Ring opening of methylenecyclopropane moieties in the palladium-catalyzed cross-coupling of methylenecyclopropyl bromides with metallated CH-acidic compounds

Article abstract of DOI:10.1002/(SICI)1099-0690(199803)1998:3<453::AID-EJOC453>3.0.CO;2-2

Palladium-catalyzed cross-coupling reactions of bromo(methylenecyclopropanes) Ic, 2c with the sodium enolate of dimethyl malonate 4a and the chlorozinc enolates of the glycine equivalent (diphenylmethyleneamino)acetate 4c and diethyl malonate 4d, respectively, have been found to proceed with opening of the three-membered ring in each case, to give the corresponding dienyl-substituted CH-acidic compounds 5-7 in moderate to good yields. On the other hand, coupling of bicyclopropylidenylzinc chloride (2d) with diethyl bromomalonate (4e) and the electrophilic glycine equivalent ethyl 2-acetoxy-2-(diphenylmethyleneamino)acetate (4f) gave 7 and 6 in 27 and 29% yield, respectively.

Full text of DOI:10.1002/(SICI)1099-0690(199803)1998:3<453::AID-EJOC453>3.0.CO;2-2

FULL PAPER
Cyclopropyl Building Blocks for Organic Synthesis, 43[᭛]
Ring Opening of Methylenecyclopropane Moieties in the Palladium-Catalyzed
Cross-Coupling of Methylenecyclopropyl Bromides with Metallated CH-Acidic
Compounds
Melanie Brandl, Sergei I. Kozhushkov, Stefan Bräse, and Armin de Meijere*
Institut für Organische Chemie der Georg-August-Universität Göttingen,
Tammannstrasse 2, D-37077 Göttingen, Germany
Fax: (internat.) ϩ 49 (0)551/399475
E-mail: ameijer1@uni-goettingen.de
Received October 21, 1997
Keywords: Amino acids / Bicyclopropylidene / Methylenecyclopropane / Palladium catalysis / Zinc reagents
Palladium-catalyzed cross-coupling reactions of bromo- case, to give the corresponding dienyl-substituted CH-acidic
(methylenecyclopropanes) 1c, 2c with the sodium enolate of
compounds 5Ϫ7 in moderate to good yields. On the other
dimethyl malonate 4a and the chlorozinc enolates of the gly- hand, coupling of bicyclopropylidenylzinc chloride (2d) with
cine equivalent (diphenylmethyleneamino)acetate 4c and
diethyl malonate 4d, respectively, have been found to
proceed with opening of the three-membered ring in each
diethyl bromomalonate (4e) and the electrophilic glycine
equivalent ethyl 2-acetoxy-2-(diphenylmethyleneamino)ace-
tate (4f) gave 7 and 6 in 27 and 29% yield, respectively.
Palladium-catalyzed nucleophilic substitution of allylic
substrates with carbon nucleophiles, proceeding via π-allyl-
palladium intermediates, has become one of the most im-
portant CϪC bond forming processes employed in modern
organic synthesis[1]. The range of applicable allylic sub-
strates covers a considerable structural variety, and even in-
cludes alkenylcyclopropyl derivatives[2]. The most com-
monly used carbon nucleophiles are malonate and other
suitably stabilized ester enolates. The enolate of ethyl α-(di-
phenylmethyleneamino)acetate (OЈDonnellЈs glycine equiv-
alent[3]) has frequently been employed in palladium-cata-
lyzed allylic substitutions to prepare precursors of α-amino
acids[4], including some containing a methylenecyclopropyl
fragment[2b][2c]. Due to their wide-ranging biological activi-
ties, α- and β-amino acids containing a three-membered
ring have attracted ever increasing interest over the last two
decades[5]. In continuation of our investigations in this
area[6] we have now tested the applicability of palladium-
catalyzed allylic substitutions with the OЈDonnell glycine
equivalent in the preparation of amino acids containing a
methylenecyclopropane fragment attached directly to the
In order to find the appropriate conditions for the pal-
ladium-catalyzed substitution of 1cϪ3c with stabilized en-
olates, 2-bromo-1-methylenecyclopropane (1c) was treated
with dimethyl sodiomalonate (4a) in the presence of pal-
ladium bis(dibenzylideneacetonate) [Pd(dba)2] and bis(di-
phenylphosphano)ethane (dppe), a commonly used catalyst
system for such transformations[2][4]. This reaction pro-
ceeded smoothly at 60°C to give dimethyl (2Ј-buta-1Ј,3Ј-
dienyl)malonate (5) as the only isolated product in 60%
yield. Apparently, the substitution of bromine in 1c had
taken place only with complete ring opening of the three-
membered ring. However, the lithiated glycine equivalent 4b
did not undergo this type of reaction with 2c under such
conditions. At room temperature, no reaction was observed,
whereas upon heating the reaction mixture to 35°C, com-
plete decomposition of the starting material 4b was ob-
served.
α-position[7]
.
The required starting materials, the allylic bromides 2-
bromo-1-methylenecyclopropane (1c), bromobicyclopro-
pylidene (2c), and 2-bromo-1-methylenespiropentane (3c)
were prepared by deprotonation[8] of the corresponding hy-
drocarbons 1aϪ3a[9] with butyllithium and subsequent re-
action of the lithio derivatives 1bϪ3b with 1,2-dibromoe-
thane[8] (see Experimental Section).
[᭛] Part 42: S. I. Kozhushkov, M. Brandl, D. S. Yufit, R. Machinek,
A. de Meijere, Liebigs Ann. 1997, 2197Ϫ2204.
Eur. J. Org. Chem. 1998, 453Ϫ457
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0303Ϫ0453 $ 17.50ϩ.50/0
453

M. Brandl, S. I. Kozhushkov, S. Bräse, A. de Meijere
FULL PAPER
Scheme 1
ported here, cyclopropylpalladium intermediates of the
types 10 and/or 11 must be involved.
The conversion of 9 to 12 corresponds to the well-known
(cyclopropylmethyl)metal to homoallylmetal[12a] rearrange-
ment, while the conversion of 10 or 11 to 13 and 14, respec-
tively, is analogous to the cyclopropylmetal (or cyclopropyl
carbanion) to allylmetal (or allyl anion) ring opening[12b]
.
Among the great number of palladium catalysts available,
To probe this mechanistic assumption, palladium-cata-
dichloro[1,1Ј-bis(diphenylphosphano)ferrocene]palladium(II) lyzed coupling of OЈDonnellЈs electrophilic glycine equiva-
[PdCl2(dppf)] has been reported to be by far the most active lent, the acetate 4f[13], with bicyclopropylidenylzinc chloride
and selective in the coupling reactions of n-, sec-, and tert- (2d) was examined. The chlorozinc derivative 2d was gener-
alkylzinc and -magnesium halides, leading to high yields ated by transmetallation of the lithio derivative 2b with
without any side reactions (β-elimination, etc.)[10]. Under ZnCl2. Indeed, only the cyclopropylideneallyl-substituted
the action of this catalyst, the coupling of 2-bromobicyclo- glycine derivative 6 was isolated from this reaction, albeit
propylidene (2c) with the chlorozinc derivative 4c of the gly- in only 29% yield. This result confirms that the ring open-
cine equivalent (prepared from the lithio derivative 4b by ing can at least occur in a cyclopropylpalladium intermedi-
transmetallation with zinc chloride) proceeded even at room ate of type 11.
temperature, to give the dienyl-substituted glycine derivative
Deprotection of compound 6 with 0.2  hydrochloric
6 as the only isolated product in 72% yield. The structure acid followed by saponification (LiOH, THF/H2O) yielded
of 6 is indicative of the same mode of cyclopropane ring the amino acid 15, which represents an interesting example
opening as that seen in the reaction of 1c with sodiomalo- of a highly unsaturated α-amino acid containing a methyl-
nate to give 5. Surprisingly, no reaction of the chlorozinc enecyclopropane moiety (Scheme 2).
derivative 4c with 2-bromo-1-methylenespiropentane (3c)
could be observed under the same conditions, even after
Scheme 2
56 h at room temperature.
In contrast, reaction of 2c with the chlorozinc derivative
of diethyl malonate 4d in the presence of PdCl2(dppf) gave
the dienylmalonate 7, but only in moderate yield (24%),
along with some polymeric material. This result can be ra-
tionalized by assuming a rapid bromine exchange between
the compounds 2c and 4d, leading to 2d and diethyl bromo-
The diene 7 was found to be rather unstable and poly-
malonate 4e. The subsequent palladium-catalyzed coupling merized even at Ϫ20°C, probably as a result of autooxi-
of 2c with 2d would then presumably produce the triene 8, dation. After a pure sample had been stored in a freezer for
which would be prone to polymerization. The 13C-NMR 6 months, only 4% of 7 could be recovered after repeated
spectrum of an unstable fraction with Rf ϭ 0.73, isolated column chromatography, along with the cyclobutanone de-
by column chromatography, showed signals consistent with rivative 18 (9.2%). The ketone 18 can be formed from 7 via
the structure 8. Thus, essentially the same product distri- the intermediate diradicals 16, 17, or 19 (Scheme 3), with a
bution was observed in the coupling of a twofold excess of cyclopropylmethyl to homoallyl radical rearrangement as a
the zinc derivative 2d with diethyl bromomalonate 4e, and key step[14]
compound 7 was isolated in 27% yield. In conclusion, palladium-catalyzed reaction of 2-bromo-
.
Formally, the structural transformations observed in 1-methylenecyclopropane (1c) and bromobicyclopropyli-
these reactions are very similar to those reported for the dene (2c) with deprotonated CH-acidic compounds 4aϪd
coupling of bicyclopropylidene (2a) itself with haloarenes proceeds with an unexpected, yet readily rationalized ring
and alkenes under Heck conditions[11]. Mechanistically, opening of a three-membered ring, to produce dienyl-sub-
however, there is a difference. Whereas in the Heck reaction stituted derivatives 5Ϫ7. Compound 15 represents a new
of 2a, ring opening occurs at the stage of the (cyclopro- potentially interesting amino acid incorporating a cyclopro-
pylmethyl)palladium intermediate 9, in the reactions re- pylidenepropenyl substituent.
454
Eur. J. Org. Chem. 1998, 453Ϫ457

Cyclopropyl Building Blocks for Organic Synthesis, 43
Scheme 3
FULL PAPER
59%) according to GP1. Ϫ 1H NMR: δ ϭ 1.25Ϫ1.35 (m, 2 H,
Cpr), 1.36Ϫ1.42 (m, 1 H, Cpr), 1.50Ϫ1.58 (m, 1 H, Cpr), 3.82 (br.
s, 1 H, CH), 5.31 (d, J ϭ 1.5 Hz, 1 H, ϭCH2), 5.65 (br. s, 1 H, ϭ
CH2). Ϫ 13C NMR: δ ϭ 12.72, 14.40, 103.12 (CH2), 23.40 (CH),
20.28, 136.29 (C). Ϫ MS (CI), m/z (%): 161/159 (25/44) [Mϩ ϩ H],
146/144 (11/16) [Mϩ Ϫ CH2], 133/131 (8/21) [Mϩ Ϫ C2H3], 121
(100). Ϫ C6H7Br (159.0): calcd. C 45.32, H 4.44; found C 46.32,
H 5.06.
Dimethyl (Buta-1,3-dien-2-yl)malonate (5): To a solution of
bis(dibenzylideneacetone)palladium(0) [Pd(dba)2] (53.4 mg, 92.9
µmol) and 1,2-bis(diphenylphosphano)ethane (dppe) (47.2 mg, 118
µmol) in THF (1 ml), which had been stirred for 5 min at room
temp., was added 2-bromo-1-methylenecyclopropane (1c) (500 mg,
3.76 mmol). After 5Ϫ10 min, the solution turned green, and a solu-
tion of dimethyl sodiomalonate, freshly prepared from NaH (100
mg, 3.33 mmol, 80% in mineral oil) and dimethyl malonate (530
mg, 4.01 mmol) in THF (3 ml), was added dropwise. After stirring
at 60°C for 24 h and allowing to cool, the solution was poured
into diethyl ether (20 ml), and the resulting mixture was washed
with 10% NH4Cl solution (40 ml). The aqueous phase was ex-
tracted with diethyl ether (3 ϫ 20 ml), the combined organic phases
were dried, and then concentrated under reduced pressure. Column
chromatography of the residue on silica gel (petroleum ether/Et2O,
20:1) gave 415 mg (60%) of 5 as a colorless oil, which readily poly-
This work was supported by the Deutsche Forschungsgemein-
schaft (SFB 416, Projekt A3) and the Fonds der Chemischen Indus-
trie. We are grateful to the companies BASF AG, Bayer AG, Cheme-
tall GmbH, Degussa AG, and Hüls AG for generous gifts of chemi-
cals and to Dr. B. Knieriem for his careful reading of the manu-
script.
Experimental Section
1H- and 13C-NMR spectra: at 250 (1H) and 62.9 MHz [13C, ad-
ditional DEPT (Distortionless Enhancement by Polarization Trans-
fer)] on a Bruker AM 250 instrument in CDCl3 solution, CHCl3/
CDCl3 as internal reference. Ϫ FT-IR: Bruker IFS 66, measured
as KBr pellets, or as oils between NaCl plates. Ϫ MS (EI) and MS
(HR-EI): Finnigan MAT 95 spectrometer (70 eV). MS (HR-EI):
pre-selected ion peak matching at R >> 10 000 to be within ±2
ppm of the exact masses. Ϫ CI-MS: with NH3. Ϫ TLC: Macherey-
Nagel precoated sheets, 0.25 mm Sil G/UV254. Ϫ Column chroma-
tography: Merck silica gel, grade 60, 230Ϫ400 mesh.
1
merized; Rf ϭ 0.31. Ϫ H NMR: δ ϭ 3.33 (s, 1 H, CH), 3.79 (s, 6
H, 2 OCH3), 5.13 (d, J ϭ 11.0 Hz, 1 H, ϭCH2), 5.20 (d, J ϭ 17.5
Hz, 1 H, ϭCH2), 5.27 (s, 1 H, ϭCH2), 5.41 (s, 1 H, ϭCH2), 6.39
(dd, J ϭ 11.0, 17.5 Hz, 1 H, ϭCH). Ϫ 13C NMR: δ ϭ 52.31 (CH3),
114.34, 120.18 (CH2), 41.10, 137.07 (CH), 138.56, 166.91 (C). Ϫ
MS (EI), m/z (%): 184 (15) [Mϩ], 153 (3) [Mϩ Ϫ CH3O], 125 (100)
[Mϩ Ϫ CH3CO2], 65 (37) [Mϩ Ϫ 2 CH3CO2 Ϫ H], 59 (55) [CH3-
CO2ϩ].
General Procedure (GP2) for the Palladium(0)-Catalyzed Substi-
tution of the Allyl Bromide 2c: To a stirred solution of lithium diiso-
propylamide (LDA), prepared from nBuLi (9 mmol, 3.86 ml of a
2.33  solution in hexane) and diisopropylamine (1.33 ml, 9.5
mmol) in THF (50 ml), a solution of ethyl N-(diphenylmethyl-
ene)glycinate (2.406 g, 9 mmol) or diethyl malonate (1.442 g, 9
mmol) in THF (10 ml) was added dropwise at Ϫ75°C over a period
of 1 h. After stirring for a further 1 h at this temperature, a solution
of anhydrous ZnCl2 ·THF complex[15] (2.085 g, 10 mmol) in THF
(10 ml) was added to the suspension of lithio compound over a
period of 15 min, with the temperature maintained at Ϫ75°C. The
mixture was stirred for 0.5 h at 0°C and then for 1 h at 20°C, before
being cannulated into a solution of bromobicyclopropylidene (2c)
(1.590 g, 10 mmol) and PdCl2(dppf) (365 mg, 5 mol%) in THF (40
ml) at 0°C. After stirring for 24 h at 20°C, the solution was poured
into a cold, satd. NH4Cl solution (40 ml), the resulting mixture
was diluted with diethyl ether (20 ml), and the organic layer was
separated. It was washed with satd. NH4Cl solution, dried, and
concentrated under reduced pressure, and the residue was purified
by column chromatography on silica gel deactivated with ammonia.
Starting Materials: Anhydrous diethyl ether and THF were ob-
tained by distillation from sodium benzophenone ketyl. Com-
pounds 2a[9a], 3a[9c], 2c[8], and 4f[13] were prepared according to
published procedures. All other chemicals were used as commer-
cially available (Merck, BASF, Bayer, Hoechst, Degussa, and Hüls
AG). Organic extracts were dried over MgSO4. All reactions were
performed under argon.
General Procedure (GP1) for the Preparation of Bromides 1c and
3c: nBuLi (10 mmol, 4.29 ml of a 2.33  solution in hexane) was
added to a solution of the hydrocarbon 1a, 3a (10 mmol) in anhy-
drous THF (20 ml) at Ϫ78°C. After stirring the solution at 0°C for
1 h, it was cooled to Ϫ78°C once more, whereupon 1,2-dibromo-
ethane (1.08 ml, 12.5 mmol) was added. The mixture was allowed
to warm to room temperature, then diluted with pentane (50 ml),
and washed with water (10 ϫ 50 ml) and satd. NaCl solution (100
ml). The organic layer was dried and slowly concentrated under nor-
mal (for 1c) or reduced (for 3c) pressure. The residue was bulb-to-
bulb distilled (20°C, 0.1 Torr) to give 1c, 3c as colorless oils.
2-Bromomethylenecyclopropane (1c): From 1a (0.82 ml, 0.70 g, 13
mmol), 0.94 g (54%) of 1c was obtained according to GP1; b.p.
92°C. Ϫ 1H NMR: δ ϭ 0.78Ϫ1.45 (m, 2 H, Cpr), 3.45 (m, 1 H,
CH), 5.65 (br. s, 1 H, ϭCH2), 5.80 (br. s, 1 H, ϭCH2). Ϫ 13C
NMR: δ ϭ 12.77, 118.43 (CH2), 35.32 (CH), 107.18 (C). Ϫ MS
(EI), m/z (%): 134/132 (14/14) [Mϩ], 109/107 (43/41) [Mϩ Ϫ C2H],
53 (100) [C4H5ϩ]. Ϫ MS (HR-EI): 131.9574 (C4H579Br, calcd.
131.9575).
Ethyl N-(Diphenylmethylene)(1-cyclopropylideneprop-2-enyl)gly-
cinate (6): By reaction of 2c (1.431 g, 9.0 mmol) and 4b [prepared
from ethyl N-(diphenylmethylene)glycinate (2.388 g, 9 mmol),
nBuLi (9.4 mmol, 4.03 ml of a 2.33  solution in hexane), diisopro-
pylamine (1.33 ml, 9.5 mmol) and anhydrous ZnCl2 ·THF (2.126
g, 10.2 mmol) in THF (50 ml)] according to GP2, 2.232 g (72%)
of 6 was obtained after column chromatography (100 g of deacti-
vated silica gel, 40 ϫ 4 cm, hexane/EtOAc, 3:1); Rf ϭ 0.49, m.p.
32Ϫ34°C (H2O/MeOH). Ϫ 1H NMR: δ ϭ 0.84Ϫ1.05 (m, 2 H,
2-Bromo-1-methylenespiropentane (3c): From 3a (0.761 g, 9.5
mmol), 3c was obtained as a 59% solution in pentane (1.495 g, Cpr), 1.03Ϫ1.35 (m, 2 H, Cpr), 1.22 (t, J ϭ 7.1 Hz, 3 H, CH3),
Eur. J. Org. Chem. 1998, 453Ϫ457 455

M. Brandl, S. I. Kozhushkov, S. Bräse, A. de Meijere
FULL PAPER
4.19 (q, J ϭ 7.1 Hz, 2 H, OCH2), 5.09 (s, 1 H, CH), 5.12 (d, J ϭ NMR (D2O): δ ϭ 1.05 (br. s, 4 H, Cpr), 4.47 (s, 1 H, CH), 5.00
11.3 Hz, 1 H, ϭCH2), 5.52 (d, J ϭ 17.8 Hz, 1 H, ϭCH2), 6.55 (dd, (d, J ϭ 11.0 Hz, 1 H, ϭCH2), 5.15 (d, J ϭ 18.4 Hz, 1 H, ϭCH2),
J ϭ 11.3, 17.8 Hz, 1 H, ϭCH), 7.09Ϫ7.88 (m, 10 H, Ph-H). Ϫ 13C 6.36 (dd, J ϭ 11.0, 18.4 Hz, 1 H, ϭCH). Ϫ 13C NMR (D2O): δ ϭ
NMR: δ ϭ 14.17 (CH3), 2.67, 3.02, 60.95, 114.0 (CH2), 127.94, 3.23, 4.09, 114.38 (CH2), 55.40, 135.81 (CH), 122.69, 134.63, 174.56
128.30, 128.42, 128.87 (2 CH), 68.12, 128.54, 130.25, 134.70 (CH),
(C). Ϫ MS (CI), m/z (%): 187 (100) [Mϩ ϩ 2 NH3]. Ϫ C8H11NO2
125.63, 128.11, 136.30, 139.50, 169.89, 171.60 (C). Ϫ MS (EI), m/z (153.2): calcd. C 62.72, H 7.24; found C 62.58, H 7.11.
(%): 345 (18) [Mϩ], 272 (50) [Mϩ Ϫ CO2C2H5], 182 (70) [NH2C-
Diethyl (2-Vinylcyclobutan-1-one-2-yl)malonate (18): Compound
Ph2ϩ], 165 (16) [Mϩ Ϫ NCPh2], 105 (100) [C7H7Nϩ], 77 (43)
7 (500 mg, 2.1 mmol) was stored at Ϫ20°C for 6 months. There-
[C6H5ϩ], 51 (10) [C4H3ϩ]. Ϫ MS (HR-EI): 345.1728 (C23H23NO2,
after, repeated column chromatography on deactivated silica gel (50
calcd. 345.1729). Ϫ C23H23NO2 (345.4): calcd. C 79.97, H 6.71;
g, column 25 ϫ 3.2 cm, hexane/Et2O, 5:2) gave 7 (21 mg, 4.2%)
found C 80.02, H 6.47.
and 18 (49 mg, 9.2%); Rf ϭ 0.32. Ϫ 1H NMR: δ ϭ 1.22 (t, J ϭ
To a suspension of 2b, prepared from 2a (1.800 g, 22.5 mmol)
and nBuLi (22.5 mmol, 9.67 ml of a 2.33  solution in hexane) as
described above, a solution of anhydrous ZnCl2 ·THF (5.620 g, 27
mmol) in THF (15 ml) was added at Ϫ78°C. After stirring at 20°C
for 1 h, the solution was cannulated into a mixture of 4f (4.880 g,
15 mmol) and PdCl2(dppf) (548 mg, 5 mol%) in THF (100 ml).
After stirring this mixture at 20°C for 24 h, the solution was
worked-up according to GP2. Yield 1.488 g (29%) of 6 after column
chromatography (200 g of deactivated silica gel, 40 ϫ 5 cm, hexane/
Et2O, 7:3).
7.1 Hz, 3 H, CH3), 1.24 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.17 (dt, J ϭ
12.1, 7.7 Hz, 1 H, CH2), 2.57 (dt, J ϭ 12.1, 9.0 Hz, 1 H, CH2),
3.08 (dd, J ϭ 7.7, 9.0 Hz, 2 H, CH2), 4.16 (q, J ϭ 7.1 Hz, 2 H,
OCH2), 4.17 (s, 1 H, CH), 4.18 (q, J ϭ 7.1 Hz, 2 H, OCH2), 5.23
(d, J ϭ 10.3 Hz, 1 H, ϭCH2), 5.29 (d, J ϭ 16.7 Hz, 1 H, ϭCH2),
5.81 (dd, J ϭ 10.3, 16.7 Hz, 1 H, ϭCH). Ϫ 13C NMR: δ ϭ 13.86,
13.97 (CH3), 19.95, 43.61, 61.43, 61.86, 116.72 (CH2), 56.44, 134.68
(CH), 68.67, 166.80, 167.28, 207.51 (C). Ϫ MS (EI), m/z (%): 254
(4) [Mϩ], 180 (8) [Mϩ Ϫ H Ϫ CO2C2H5], 160 (8) [Mϩ Ϫ C6H6O],
133 (61) [Mϩ Ϫ C6H7O Ϫ C2H2], 115 (100) [Mϩ Ϫ C6H7O Ϫ C2H2
Ϫ H2O], 111 (5), 88 (32). Ϫ MS (HR-EI): 254.1154 (C13H18O5,
calcd. 254.1154). Ϫ C13H18O5 (254.3): calcd. C 61.41, H 7.14;
found C 61.72, H 7.35.
Diethyl (1-Cyclopropylideneprop-2-enyl)malonate (7): By reac-
tion of 2c (1.590 g, 10.0 mmol) and 4d [prepared from nBuLi (10.5
mmol, 4.51 ml of a 2.33  solution in hexane), diisopropylamine
(1.47 ml, 10.5 mmol), diethyl malonate (1.52 ml, 10.0 mmol), and
a solution of anhydrous ZnCl2 ·THF (2.50 g, 12 mmol) in THF (15
ml) as described above] according to GP2, 7 (0.563 g, 24%) was
obtained after column chromatography on deactivated silica gel
[1]
[1a]
For reviews see:
B. M. Trost, Tetrahedron 1977, 33,
[1b]
2615Ϫ2649. Ϫ
B. M. Trost, Acc. Chem. Res. 1980, 13,
385Ϫ393. Ϫ [1c] J. Tsuji, Organic Synthesis with Palladium Com-
(hexane/diethyl ether, 5:2); Rf ϭ 0.40. Ϫ IR (film): ν˜ ϭ 2982 cmϪ1
,
[1d]
pounds, Springer, Berlin 1980. Ϫ
J. Tsuji, Tetrahedron 1986,
1734, 1446, 1368, 1311, 1247, 1153, 1035. Ϫ 1H NMR: δ ϭ
1.20Ϫ1.29 (m, 10 H, 2 Cpr, 2 CH3), 4.14Ϫ4.25 (m, 4 H, 2 OCH2),
4.49 (br. s, 1 H, CH), 5.04 (d, J ϭ 12.8 Hz, 1 H, ϭCH2), 5.10 (d,
J ϭ 19.2 Hz, 1 H, ϭCH2), 6.59 (dd, J ϭ 12.8, 19.2 Hz, 1 H, ϭ
CH). Ϫ 13C NMR: δ ϭ 13.96 (2 CH3), 61.41 (2 CH2), 2.27, 3.55,
111.62 (CH2), 53.94, 136.29 (CH), 120.57, 129.84, 168.01 (C). Ϫ
MS (EI), m/z (%): 238 (3) [Mϩ], 209 (7) [Mϩ Ϫ C2H5], 165 (100)
[Mϩ Ϫ CO2C2H5], 137 (5), 119 (17), 91 (27). Ϫ MS (HR-EI):
238.1205 (C13H18O4, calcd. 238.1205). Ϫ C13H18O4 (238.3): calcd.
C 65.53, H 7.61; found C 65.27, H 7.81.
42, 4361Ϫ4401. Ϫ [1e] J. Tsuji, I. Minami, Acc. Chem. Res. 1987,
20, 140Ϫ145. Ϫ [1f] G. Consiglio, R. M. Waymouth, Chem. Rev.
1989, 89, 257Ϫ276. Ϫ [1g] B. M. Trost, Angew. Chem. 1989, 101,
1199Ϫ1219; Angew. Chem. Int. Ed. Engl. 1989, 28, 1173Ϫ1192.
[1h]
Ϫ
C. G. Frost, J. Howarth, J. M. J. Williams, Tetrahedron
[1i]
Asymmetry 1992, 3, 1089Ϫ1122. Ϫ
S. Bräse, A. de Meijere
in Metal-Catalyzed Cross Coupling Reactions (Eds.: P. J. Stang,
F. Diederich), Wiley-VCH, Weinheim, 1997.
[2] [2a]
A. Stolle, J. Salaün, A. de Meijere, Synlett 1991, 327Ϫ330.
[2b]
Ϫ
A. Stolle, J. Ollivier, P. P. Piras, J. Salaün, A. de Meijere,
[2c]
J. Am. Chem. Soc. 1992, 114, 4051Ϫ4067. Ϫ
K. Voigt, A.
Stolle, J. Salaün, A. de Meijere, Synlett 1995, 226Ϫ228.
M. J. OЈDonnell, R. L. Polt, J. Org. Chem. 1982, 47,
2663Ϫ2666.
[3]
The solution of 2d, prepared as described above from 2a (1.593
g, 19.9 mmol), nBuLi (19.9 mmol, 8.54 ml of a 2.33  solution in
hexane) in THF (35 ml) and anhydrous ZnCl2 ·THF (4.585 g, 22
mmol) in THF (10 ml), was cannulated into a mixture of diethyl
bromomalonate (4e) (2.391 g, 1.71 ml, 10 mmol) and PdCl2(dppf)
(366 mg, 5 mol%) in THF (50 ml). After stirring at 20°C for 24 h,
the solution was worked-up according to GP2. Yield 0.641 g (27%)
of 7 after column chromatography (150 g of deactivated silica gel,
40 ϫ 4 cm, hexane/Et2O, 5:2).
[4] [4a]
D. Ferroud, J.-P. Genet, R. Kiolle, Tetrahedron Lett. 1986,
[4b]
27, 23Ϫ26. Ϫ
J.-P. Genet, S. Juge, S. Achi, S. Mallart, J.
Ruiz-Montes, G. Levif, Tetrahedron 1988, 44, 5263Ϫ5273. Ϫ
[4c] B. Cazes, D. Djahanbini, J. Gore, J.-P. Genet, J.-M. Gaudin,
Synthesis 1988, 983Ϫ985. Ϫ [4d] J.-P. Genet, N. Kopola, S. Juge,
J. Ruiz-Montes, O. A. C. Antunes, S. Tanier, Tetrahedon Lett.
1990, 31, 3133Ϫ3136.
[5]
[5a] J. Salaün, M. S. Baird, Curr. Med. Chem. 1995, 2, 511Ϫ542.
[5b]
Ϫ
C. H. Stammer, Tetrahedron 1990, 46, 2231Ϫ2254. Ϫ
[5c]
H. C. Pirrung, J. Cao, J. Chen, J. Org. Chem. 1995, 60,
[5d]
5790Ϫ5794. Ϫ
K. Burgess, D. Lim, K.-K. Ho, C.-Y. Ke, J.
[3-(Cyclopropylidene)prop-1-en-3-yl]glycine (15): Compound 6
(2.304 g, 6.67 mmol) was stirred in 0.2  HCl solution (200 ml) for
70 h at 20°C, completely protected from light. The reaction mixture
was adjusted to pH 8 with conc. NH4OH solution and then ex-
tracted with Et2O. After concentration under reduced pressure, the
ethereal extract was diluted with a 3:1 mixture of THF and H2O
(120 ml) and stirred with LiOH (156 mg, 6.5 mmol) for 24 h at
20°C. The reaction mixture was then concentrated under reduced
pressure and brought to pH 2 with 0.2  HCl solution. Subsequent
concentration of the solution, filtration through Dowex-50 (3 ϫ 20
cm column, eluent 0.9  NH4OH), followed by repeated concen-
tration and recrystallization from acetone/H2O gave 139 mg (14%)
Org. Chem. 1994, 59, 2179Ϫ2185.
[6] [6a]
M. Es-Sayed, C. Gratkowski, N. Krass, A. I. Meyers, A. de
[6b]
Meijere, Synlett 1992, 962Ϫ964. Ϫ
P. Aufranc, J. Ollivier,
A. Stolle, C. Bremer, M. Es-Sayed, A. de Meijere, J. Salaün,
[6c]
Tetrahedron Lett. 1993, 34, 4193Ϫ4196. Ϫ
Heiner, A. de Meijere, Synlett 1993, 57Ϫ58. Ϫ
M. Es-Sayed, T.
[6d]
J. Zindel, A.
Zeeck, W. A. König, A. de Meijere, Tetrahedron Lett. 1993, 34,
[6e]
1917Ϫ1920. Ϫ
190Ϫ194. Ϫ
J. Zindel, A. de Meijere, Synthesis 1994,
[6f]
M. Es-Sayed, P. Devine, L. E. Burgess, A. de
Meijere, A. I. Meyers, J. Chem. Soc., Chem. Commun. 1995,
[6g]
141Ϫ142. Ϫ
60, 2968Ϫ2973.
J. Zindel, A. de Meijere, J. Org. Chem. 1995,
[7] [7a]
D. O. Gray, L. Fowden, Biochem. J. 1962, 82, 385Ϫ389. Ϫ
L. Fowden, H. M. Pratt, A. Smith, Phytochemistry 1972,
[7b]
11, 3521Ϫ3523.
of 15, m.p. 148Ϫ150°C (decomp.). Ϫ IR (KBr): ν˜ ϭ 2978 cmϪ1
,
[8]
A. de Meijere, S. I. Kozhushkov, N. S. Zefirov, Synthesis 1993,
681Ϫ683.
1735, 1617, 1576, 1446, 1284, 1181, 1030, 911, 732, 696. Ϫ 1H
456
Eur. J. Org. Chem. 1998, 453Ϫ457

Cyclopropyl Building Blocks for Organic Synthesis, 43
FULL PAPER
[9] [9a]
[13] [13a]
A. de Meijere, S. I. Kozhushkov, T. Spaeth, N. S. Zefirov, J.
M. J. OЈDonnell, W. D. Bennett, R. L. Polt, Tetrahedron
[9b]
[13b]
Org. Chem. 1993, 58, 502Ϫ505. Ϫ
P. Binger, H. M. Büch,
Lett. 1985, 26, 695Ϫ698. Ϫ
M. J. OЈDonnell, C. Zhou, A.
[9c]
Top. Curr. Chem. 1987, 135, 77Ϫ151. Ϫ
S. Arora, P. Binger,
Mi, N. Chen, J. A. Kyle, Tetrahedron Lett. 1995, 36, 4205Ϫ4208.
[9d]
Synthesis 1974, 801Ϫ803. Ϫ
P. Binger, T. Schmidt in
Ϫ
[13c] M. J. OЈDonnell, X. Yang, M. Li, Tetrahedron Lett. 1990,
Houben-Weyl, Vol. E 17c (Ed.: A. de Meijere), Thieme,
Stuttgart, 1997, pp. 2217Ϫ2294.
31, 5135Ϫ5138.
[14]
[15]
J. C. Walton in Houben-Weyl, Vol. E 17c (Ed.: A. de Meijere),
Thieme, Stuttgart, 1997, p. 2438Ϫ2525.
[10]
[11]
T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higuchi,
K. Hirotsu, J. Am. Chem Soc. 1984, 106, 158Ϫ163.
S. Bräse, A. de Meijere, Angew. Chem. 1995, 107, 2741Ϫ2743;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2545Ϫ2547.
Commercial ZnCl2 was twice melted in vacuo (0.1 Torr), recrys-
tallized from anhydrous THF, and dried at 20°C/0.1 Torr for 4
h. 1H-NMR spectroscopic analysis (D2O, DMSO as internal
reference) of a precisely weighed sample of the product showed
it to be a 1:1 ZnCl2 ·THF complex. This complex shows much
better solubility in THF than pure ZnCl2 and was used in the
described coupling experiments.
[12] [12a]
D. Wendisch in Houben-Weyl, Vol. 4/3, Thieme, Stuttgart,
1971, pp. 399Ϫ405. For (cyclopropylcarbinyl)palladium inter-
mediates see also: G. Dyker, Angew. Chem. 1995, 107,
2407Ϫ2408; Angew. Chem. Int. Ed. Engl. 1995, 34, 2223Ϫ2224.
Ϫ
[12b] G. Boche, H. M. Walborsky, Cyclopropane-Derived Reac-
[97316]
tive Intermediates (Eds.: S. Patai, Z. Rappoport), Wiley, Chi-
chester, 1990, and references cited therein.
Eur. J. Org. Chem. 1998, 453Ϫ457
457