between the resonances of the
0
0
00
the resonances of the following protons: H-3 a and H-2 ;
0
0
0
0
0
00 0 00 00 00 00
following protons: H-3 b and H-5 ; H-3 b and H-9 ; H-1
H-3 a and H-3 ; H-3 b and H-5 ; H-3 b and H-1 . There-
fore, it was possible to infer that either the H-3 a and H-2
00
0
were not observed between the resonance of the H-3 a
0
0
00
protons or the H-3 b and H-1 protons are near in the space.
00
and H-5 ; H-1 and H-9 . On the other hand, cross-peaks
0
proton and those of the aromatic protons. Therefore, it
00
0
0
was possible to infer that either the H-3 a and the H-2
0
Finally, as regards 2-bromostilbenes (E)-14a±c, which we
p
p
0
protons or the H-3 b and H-1 protons are close in
proximity.
used as precursors to compounds (1R ,2R )-10a±c, it must
be mentioned that a variety of compounds of this class
which include (E)-14a have been prepared either by
Wittig±Horner±Emmons ole®nation of arenecarbaldehydes
We then directed our attention to the synthesis of
compounds (1R ,2R )-10a±c. Their preparation was
performed as shown in Scheme 2.
p
p
16
with diethyl 2-bromobenzylphosphonate or by Wittig
reaction of 2-bromobenzaldehyde with the ylides derived
from substituted benzyltriphenylphosphonium bromides,
followed by photoisomerization of the (Z)-2-bromostilbenes
which were obtained as major products from this ole®nation
In particular, (E)-2-bromostilbenes (E)-14a±c were stereo-
speci®cally cyclopropanated according to a modi®cation of
1
5
16
the general procedure, which involves treatment of a
CH Cl solution of the alkene with 2 equiv. of the organo-
zinc species CF COOZnCH I generated by reaction of
reaction. Nevertheless, we preferred to prepare these
bromoalkenes by Heck reaction between 2-bromoiodo-
benzene (20) and styrenes 19a, b and c, respectively.
1
7
2
2
1
8,19
3
2
ZnEt with equimolar amounts of tri¯uoroacetic acid and
2
In fact, all these reagents were commercially available
and we expected that their Heck reaction could afford the
desired (E)-2-bromostilbenes chemo- and stereoselectively
and in good yields. In the event, we found that, when this
reaction was performed in acetonitrile at 958C in the
CH I . We found that the cyclopropanation reaction of
2
2
(
E)-14a and (E)-14c required the use of a very large molar
excess (5 equiv.) of CF COOZnCH I, occurred at rt in 40
3
2
p
and 42 h, respectively, and provided compounds (1R ,2R )-
1
p
p
5a and (1R ,2R )-15c in 52 and 59% yield, respectively.
p
presence of 1.1 equiv. of Et N and a catalytic amount of
3

2
850
R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
2 3 3
Scheme 3. (a) Pd(OAc) (8 mol%), Et N (1.1 equiv.), CH CN, 958C, 24 h.
Scheme 4. (a) Cp
on 17).
2 3 2
ZrHCl (1.2 equiv.), benzene, rt, 2.5 h; (b) 1,2-dibromobenzene (23) (1.5 equiv.), Pd(PPh ) (10 mol%), THF, 508C, 34 h (48% yield based
p
(E)(1R ,2R )-2-[2-(phenyl)cyclopropyl]-3-methoxypropen-
p
Pd(OAc) and using compounds 19a±c and 20 in a 1.16:1
2
molar ratio, mixtures which contained compounds (E)-14a±
c as the major products besides a very small amount (ca.
1%) of their (Z)-stereoisomers, (Z)-14a±c, and 4±11% of
the corresponding regioisomers 21a±c were chemoselec-
tively obtained (Scheme 3).
p
p
oate [(1R ,2R )-9], was synthesized in 59% overall yield by
a reaction sequence in which a key step was the palladium-
catalyzed cross-coupling reaction between a cyclopropyl-
boronic acid and methyl (Z)-2-iodo-3-methoxypropenoate
(11). On the other hand, the synthesis of three other struc-
p
p
p
p
tural analogues of 1, i.e. [(1R ,2R )-10a], [(1R ,2R )-10b]
p
p
The amount of these regioisomers was higher (11%) for the
Heck reaction between 19b and 20 and was lower (4%) in
the case of the reaction involving 19c. Puri®cation of the
crude reaction mixtures by MPLC on silica gel allowed to
and [(1R ,2R )-10c], was accomplished according to a
strategy which involved the stereospeci®c cyclopropanation
of (E)-2-bromostilbenes (E)-14a±c by treatment with the
organozinc species CF COOZnCH I and the conversion of
3
2
2
0
21
obtain compounds (E)-14a, (E)-14b, and (E)-14c in 85,
1 and 84% yield, respectively. These 2-bromostilbenes had
the organic bromides so obtained into the corresponding
organozinc bromides followed by the palladium-catalyzed
cross-coupling reaction between these organometallics and
11. This strategy is very ¯exible and appears to be suitable
for the synthesis of a great variety of analogues of 1 in which
the Z and E carbon±carbon double bonds, which are present
in the lipophilic subunit of these natural products, are locked
in an ortho-substituted benzene ring and in a trans-1,2-
disubstituted cyclopropane ring, respectively. Finally, it
must be noted that compounds (E)-14a±c, which we used
7
isomeric purity higher than 98%. On the other hand, regio-
and stereoisomerically pure (E)-14a was prepared by the
reaction sequence illustrated in Scheme 4.
Thus, a benzene solution of 17 was treated with 1.2 equiv. of
bis(cyclopentadienyl)zirconium chloride hydride for 2.5 h
in dark at rt. The resulting organozirconium derivative 22
was then cross-coupled with 1.5 equiv. of 1,2-dibromo-
benzene (23) for 34 h at 508C in the presence of a palla-
dium(0) catalyst (10 mol%) which was prepared in situ by
reaction of a THF suspension of PdCl (PPh ) with 2 equiv.
p
p
as precursors to (1R ,2R )-10a±c, were conveniently and
ef®ciently synthesized by a chemo- and stereoselective
Heck reaction between 2-bromoiodobenzene (20) and
styrenes 19a±c.
2
3 2
of a 1 M hexane solution of diisobutylaluminum hydride
DIBAH) at 08C over 10 min. This cross-coupling reaction
(
yielded pure (E)-14a in 48% isolated yield. However, the
high cost of the Schwartz's reagent as well as the modest
yield of the reaction sequence used to prepare (E)-14a
discouraged us from using a similar protocol for the
synthesis of (E)-14b and (E)-14c.
3
. Experimental
3
.1. General
Melting points and boiling points are uncorrected. Precoated
plastic silica gel sheets Merck 60 F254 were used for TLC
analyses. GLC analyses were performed on a Dani GC 1000
instrument with a PTV injector, which was equipped with a
Dani data station 86.01. Two types of capillary columns
were used: an Alltech AT-1 bonded FSOT column
(30 m£0.25 mm i.d.) and an Alltech AT-35 bonded FSOT
column (30 mm£0.25 mm i.d.). Puri®cations by MPLC
were performed on a B uÈ chi instrument using a Bischoff
2
. Conclusions
In this study, we developed concise procedures for the
stereocontrolled synthesis of carbon±carbon double bond
locked analogues of strobilurins (1), which are characterized
by a trans-1,2-disubstituted cyclopropane ring in their lipo-
philic subunit. One of these racemic analogues, i.e. methyl

R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
2851
p
(1R ,2R )-2-Phenylcyclopropyl-1,3,2-dioxabori-
nane [(1R ,2R )-18]. Under a nitrogen atmosphere, an
ethereal solution of diazomethane24 (260 ml, ca. 133
mmol) was added over a period of 50 min to a stirred
p
8
110 differential refractometer as detector. GLC/MS
3.1.2.
p p
analyses were performed using a Q-mass 910 spectrometer
interfaced with a Perkin±Elmer 8500 gas chromatograph.
NMR spectra were recorded on Varian Gemini 200 MHz
spectrometer or a Bruker AMX 600 spectrometer using
mixture of 12a (5.00 g, 26.6 mmol) and Pd(OAc) (0.12 g,
2
TMS and CDCl as internal standard, respectively. The
3
0.53 mmol) in dry diethyl ether (55 ml) which was cooled to
0±58C. When half of the ethereal solution of diazomethane
had been added, more Pd(OAc) (0.12 g, 0.53 mmol) was
2
structure and relative stereochemistry of compounds
p
p
p
p
p
p
p
p
(
1R ,2R )-9, (1R ,2R )-15b, (1R ,2R )-15c and ꢀ1R ; 2R †-
10a±c were assigned by a combination of NMR techniques
which included H± H COSY, NOESY, H± C hetero-
added. The reaction mixture was then allowed to warm up to
rt and the catalyst was removed by ®ltration over Celite. The
®ltrate was concentrated under reduced pressure and the
1
1
1
13
1
13
nuclear shift correlation and H± C long-range heteronuc-
lear shift correlation. IR spectra were recorded on a Perkin±
Elmer 1725 FT-IR spectrophotometer. All reactions of air
and water sensitive materials were performed in ¯ame-dried
glassware under an atmosphere of nitrogen or argon using
standard syringe, cannula and septa techniques. The follow-
ing compounds were prepared by published procedures:
p
p
residue was fractionally distilled to give (1R ,2R )-18
(5.18 g, 96%) as a colourless liquid. Bp 958C/ 0.02 Torr.
MS: m/z (%): 202 (26), 143 (25), 130 (33), 129 (23), 128
(9), 118 (9), 117 (44), 116 (100), 115 (74), 91 (25), 89 (11).
2
1 1
IR (®lm): n 1442, 1405, 1341, 1278, 1231, 1202 cm . H
NMR (200 MHz, CDCl ): d 7.27±7.01 (5H, m, Harom),
3
2
2
23
Pd(PPh ) , PdCl (PPh ) , methyl (Z)-2-iodo-3-methoxy-
3
3.96 (4H, t, Jˆ5.5 Hz, O±CH ), 2.00 (1H, ddd, Jˆ8.1, 5.5
4
2
a,e
3 2
24
and diazomethane. All the other
2
7
propenoate (11)
and 5.2 Hz, H-2), 1.92 (2H, q, Jˆ5.5 Hz, C±CH ±C), 1.08
2
reagents are commercially available and were used as
purchased. Solvents were dried and distilled before use.
(1H, ddd, Jˆ8.1, 6.8 and 3.4 Hz, H-3a), 0.92 (1H, ddd, Jˆ
9.5, 5.2 and 3.4 Hz, H-3b), 0.14 (1H, ddd, Jˆ9.5, 6.8 and
5
Found: C, 71.01; H, 7.24. GLC analysis showed that
.5 Hz, H-1). Anal. calcd for C H BO : C, 71.33; H, 7.48.
12 15 2
3
.1.1. (E)-2-Phenylethenyl-1,3,2-dioxaborinane (12a).
Under a nitrogen atmosphere, catecholborane (7.20 g,
0.0 mmol) was added over a period of 15 min to freshly
p
(1R ,2R )-18 had purity higher than 97%.
p
6
p
3.1.3. (1R ,2R )-2-Phenylcyclopropylboronic acid [(1R ,
p
p
distilled phenylethyne (17) (6.13 g, 60.0 mmol), and the
resulting mixture was stirred at 708C for 15 h. It was then
cooled to rt and diluted with deaerated hexane (54 ml).
Freshly distilled 1,3-propanediol (5.02 g, 66.0 mmol) was
then added dropwise and the resulting mixture was stirred
at rt for 20 h. After this period of time, the hexane phase of
this heterogeneous reaction mixture was separated. The
residue was washed with hexane (5£20 ml), and the
collected hexane solutions were concentrated under reduced
pressure. The residue was fractionally distilled to give 12a
p
p
p
2R )-13]. The cyclopropyl boronic acid ester (1R ,2R )-18
(3.00 g, 14.8 mmol) was added dropwise to a 1.5N aqueous
solution of KOH (29.6 ml, 44.3 mmol), and the mixture was
stirred at rt for 1.5 h. It was then extracted with diethyl ether
(4£10 ml), and the resulting solution was cooled to 08C and
acidi®ed with 2N HCl. The so formed colourless solid was
separated, washed with cold water (2£5 ml) and maintained
p
p
at 0.01 Torr for 10 h to give (1R ,2R )-13 (2.23 g, 93%) as a
colourless solid. IR (KBr): n 3220, 1605, 1462, 1195, 698,
642 cm . H NMR (200 MHz, acetone-d ): d 7.50±6.90
2
1 1
(7.98 g, 71%) as a colourless liquid. Bp 908C/0.01 Torr.
MS: m/z: 188 (100), 187 (28), 130 (76), 129 (74), 115
6
(5H, m, Harom), 6.69 (2H, s, OH), 2.06±1.90 (1H, m,
H-2), 1.13 (1H, ddd, Jˆ8.1, 6.9 and 3.4 Hz, H-3a), 0.94
(1H, ddd, Jˆ9.6, 5.2 and 3.4 Hz, H-3b), 0.13 (1H, ddd,
Jˆ9.6, 6.9 and 6.6 Hz, H-1). This boronic acid was directly
used in the next step without any further puri®cation and
characterization.
(
1
19), 104 (34), 103 (44), 78 (56), 77 (65). IR (®lm): n
2
623, 1422, 1341, 1313, 1278, 1228 cm . H NMR
1
1
(
200 MHz, CDCl ): d 7.65±7.25 (5H, m, Harom), 7.29
3
(
4
1H, d, Jˆ18.2 Hz, H-2), 6.07 (1H, d, Jˆ18.2 Hz, H-1),
.07 (4H, t, Jˆ5.5 Hz, OCH ), 1.98 (2H, q, Jˆ5.5 Hz,
2
C±CH ±C). Anal. calcd for C H BO : C, 70.26; H, 6.97.
2
11 13
2
p
3.1.4. Methyl (E)(1R ,2R )-2-[2-(phenyl)cyclopropyl]-3-
p
Found: C, 70.52; H, 7.14. GLC and GLC/MS analyses
showed that 12a had purity higher than 95%. This same
compound was alternatively synthesized according to the
following procedure. Crude (E)-2-phenylethenylcatechol-
borane, which was obtained by reaction of 17 (7.46 g,
p p
methoxypropenoate [(1R ,2R )-9]. A deaerated solution
of methyl (Z)-2-iodo-3-methoxypropenoate (11) (1.56 g,
6.44 mmol) in toluene (10 ml) and a suspension of the
p
p
crude cyclopropylboronic acid (1R ,2R )-13 (1.20 g,
7.40 mmol) in deareated toluene (10 ml) were sequentially
added under argon to a deaerated mixture of K PO (4.72 g,
7
8
5
3.0 mmol) with catecholborane (8.75 g, 73.0 mmol) for
h at 708C, was stirred with deaerated water (70 ml) for
h at rt and the mixture was cooled to 08C. The so obtained
3
4
22.2 mmol), water (1.20 ml, 66.6 mmol) and toluene
(30 ml), and the resulting mixture was stirred at 1108C for
20 h. It was then cooled to rt and water (100 ml) was added.
The mixture was extracted with diethyl ether (5£60 ml), and
the organic extract was washed with water, dried with
colourless solid was separated, maintained at 0.01 Torr for
h and identi®ed as (E)-2-phenylethenylboronic acid on the
4
1
1
basis of its H NMR spectrum. H NMR (200 MHz, DMSO-
d6): d 7.80 (2H, s, OH), 7.55 (5H, m, Harom), 7.26 (1H, d,
Jˆ18.4 Hz, H-2), 6.13 (1H, d, Jˆ18.4 Hz, H-1). This
boronic acid (6.15 g) was treated with pentane (80 ml) and
Na SO4 and concentrated under reduced pressure. The
2
residue was diluted with the solvent used for its puri®cation
by MPLC and ®ltered over Celite. The ®ltrate was concen-
trated under reduced pressure and the residue was puri®ed
by MPLC on silica gel using benzene as eluant to give
1,3-propanediol (3.60 g, 47.3 mmol) and the resulting
mixture was stirred for 1.5 h at rt. The pentane phase of
this mixture was separated, concentrated under reduced pres-
sure, and the residue was fractionally distilled to give 12a
p
p
(1R ,2R )-9 (1.35 g, 90%) as a colourless solid. Mp 43±
458C. MS: m/z (%): 201 (23), 200 (100), 172 (34), 168
(21), 157 (36), 155 (15), 141 (57), 129 (23), 128 (42), 127
(6.60 g, 48%). Bp 92±938C/0.01 Torr. GLC analysis showed
that this compound had isomeric purity higher than 98%.

2
852
R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
(
1
0
15), 115 (42). IR (KBr): n 1700, 1632, 1281, 1245, 1144,
by concentration of a ®rst eluted chromatographic fraction,
which contained 86% of (Z)-14a, 8% of 21a together with
other minor byproducts. Compound (Z)-14a had MS: m/z
(%): 260/258 (11/11), 180 (19), 179 (100), 178 (94), 152
2
1 1
101 cm . H NMR (600 MHz, CDCl ): d 7.34 (1H, d, Jˆ
3
0
0
.6 Hz, H-3), 7.27 (2H, m, H-6 and H-8 ), 7.15 (3H, m,
0
0
0
H-5 , H-7 and H-9 ), 3.82 (3H, brs, H-5), 3.70 (3H, brs,
0
1
H-4), 2.30 (1H, ddd, Jˆ8.7, 5.5 and 5.3 Hz, H-2 ), 1.75 (1H,
(18), 89 (87), 88 (30), 77 (19), 76 (55), 75 (20). H NMR
(200 MHz, CDCl ): d 7.62±6.98 (9H, m, Harom), 6.69 (1H,
0
dddd, Jˆ8.9, 6.1, 5.3 and 0.6 Hz, H-1 ), 1.45 (1H, ddd, Jˆ
3
0
.7 Hz, H-3 b). C NMR (150 MHz, CDCl ): d 168.56
8
4
.7, 6.1 and 4.7 Hz, H-3 a), 1.18 (1H, ddd, Jˆ8.9, 5.5 and
d, Jˆ11.6 Hz, vCH), 6.61 (1H, d, Jˆ11.6 Hz, vCH).
0
C-1), 159.95 (C-3), 143.74 (C-4 ), 126.11 (C-5 and
13
3
0
C-9 ), 128.22 (C-6 and C-8 ), 125.46 (C-7 ), 109.94
0
0
(
3.2.2. (E)-2-Bromo-4 -methoxystilbene [(E)-14b]. GLC
0
0
0
C-2), 61.63 (C-5), 51.19 (C-4), 23.56 (C-2 ), 18.96
0
analysis of the crude reaction mixture, which was obtained
from the Heck reaction between 19b and 20, showed the
presence of three compounds in a ca. 88:11:1 molar ratio.
The ®rst of these compounds was subsequently identi®ed as
(E)-14b. On the other hand, the second and the third
compounds were tentatively identi®ed as 2-(2-bromo-
0
C-1 ), 15.42 (C-3 ). Anal. calcd for C H O : C, 72.39;
(
0
H, 6.94. Found: C, 72.45; H, 7.03. GLC analysis showed
0
(
1
4
16
3
p
that (1R ,2R )-9 had purity higher than 98%.
p
0
3
.2. General procedure for the synthesis of 2-bromo-
stilbenes (E)-14a±c starting from 2-bromoiodobenzene
20)
phenyl)-4 -methoxystyrene (21b) and (Z)-14b, respectively.
This crude reaction mixture was puri®ed by MPLC on silica
gel, using a mixture of hexane and benzene (86/14) as
eluant, to yield (E)-14b (5.94 g, 71%) as a colourless
(
2
1
Compound 20 (8.15 g, 28.8 mmol), a styrene derivative 19
33.6 mmol) and dry Et N (3.40 g, 33.6 mmol) were
solid. Mp 67±698C (mp 64±658C). MS: m/z (%): 290/
288 (68/68), 289 (12), 194 (51), 178 (26), 177 (27), 166
(75), 165 (100), 164 (12), 139 (13), 82 (14). IR (KBr): n
(
3
sequentially added under nitrogen to a deaerated mixture
of Pd(OAc)2 (485 mg, 2.16 mmol) and acetonitrile
2
1
1
1602, 1509, 1255, 1175, 1025, 748 cm . H NMR
(200 MHz, CDCl
(
13.5 ml), and the resulting mixture was stirred at 958C
3
): d 7.64 (1H, dd, Jˆ7.8 and 1.4 Hz,
for 24 h. After this period of time, a GLC analysis indicated
that compound 20 had been completely consumed. After
being cooled to rt, the reaction mixture was stirred with
cold 10% aqueous HCl solution (120 ml) and extracted
with diethyl ether (3£70 ml). The organic extract was
washed with water (50 ml), dried with Na SO , ®ltered
Harom), 7.57 (1H, dd, Jˆ7.8 and 1.2 Hz, Harom), 7.49
(2H, d, Jˆ8.8 Hz, Harom), 7.33 (1H, d, Jˆ16.6 Hz,
vCH), 7.28 (1H, td, Jˆ7.8 and 1.2 Hz, Harom), 7.08
(1H, td, Jˆ7.8 and 1.4 Hz, Harom), 6.98 (1H, d, Jˆ
16.6 Hz, vCH), 6.91 (2H, d, Jˆ8.8 Hz, Harom), 3.83
1
3
(3H, s, OCH ). C NMR (50 MHz, CDCl ): d 159.5,
3 3
2
4
over Celite and concentrated under reduced pressure. This
procedure was employed to prepare (E)-2-bromostilbene
137.3, 132.9, 130.9, 129.2, 128.3, 128.0, 127.4, 126.3,
125.2, 123.8, 114.1, 55.3. The spectral properties of this
compound were in agreement with those previously
0
(E)-14a], (E)-2-bromo-4 -methoxystilbene [(E)-14b] and
[
(
1
6
0
E)-2-bromo-3 -¯uorostilbene [(E)-14c], starting from
reported.
styrene (19a), 4-methoxystyrene (19b) and 3-¯uorostyrene
19c), respectively.
0
(
3.2.3. (E)-2-Bromo-3 -¯uorostilbene [(E)-14c]. GLC
analysis of the crude reaction mixture, which was obtained
from the Heck reaction between 19c and 20 showed the
presence of three compounds in a ca. 95:4:1 molar ratio.
The ®rst two compounds were subsequently identi®ed as
3.2.1. (E)-2-Bromostilbene [(E)-14a]. GLC analysis of the
crude reaction mixture, which was obtained from the Heck
reaction between 19a and 20, showed the presence of three
compounds in a ca. 92:7:1 molar ratio, which were subse-
quently identi®ed as (E)-14a, 2-(2-bromophenyl)styrene
0
(E)-14c and 2-(2-bromophenyl)-3 -¯uorostyrene (21c),
respectively. The third compound very likely corresponded
to (Z)-14c. This crude reaction mixture was puri®ed by
MPLC on silica gel using hexane as eluant to yield (E)-
14c (6.71 g, 84%) as a pale yellow liquid. MS: m/z (%):
279/277 (10/11), 278/276 (69/73), 198 (12), 197 (90), 196
(100), 195 (12), 194 (18), 177 (72), 176 (24). IR (®lm): n
(
21a) and (Z)-14a, respectively. This crude reaction mixture
was puri®ed by MPLC on silica gel, using hexane as eluant
to give (E)-14a (6.37 g, 85%) as a colourless liquid. MS: m/z
(
%): 260/258 (30/33), 180 (10), 179 (96), 178 (100), 177
11), 176 (15), 152 (7), 151 (6), 89 (9), 76 (7). IR (®lm): n
1
(
2
1
466, 1025, 960, 757, 708, 690 cm . H NMR (200 MHz,
1
21 1
1609, 1582, 1488, 958, 779, 748 cm . H NMR (200 MHz,
CDCl
CDCl ): d 7.69±7.19 (9H, m, Harom), 7.47 (1H, d, Jˆ
3
): d 7.62 (1H, dd, Jˆ8.0 and 1.4 Hz, Harom), 7.56
3
1
3
1
6.5 Hz, vCH), 7.02 (1H, d, Jˆ16.5 Hz, vCH). C
NMR (50 MHz, CDCl ): d 137.1, 137.0, 133.0, 131.3,
(1H, dd, Jˆ7.8 and 1.4 Hz, Harom), 7.45 (1H, d, Jˆ
16.2 Hz, vCH), 7.38±7.15 (4H, m, Harom), 7.10 (1H, dt,
Jˆ7.8 and 1.4 Hz, Harom), 7.02±6.92 (1H, m, Harom), 6.95
3
128.6, 128.0, 127.4, 127.3, 126.7, 126.6, 124.1. The spectral
properties of this compound were in agreement with those
1
3
(1H, d, Jˆ16.2 Hz, vCH). C NMR (50 MHz, CDCl
): d
3
1
previously reported. Anal. calcd for C H Br: C, 64.89;
6
1
3
163.0 ( JC±Fˆ244.2 Hz), 139.2 ( JC±Fˆ8.2 Hz), 136.5,
1
4
11
H, 4.28. Found: C, 64.90; H, 4.59. Concentration of an
intermediate chromatographic fraction, which contained
133.0, 130.1, 129.0, 128.6, 127.5, 126.7, 124.1, 122.6,
2
2
114.7 ( JC±Fˆ21.3 Hz), 113.0 ( JC±Fˆ21.3 Hz). Anal.
(E)-14a and 21a in a ca. 2:1 molar ratio, respectively,
allowed to characterize in part this last compound. MS:
m/z (%): 260/258 (6/7), 179 (100), 178 (78), 176 (15), 152
calcd for C14H10BrF: C, 60.67; H, 3.64. Found: C, 60.68;
H, 3.72. Concentration of a ®rst eluted chromatographic
fraction, which contained (E)-14c and 21c in a ca. 1:1
molar ratio, allowed to characterize in part this last
compound. Compound 21c had MS: m/z (%): 278/276
1
15), 151 (10), 89 (76), 88 (25), 76 (62), 75 (21). H NMR
200 MHz, CDCl ): d 7.68±7.05 (9H, m, Harom), 5.83 (1H,
3
(
(
s, vCH), 5.26 (1H, s, vCH). On the other hand, (Z)-14a
was in part characterized by analysis of the residue obtained
(23/30), 198 (12), 197 (100), 196 (73), 194 (13), 178 (9),
177 (48), 176 (19). H NMR (200 MHz, CDCl ): d
1
3

R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
2853
7
5
.66±6.86 (8H, m, Harom), 5.83 (1H, d, Jˆ0.8 Hz, vCH),
.30 (1H, d, Jˆ0.8 Hz, vCH).
acetic acid (3.08 g, 27.0 mmol), CH2I2 (7.23 g, 27.0
mmol) and CH Cl (50 ml), according to the procedure
2
2
p
p
employed for the preparation of (1R ,2R )-15a. This
solution was stirred under argon at 08C for 20 min, then a
solution of (E)-14b (2.23 g, 7.71 mmol) in freshly distilled
CH Cl (10 ml) was added and the resulting mixture was
3
.2.4. Synthesis of (E)-14a via Pd-catalyzed cross-
coupling reaction between (E)(2-phenylethenyl)-bis-
cyclopentadienyl)zirconium chloride (22) and 1,2-
(
2
2
dibromobenzene (23). Bis(cyclopentadienyl)zirconium
chloride hydride (12.38 g, 48.00 mmol) was added under
argon over 20 min to a deaerated solution of 17 (4.08 g,
stirred for 6 h at rt. The crude reaction product, which was
obtained after usual workup, was puri®ed by MPLC on
silica gel, using a mixture of hexane and benzene (86/14)
p
p
40.0 mmol) in benzene (150 ml), and the mixture was
as eluant, to give (1R ,2R )-15b (1.12 g, 48%) as a colour-
less solid. Mp 44±478C. MS: m/z (%): 304/302 (91/100),
223 (83), 208 (55), 192 (35), 191 (27), 179 (32), 178 (46),
stirred for 2.5 h at rt under exclusion of light. A mixture
of PdCl (PPh ) (2.80 g, 4.00 mmol) and THF (500 ml) was
2
3 2
2
1
treated with a 1 M hexane solution of DIBAH (8.0 ml,
.0 mmol) at 08C over 10 min and the dark suspension
165 (28), 121 (28), 115 (49). IR (KBr): n 1515 cm . 1248,
1033, 1019, 823, 815. H NMR (600 MHz, CDCl ): d 7.56
1
8
3
0
obtained was sequentially treated at 08C with the benzene
solution of (E)(2-phenylethenyl)bis(cyclopentadienyl)-
zirconium chloride prepared above and with a solution of
(1H, dd, Jˆ7.4 and 1.2 Hz, H-3 ), 7.25 (1H, ddd, Jˆ7.4, 7.4
0
00
00
and 1.2 Hz, H-5 ), 7.16 (2H, d, Jˆ8.7 Hz, H-2 and H-6 ),
0
7.07 (1H, dd, Jˆ7.4 and 1.6 Hz, H-6 ), 7.06 (1H, ddd,
0
00
23 (14.16 g, 60.00 mmol) in THF (100 ml). After stirring for
Jˆ7.4, 7.4 and 1.6 Hz, H-4 ), 6.86 (2H, d, Jˆ8.7 Hz, H-3
0
0
34 h at 508C in dark, the reaction mixture was cooled to rt,
and H-5 ), 3.80 (3H, s, OCH ), 2.40 (1H, ddd, Jˆ8.6, 6.3
3
poured into cold 2N HCl (200 ml), and extracted with
diethyl ether (3£100 ml). The organic extract was washed
with water (100 ml), dried with Na SO , and concentrated
and 4.9 Hz, H-1), 2.08 (1H, ddd, Jˆ8.6, 6.3 and 4.9 Hz,
H-2), 1.39 (1H, ddd, Jˆ8.6, 6.3 and 5.0 Hz, H-3a), 1.38
1
3
(1H, ddd, Jˆ8.6, 6.3 and 5.0 Hz, H-3b). C NMR (150
00 0
MHz, CDCl ): d 157.95 (C-4 ), 141.57 (C-1 ), 134.18
3
2
4
under reduced pressure. The residue was puri®ed by MPLC
on silica gel using hexane as eluant to give (E)-14a (4.95 g,
00 0 0 0
(C-1 ), 132.51 (C-3 ), 127.36 (C-5 ), 127.32 (C-4 ),
00 00 0 0
127.28 (C-6 and C-2 ), 126.80 (C-6 ), 126.07 (C-2 ),
48%) as a colourless liquid. GLC analysis showed that this
0
(C-2), 16.63 (C-3). Anal. calcd for C H BrO: C, 63.38; H,
0
00
compound had chemical purity higher than 97%. Its spectral
properties were in good agreement with those of (E)-14a
prepared by Heck reaction between 19a and 20.
113.88 (C-3 and C-5 ), 55.32 (OCH ), 27.41 (C-1), 26.28
3
1
6
15
4.99. Found: C, 63.21; H, 5.08. GLC analysis showed that
(
p
1R ,2R )-15b had chemical purity higher than 97%.
p
p
.2.5. (E)(1R ,2R )-1-(2-Bromophenyl)-2-phenylcyclo-
p
3
propane [(1R ,2R )-15a]. A solution of tri¯uoroacetic
p p
p
3.2.7. (E)(1R ,2R )-1-(2-Bromophenyl)-2-(3-¯uorophenyl)-
p
p p
cyclopropane [(1R ,2R )-15c]. An ice cooled solution of
acid (8.80 g, 77.2 mmol) in freshly distilled CH Cl2
2
(
1
35 ml) was added over 30 min to a stirred mixture of a
M hexane solution of ZnEt (77.2 ml, 77.2 mmol) and
CH Cl (77 ml) which was stirred under argon at 08C.
CF COOZnCH I was prepared starting from a 1 M hexane
3
solution of ZnEt (87.5 ml, 87.5 mmol), tri¯uoroacetic acid
2
2
2
(9.98 g, 87.5 mmol), CH2I2 (23.44 g, 87.50 mmol) and
CH Cl (170 ml), according to the procedure employed for
2
2
Upon stirring for 20 min at 08C, a solution of CH2I2
20.68 g, 77.20 mmol) in CH Cl (30 ml) was added. After
2
2
p
p
(
the preparation of (1R ,2R )-15a. This solution was stirred
under argon at 08C for 20 min, then a solution of (E)-14c
(4.85 g, 17.5 mmol) in freshly distilled CH Cl (22 ml) was
2
2
an additional 20 min, a solution of (E)-14a (4.00 g,
5.44 mmol) in CH Cl (20 ml) was added and the resulting
mixture was stirred at rt for 40 h. It was then poured into a
1
2
2
2
2
added and the resulting mixture was stirred for 42 h at rt.
The crude reaction product, which was obtained after usual
workup, was puri®ed by MPLC on silica gel using hexane as
saturated aqueous NH Cl solution (200 ml) and extracted
4
with hexane (3£70 ml). The organic extract was washed
p
p
with water, dried with Na SO , and concentrated under
4
eluant to give (1R ,2R )-15c (3.00 g, 59%) as a colourless
solid. Mp 50±538C. MS: m/z (%): 292/290 (10/10), 211
(53), 196 (35), 183 (19), 133 (73), 116 (17), 115 (100),
109 (24), 91 (19), 89 (16). IR (KBr): n 1587, 1454, 782,
2
reduced pressure. The residue was puri®ed by MPLC on
silica gel using hexane as eluant to give (1R ,2R )-15a
p
p
(2.18 g, 52%) as a colourless solid. Mp 33±358C. MS: m/z
(%): 274/272 (23/27), 193 (77), 192 (25), 191 (29), 189 (18),
2
1 1
772, 746, 687 cm . H NMR (600 MHz, CDCl ): d 7.57
3
0
1
1
79 (23), 178 (79), 165 (27), 115 (100), 91 (21). IR (®lm): n
(1H, dd, Jˆ8.2 and 1.4 Hz, H-3 ), 7.26 (1H, ddd, Jˆ7.4, 7.4
2
498, 1477, 1438, 1024, 751, 697 cm . H NMR
1
1
0
and 1.4 Hz, H-5 ), 7.25 (1H, ddd, Jˆ7.8, 7.8 and 6.0 Hz,
0
0
0
(
(
(
200 MHz, CDCl ): d 7.56 (1H, m, Harom), 7.36±7.16
3
H-5 ), 7.08 (1H, dd, Jˆ7.4 and 1.6 Hz, H-6 ), 7.08 (1H,
0
6H, m, Harom), 7.07 (2H, brd, Jˆ7.2 Hz, Harom), 2.46
ddd, Jˆ8.2, 7.4 and 1.6 Hz, H-4 ), 7.00 (1H, ddd, Jˆ7.8,
0
0
1H, dt, Jˆ7.2 and 5.2 Hz, H-1 or H-2), 2.12 (1H, dt, Jˆ
1.4 and 1.0 Hz, H-6 ), 6.90 (1H, ddd, Jˆ10.2, 2.5 and
0
0
7
.2 and 5.2 Hz, H-2 or H-1), 1.43 (2H, t, Jˆ7.2 Hz, H-3).
1.0 Hz, H-2 ), 6.89 (1H, dddd, Jˆ8.8, 7.8, 2.5 and 1.0 Hz,
1
3
00
C NMR (50 MHz, CDCl ): d 142.1, 141.3, 132.5, 128.7,
3
H-4 ), 2.45 (1H, ddd, Jˆ8.8, 6.3 and 5.0 Hz, H-1), 2.09 (1H,
128.3, 127.4, 126.9, 126.0, 125.8, 27.9, 26.9, 17.1. Anal.
calcd for C H Br: C, 65.95; H, 4.80. Found: C, 66.10;
ddd, Jˆ8.8, 5.5 and 5.0 Hz, H-2), 1.48 (1H, ddd, Jˆ8.8, 6.3
and 5.3 Hz, H-3a), 1.43 (1H, ddd, Jˆ8.8, 5.5 and 5.3 Hz,
1
5
13
p
H, 4.59. GLC analysis showed that (1R ,2R )-15a had
p
13
1
H-3b). C NMR (150 MHz, CDCl ): d 163.07 ( J
ˆ
00
3
C±F
0
0
3
00
9
7% chemical purity.
245.2 Hz, C-3 ), 145.02 ( J ˆ7.1 Hz, C-1 ), 140.89
C±F
0
0
3
(
C-1 ), 132.58 (C-3 ), 129.73 ( J ˆ9.2 Hz, C-5 ),
0 0 0 0
127.65 (C-4 ), 127.40 (C-5 ), 127.04 (C-6 ), 126.18 (C-2 ),
C±F
p
(E)(1R ,2R )-1-(2-Bromophenyl)-2-(4-methoxy-
p
3.2.6.
phenyl)cyclopropane [(1R ,2R )-15b]. An ice cooled solu-
tion of CF COOZnCH I was prepared starting from a 1 M
3
p
p
4
00
2
121.84 ( J ˆ3.1 Hz, C-6 ), 112.82 ( J ˆ21.4 Hz,
C±F
C±F
0
0
2
00
C-2 ), 112.72 ( J ˆ21.4 Hz, C-4 ), 28.32 (C-1), 26.57
C±F
2
4
hexane solution of ZnEt (27.0 ml, 27.0 mmol), tri¯uoro-
2
( JC±Fˆ2.0 Hz, C-2), 17.07 (C-3). Anal. calcd for

2
854
R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
p
p
C H BrF: C, 61.88; H, 4.15. Found: C, 61.54; H, 4.15.
1
cyclopropyl]phenyl}-3-methoxypropenoate [(1R ,2R )-
10b]. A 0.30 M solution of the Grignard reagent derived
from (1R ,2R )-15b (21.4 ml, 6.42 mmol) was added drop-
5
12
p
GLC analysis showed that compound (1R ,2R )-15c had
p
p
p
chemical purity higher than 97%.
wise to a slurry of dry ZnBr (1.88 g, 8.35 mmol) in THF
2
(
for 15 min at 08C, a solution of 11 (1.29 g, 5.35 mmol) in
15 ml) which was stirred under argon at 08C. After stirring
3.3. Preparation of the Grignard reagents corresponding
to compounds (1R ,2R )-15a±c
p
p
THF (13 ml) and Pd(PPh ) (0.309 g, 0.267 mmol) was
4
3
sequentially added and the reaction mixture was stirred
for 72 h at rt. It was then poured into a cold saturated
aqueous NH Cl solution (100 ml) and extracted with diethyl
1
,2-Dibromoethane (25.8 ml, 0.3 mmol) was added to
mixture of Mg turnings (0.365 g, 15.0 mmol) and dry THF
8 ml), which was stirred under nitrogen. The resulting
mixture was maintained under re¯ux and a solution of
(
4
ether (4£50 ml). After usual workup, the crude reaction
product was diluted with the solvent which was subse-
quently used for its puri®cation by MPLC and ®ltered
over Celite. The ®ltrate was concentrated under reduced
pressure and the residue was puri®ed by MPLC on silica
gel, using a mixture of petroleum ether and diethyl ether
p
p
(
1R ,2R )-15a (2.73 g, 10.0 mmol) in dry THF (25 ml)
was added dropwise. The mixture was re¯uxed for 4 h and
then cooled to rt. GLC analysis of a sample of this mixture,
which was hydrolyzed with a saturated aqueous NH Cl
solution, showed that (1R ,2R )-15a had been completely
consumed. The solution of this Grignard reagent was
4
p
p
p
p
(
colourless solid. Mp 86±888C. MS: m/z (%): 338 (2), 247
60/40) as eluant, to give (1R ,2R )-10b (1.23 g, 68%) as a
2
5
standardized by the Gilman double-titration method.
similar procedure was employed to prepare the Grignard
A
(
(
1
13), 215 (13), 189 (15), 165 (25), 164 (100), 151 (69), 149
26), 121 (79), 115 (73), 91 (22). IR (KBr): n 1702, 1616,
515, 1247, 1127, 1101 cm . H NMR (600 MHz, CDCl ):
3
p
p
reagents corresponding to bromides (1R ,2R )-15b and
2
1 1
p
1R ,2R )-15c.
p
(
d 7.46 (1H, s, H-3), 7.28 (1H, ddd, Jˆ7.5, 7.5 and 1.4 Hz,
p
p
.3.1. Methyl (E)(1R ,2R )-2-{2-[2-(phenyl)cyclopropyl]-
0
0
3
phenyl}-3-methoxypropenoate [(1R ,2R )-10a]. A 0.30 M
THF solution of the Grignard reagent derived from
H-4 ), 7.19 (1H, ddd, Jˆ7.5, 7.5 and 1.4 Hz, H-5 ), 7.12
p
p
0
(1H, dd, Jˆ7.5 and 1.4 Hz, H-6 ), 7.04 (1H, d, Jˆ7.5 Hz,
0
00
00
H-3 ), 7.01 (2H, d, Jˆ8.7 Hz, H-5 and H-9 ), 6.81 (2H, d,
00 00 00
p
p
(
1R ,2R )-15a (20.0 ml, 6.00 mmol) was added dropwise
to a slurry of dry ZnBr2 (1.76 g, 7.80 mmol) in THF
14 ml) which was stirred under argon at 08C. After stirring
for 15 min at 08C, a solution of methyl (Z)-2-iodo-3-meth-
oxypropenoate (11) (1.21 g, 5.00 mmol) in THF (12 ml)
and Pd(PPh3)4 (0.289 g, 0.250 mmol) were sequentially
added and the resulting mixture, which was periodically
monitored by GLC, was stirred for 70 h at rt. It was then
Jˆ8.7 Hz, H-6 and H-8 ), 3.79 (3H, s, H-10 ), 3.59 (3H,
brs, H-5), 3.56 (3H, brs, H-4), 2.06 (1H, ddd, Jˆ8.7, 5.3 and
0
0
(
5.3 Hz, H-1 ), 1.99 (1H, ddd, Jˆ8.7, 5.3 and 5.3 Hz,
0
0
0
0
H-2 1.39 (1H, ddd, Jˆ8.7, 5.5 and 5.3 Hz, H-3 a), 1.23
00
(150 MHz, CDCl ): d 168.30 (C-1), 159.82 (C-3), 157.71
13
(1H, ddd, Jˆ8.7, 5.5 and 5.3 Hz, H-3 b). C NMR
3
0
0
0
(C-6 ), 128.02 (C-4 ), 126.63 (C-5 and C-9 ), 125.45
0
00
0
(C-7 ), 141.36 (C-2 ), 135.09 (C-4 ), 132.84 (C-1 ), 130.67
0
00
00
0 0 00 00
poured into a cold saturated aqueous NH Cl solution
4
(C-5 ), 124.17 (C-3 ), 113.73 (C-6 and C-8 ), 111.00
00
(C-2), 61.71 (C-5), 55.32 (C-10 ), 51.53 (C-4), 26.64
(
150 ml) and extracted with diethyl ether (4£50 ml). The
0
0
00
00
organic extract was washed with water, dried with
Na SO , ®ltered over Celite, and concentrated under
reduced pressure. The residue was puri®ed by MPLC on
(C-2 ), 25.29 (C-1 ), 17.07 (C-3 ). Anal. calcd for
: C, 74.54; H, 6.55. Found: C, 74.87; H, 6.35.
GLC analysis showed that (1R ,2R )-10b had purity higher
C H O
21 22 4
2
4
p
p
p
p
silica gel using benzene as eluant to yield (1R ,2R )-10a
than 99%.
(
(
(
(
(
1.23 g, 80%) as a colourless solid. Mp 67±708C. MS: m/z
%): 308 (1), 217 (93), 216 (62), 215 (59), 204 (95), 202
56), 189 (49), 134 (100), 121 (35), 115 (30), 91 (52). IR
p
3.3.3. Methyl (E)(1R ,2R )-2-{2-[2-(3-¯uorophenyl)cyclo-
p
p
propyl]phenyl}-3-methoxypropenoate [(1R ,2R )-10c]. A
p
2
1 1
KBr): n 1705, 1638, 1254, 1136, 1043, 745 cm . H NMR
600 MHz, CDCl ): d 7.44 (1H, s, H-3), 7.30 (1H, dd, Jˆ7.6
0.30 M solution of the Grignard reagent derived from
p
p
(1R ,2R )-15c (25.0 ml, 7.50 mmol) was added dropwise
to a slurry of dry ZnBr (2.20 g, 9.77 mmol) in THF
3
0
00
and 7.6 Hz, H-4 ), 7.28 (1H, dd, Jˆ7.6 and 7.6 Hz, H-6 ),
2
00
7
.26 (1H, dd, Jˆ7.6 and 7.6 Hz, H-8 ), 7.21 (1H, dd, Jˆ7.6
(18 ml) which was stirred under argon at 08C. After stirring
for 15 min at 08C, a solution of 11 (1.52 g, 6.26 mmol) in
THF (15 ml) and Pd(PPh ) (0.362 g, 0.313 mmol) was
3 4
0
00
and 7.6 Hz, H-5 ), 7.16 (1H, m, H-7 ), 7.13 (1H, d, Jˆ
0
H-5 and H-9 ), 3.72 (3H, brs, H-5), 3.40 (3H, brs, H-4),
0
7
.6 Hz, H-6 ), 7.07 (1H, m, H-3 ), 7.07 (2H, d, Jˆ7.6 Hz,
00
00
sequentially added and the reaction mixture was stirred
for 96 h at rt. After usual workup the crude reaction product
was diluted with the solvent, which was subsequently used
for its puri®cation by MPLC and ®ltered over Celite. The
®ltrate was concentrated under reduced pressure and the
residue was puri®ed by MPLC on silica gel, using benzene
00
2
.13 (1H, ddd, Jˆ8.9, 5.5 and 5.5 Hz, H-2 ), 2.02 (1H, ddd,
00
Jˆ8.7, 5.5 and 5.5 Hz, H-1 ), 1.47 (1H, ddd, Jˆ8.7, 5.5 and
0
0
5
.5 Hz, H-3 b), 1.30 (1H, ddd, Jˆ8.9, 5.5 and 5.5 Hz,
00
3
13
H-3 a). C NMR (150 MHz, CDCl ): d 168.30 (C-1),
00 0 0
1
1
1
1
2
59.92 (C-3), 143.03 (C-4 ), 141.12 (C-2 ), 132.95 (C-1 ),
0
p
p
00
00
0
0
30.65 (C-6 ), 128.23 (C-6 and C-8 ), 128.06 (C-4 ),
0
as eluant, to give (1R ,2R )-10c (1.55 g, 76%) as a colour-
less solid. Mp 72±758C. MS: m/z (%): 326 (1), 235 (20), 204
(53), 189 (26), 152 (100), 139 (39), 129 (15), 115 (46), 109
(60), 102 (24), 75 (35). IR (KBr): n 1703, 1635, 1284, 1261,
00
23.88 (C-7 ), 110.48 (C-2), 61.68 (C-5), 51.56 (C-4),
00
25.48 (C-5 ), 125.39 (C-5 and C-9 ), 125.38 (C-3 ),
0
0
00
00
00
7.73 (C-2 ), 26.01 (C-1 ), 17.41 (C-3 ). Anal. calcd for
2
1
1
C H O : C, 77.90; H, 6.54. Found: C, 78.18; H, 6.77. GLC
2
1139 cm . H NMR (600 MHz, CDCl
H-3), 7.29 (1H, ddd, Jˆ7.5, 7.5 and 1.4 Hz, H-4 ), 7.21
3
): d 7.44 (1H, s,
0
0
20
3
p
p
analysis showed that (1R ,2R )-10a had purity higher than
0
9
8.5%.
(1H, ddd, Jˆ7.5, 7.5 and 4.0 Hz, H-5 ), 7.21 (1H, ddd,
0
0
Jˆ8.2, 7.8 and 6.0 Hz, H-8 ), 7.13 (1H, dd, Jˆ7.5 and
p
.3.2. Methyl (E)(1R ,2R )-2-{2-[2-(4-methoxyphenyl)-
p
0
0
3
1.4 Hz, H-6 ), 7.06 (1H, d, Jˆ7.5 Hz, H-3 ), 6.86 (1H,

R. Rossi et al. / Tetrahedron 57 (2001) 2847±2856
2855
0
0
ddd, Jˆ7.8, 1.4 and 1.0 Hz, H-9 ), 6.84 (1H, dddd, Jˆ8.6,
Tetrahedron Lett. 1996, 37, 8213±8216. (e) Rossi, R.; Bellina,
F.; Ciucci, D.; Carpita, A.; Fanelli, C. Tetrahedron 1998, 54,
7595±7614.
00
8
.2, 2.5 and 1.0 Hz, H-7 ), 6.75 (1H, ddd, Jˆ10.4, 2.5 and
00
.4 Hz, H-5 ), 3.62 (3H, brs, H-5), 3.56 (3H, brs, H-4), 2.13
1
(
00
1H, ddd, Jˆ9.0, 6.0 and 5.0 Hz, H-1 ), 2.00 (1H, ddd,
8. For the synthesis of analogues of strobilurins in which the
methyl (E)-O-methyloximinoacetate group is linked to a
substituted aromatic ring, see: (a) Rossi, R.; Carpita, A.;
Pazzi, P.; Mannina, L.; Valensin, D. Tetrahedron, 1999, 55,
11343±11364, and references cited therein. (b) Ref 7c.
9. For a summarizing account which describes the known
processes for the construction of enol ether, oxime ether and
oxime ether amide pharmacophores as well as Pd-catalyzed
couplings of entire pharmacophores to bridging arene ortho to
preexisting side chains, see: Ref. 7c.
0
0
Jˆ8.8, 5.4 and 5.0 Hz, H-2 ), 1.49 (1H, ddd, Jˆ8.8, 6.0
00
and 5.3 Hz, H-3 a), 1.30 (1H, ddd, Jˆ9.0, 5.4 and 5.3 Hz,
0
0
13
H-3 b). C NMR (150 MHz, CDCl ): d 168.10 (C-1),
3
1
00
1
63.04 ( J ˆ244.1 Hz, C-6 ), 159.79 (C-3), 146.00
C±F
3
00
0
0
(
JC±Fˆ7.1 Hz, C-4 ), 140.68 (C-2 ), 133.01 (C-1 ),
0 00
C±F
3
1
(
30.77 (C-6 ), 129.61 ( J ˆ7.5 Hz, C-8 ), 128.06
0
0
0
4
C-4 ), 125.78 (C-5 ), 124.57 (C-3 ), 121.27 ( J
ˆ
C±F
00
2
00
3
(
.0 Hz, C-9 ), 112.31 ( J ˆ21.4 Hz, C-7 ), 112.29
C±F
2
00
JC±Fˆ21.4 Hz, C-5 ), 111.10 (C-2), 61.70 (C-5), 51.50
00
00
00
(C-4), 27.07 (C-2 ), 26.27 (C-1 ), 17.36 (C-3 ). Anal.
calcd for C H FO : C, 73.60; H, 5.87. Found: C, 73.49;
10. For reactivity studies and molecular orbital calculations of
cyclopropanes, see: Wiberg, K. B. Acc. Chem. Res. 1996,
29, 229±234.
2
0
19
3
p
H, 5.86. GLC analysis showed that (1R ,2R )-10c was 98%
p
chemically pure.
11. (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94,
370±4371. (b) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc.
975, 97, 5249±5255.
4
1
Acknowledgements
12. For the synthesis of cyclopropylboronic acid esters by
treatment of alkenylboronic acid esters with diazomethane
This work was supported by the Ministero dell'Universit aÁ e
della Ricerca Scienti®ca
the University of Pisa and the Progetto Finalizzato Beni
Culturali (CNR, Roma). We thank Professor Annalaura
Segre for the use of NMR facilities of the Servizio NMR
dell'Area della Ricerca di Roma (CNR).
in the presence of catalytic quantities of Pd(OAc) , see: (a)
2
e
Tecnologica, (MURST),
Fontani, P.; Carboni, B.; Vaultier, M.; Maas, G. Synthesis
1991, 605±609. (b) Zhou, S.-M.; Deng, M.-Z.; Xia, L.-J.;
Tang, M.-H. Angew. Chem., Int. Ed. 1998, 37, 2845±2847.
(c) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999, 64,
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1
1
3. (a) Takai, K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994,
59, 2671±2673. (b) Imai, T.; Mineta, H.; Nishida, S. J. Org.
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51.