Highly diastereoselective sequential Michael-aldol reactions of methyl 2-chloro-2-cyclopropylideneacetate with Grignard reagents and aldehydes

Article abstract of DOI:10.1055/s-2006-926276

Grignard reagents, especially isopropylmagnesium chloride, smoothly undergo Michael addition onto methyl 2-bromo- and 2-chloro-2-cyclopropylideneacetate (1-Cl), and the thus formed magnesium enolates are particularly efficiently trapped with aromatic aldehydes. This one-pot reaction provides highly substituted chlorohydrines, mostly in high yields (10 out of 18 examples with 72-92%) and as pure (2S*,3R*)-diastereomers (anti-aldols). These chlorohydrines can be transformed to Darzens-type α,β-epoxyesters in good yields, as demonstrated for one example. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926276

PAPER
471
Highly Diastereoselective Sequential Michael-Aldol Reactions of Methyl 2-
Chloro-2-cyclopropylideneacetate with Grignard Reagents and Aldehydes1
M
ichael-Aldo
u
Reactions
o
r
f
Methyl
y
2-Chloro-2-
a
cyclopropy
k
lideneacetateanta Dalai,a Michael Limbach,a Ligang Zhao,a Markus Tamm,a Madhumati Sevvana,b Viktor V. Sokolov,a
Armin de Meijere*a
a
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen,
Germany
Fax +49(551)394795; E-mail: ameijer1@gwdg.de
Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany
b
Received 18 May 2005; revised 18 July 2005
nesium halides, as reported by Knochel et al.,16 has led to
functionalized alkenylmagnesium halides which cleanly
reacted with various electrophiles. In an attempt to adopt
these conditions for the conversion of methyl 2-chloro-2-
Abstract: Grignard reagents, especially isopropylmagnesium chlo-
ride, smoothly undergo Michael addition onto methyl 2-bromo- and
2-chloro-2-cyclopropylideneacetate (1-Cl), and the thus formed
magnesium enolates are particularly efficiently trapped with aro-
matic aldehydes. This one-pot reaction provides highly substituted cyclopropylideneacetate (1-Cl) to the corresponding
chlorohydrines, mostly in high yields (10 out of 18 examples with
methyl 2-cyclopropylidene-2-(chloromagnesium)acetate,
72–92%) and as pure (2S*,3R*)-diastereomers (anti-aldols). These
treatment of 1-Cl with one equivalent of i-PrMgCl at 0 °C
chlorohydrines can be transformed to Darzens-type a,b-epoxyesters
apparently did not proceed with chlorine-metal exchange,
in good yields, as demonstrated for one example.
but with 1,4-addition onto the a,b-unsaturated ester. Upon
Key words: small ring systems, Michael additions, aldol reactions,
domino reactions, diastereoselectivity, synthetic methods
trapping of the thus formed magnesium enolate with
benzaldehyde, the Michael-aldol product 2a-i-Pr was iso-
lated in very good yield (92%, Scheme 1) and as a single
diastereomer (> 97% anti, 2S*,3R*), as indicated by the
1H NMR spectrum of the crude product.
Cyclopropylideneacetates, and in particular the easily
accessible methyl 2-chloro-2-cyclopropylideneacetate
(1-Cl),2 are uniquely reactive and synthetically useful
Michael acceptors.3 Like any other methylenecyclopro-
pane,4 1-Cl exhibits an enhanced double bond reactivity,
and due to its two electron-withdrawing substituents, it
particularly easily reacts with nucleophiles.5 This combi-
nation of reactivity and multifunctionality in 1-Cl has led
to its application in facile syntheses of spirocyclopropan-
ated carbo-6 and heterocycles,7 various cyclopropyl-group
containing amino acids8 as well as conformationally re-
stricted peptidomimetics.9
Michael additions with immediately ensuing aldol reac-
tions, especially the well-known Robinson annelation10
were among the first of the various, now extremely popu-
Figure 1 Structure of compound 2b-i-Pr in the crystal indicating a
(2S*,3R*)-configuration corresponding to an anti-aldol addition of
lar sequential reactions which provide convenient one-pot the intermediate magnesium enolate to the aldehyde.17
accesses to complex skeletons from relatively simple
starting materials.11 The stereochemical outcome of a
Michael addition-aldol sequence can be controlled, either
The scope of this reaction sequence of 1-Cl was screened
varying the Grignard reagents and the aldehydes to lead to
the corresponding b-chloroalcohols 2a–l-R1 in moderate
by a stereogenic center in one of the reactants or by use of
chiral catalysts.12–14 As far as the aldol step is concerned,
to excellent yields (27–92%, Scheme 1, Table 1), all of
magnesium enolates have been found to add to aldehydes
which could be purified by column chromatography.
with particularly high anti diastereoselectivity,15 which
Since compound 2b-i-Pr readily crystallized, the relative
has been attributed to the steric demand of magnesium
configurations of the quaternary and the tertiary stereo-
enolates.
genic center could be deduced from a single crystal X-ray
structure analysis (Figure 1)17 to correspond to the out-
The smooth bromine-magnesium exchange on Michael
come of an anti-diastereoselective aldol reaction in the
second step.
acceptors like tert-butyl a-bromocrotonate and even b,b-
disubstituted a-bromoacrylonitriles with isopropyl mag-
Comparable processes with trialkylboranes18 yielded mix-
tures of syn- and anti-diastereomers (20:80–70:30, in the
best cases) in good chemical yields but with the waste of
two organyl residues from the borane. The extraordinarily
high diastereoselectivity upon the addition of the enolate
SYNTHESIS 2006, No. 3, pp 0471–0479
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926276; Art ID: T06305SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

472
S. Dalai et al.
PAPER
disubstituted cyclopropane ring, prefers an equatorial as
in 3 rather than an axial position as in 4 (Scheme 2).
The same diastereoselectivity was observed for the reac-
tions with cyclohexyl- and ethylmagnesium bromide, but
the yields were poor (27% and 32%, respectively). How-
ever, the reaction with phenyl- and with p-fluorophenyl-
magnesium chloride did not proceed as cleanly as those
with isopropylmagnesium chloride, albeit the product
could be purified by column chromatography followed by
crystallization (Table 1, entries 4 and 6). The reactions of
vinylmagnesium bromide and phenylethynylmagnesium
chloride led to an unidentified mixture of products and a
60% yield of 1,3-diphenylprop-2-ynol, respectively, the
latter resulting from a direct attack of the Grignard reagent
Scheme 1 Addition of organylmagnesium halides to methyl 2-chlo-
ro-2-cyclopropylideneacetate (1-Cl) and trapping of the formed ma-
gnesium enolate with aldehydes. For details see Table 1.
formed upon reaction of isopropylmagnesium chloride
with 1-Cl and benzaldehydes may be rationalized with the
six-membered transition structure, typical for aldol addi-
tions, in which the bulky alkyl residue containing the 1,1-
Table 1 Addition of Organylmagnesium Halides to Methyl 2-Chloro-2-cyclopropylideneacetate (1-Cl) and Trapping of the Formed Magne-
sium Enolate with Aldehydes (see Scheme 1)
Entry
1
R1
X
R2
Product
2a-i-Pr
Yield (%)a [dr]
92 [> 97:3]
27 [> 97:3]
32 [> 97:3]
42 [> 97:3]
35b [66:34]
39 [> 97:3]
i-Pr
Cl
Br
Br
Cl
Cl
Cl
Br
Br
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ph
2
c-Hex
Et
Ph
2a-c-Hex
2a-Et
3
Ph
4
Ph
Ph
2a-Ph
5
Ph
Ph
2a-Ph
6
4-FC6H4
Vin
Ph
2a-4-FC6H4
2a-Vin
c
7
Ph
–
8
Vin
Ph
2a-Vin
64b [69:31]
d
9
PhC≡C
2,4,6-Me3C6H2
i-Pr
Ph
2a-PhC≡C
2a-2,4,6-Me3C6H2
2b-i-Pr
2c-i-Pr
–
10
11
12
13
14
15
16
17
18
19
20
21
Ph
0c
4-OMeC6H4
3,4-(OCH2O)C6H3
4-NMe2C6H4
3,4,5-(OMe)3C6H2
C6F5
72 [>97:3]
78 [>97:3]
80 [>97:3]
72 [>97:3]
78 [>97:3]
83 [>97:3]
80 [> 97:3]
73 [> 97:3]
61e
i-Pr
i-Pr
2d-i-Pr
2e-i-Pr
i-Pr
i-Pr
2f-i-Pr
i-Pr
2-F-4-NO2C6H3
4-FC6H4
4-NO2C6H4
H
2g-i-Pr
i-Pr
2h-i-Pr
2i-i-Pr
i-Pr
i-Pr
2j-i-Pr
i-Pr
CO2Et
2k-i-Pr
2l-i-Pr
72 [> 3:97]f
32e [> 97:3]
i-Pr
C3H7
a Stoichiometry used normally: 1-Cl/R1MgX/R2CHO = 1:1:1.05.
b CuCN (1 equiv) was added prior to the aldehyde.
c Complicated mixture of unidentified products.
d Only 1,3-diphenylprop-2-ynol was isolated in 60% yield.
e Aldehyde (5 equiv) was used.
f Additional experiments with various Grignard reagents have shown that the addition of the magnesium enolate formed from 1-Cl to ethyl
glyoxylate in all cases occurs with virtually exclusive formation of the syn-diastereomer.19
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

PAPER
Michael-Aldol Reactions of Methyl 2-Chloro-2-cyclopropylideneacetate
473
Scheme 2 Rationalization of the selective formation of the anti-al-
dols in the sequential addition of isopropylmagnesium chloride and
aldehydes (exept for ethyl glyoxylate) to 1-Cl.
Scheme 3 Diastereoselective formation of the Darzens-type a,b-
epoxyesters 6-i-Pr under basic conditions from the chlorohydrine 2b-
i-Pr and directly from 1-Br.
anisaldehyde was also formed due to retroaldol fragmen-
tation. Considering an anti-elimination mechanism for the
chloride anion during the cyclization of chlorohydrine 2b-
i-Pr, one can predict the formation of the epoxide 6b-i-Pr,
in which the aryl and the ester groups are on the same side
of the oxirane ring. Unfortunately, a NOESY-NMR mea-
surement could neither support nor disprove this state-
ment. The analogous a,b-epoxyester 6a-i-Pr was obtained
directly from methyl 2-bromo-2-cyclopropylideneacetate
(1-Br)2c upon treatment with isopropylmagnesium chlo-
ride and benzaldehyde in 96% yield (Scheme 3). Appar-
ently, the magnesium alcoholate of the bromohydrine
analogous to 2a-i-Pr is not stable under the reaction con-
ditions and loses a bromide anion spontaneously.
on benzyldehyde. Mesitylmagnesium bromide did not re-
act cleanly with 1-Cl to yield the Michael adduct, most
probably due to its steric bulk. Upon addition of one
equivalent of CuCN to the reaction mixture of 1-Cl and vi-
nylmagnesium bromide prior to the addition of benzalde-
hyde, the Michael-aldol adduct 2a-Vin was formed, but as
a mixture of anti- and syn-diastereomers (69:31). The
same decreased diastereoselectivity was observed in the
reaction of 1-Cl with PhMgCl and PhCHO in the presence
of CuCN (entries 8 and 5).
As far as the aldehydes are concerned, various substituted
benzaldehydes were screened and found to give consis-
tently good yields (72–83%) independent of their substit-
uents and substitution patterns (Table 1, entries 11–18).
All reagents were used as purchased from commercial suppliers
without further purification. All reactions in non-aqueous solvents
were carried out using standard Schlenk techniques under an atmo-
sphere of dry N2. Solvents were purified and dried according to con-
ventional methods prior to use; Et2O and THF were freshly distilled
1
from Na–benzophenone. H- and 13C NMR spectra were recorded
at ambient temperature with a Bruker AM 250 (250 MHz for 1H and
62.9 MHz for 13C), a Varian UNITY-200 (200 MHz for 1H and 50.3
Figure 2
1
MHz for 13C) or a Varian UNITY-300 (300 MHz for H and 75.5
The Michael adduct 5-i-Pr (Figure 2) of isopropylmagne-
sium chloride to 1-Cl was obtained in virtually quantita-
tive yield (98%), upon quenching the reaction before
adding an aldehyde, after 30 minutes with aqueous NH4Cl
solution. The corresponding adduct 5-Vin (Figure 2) of
vinylmagnesium bromide could also be isolated in 80%
yield by adding 1-Cl to the Grignard reagent in the pres-
ence of 1 equivalent of CuCN, and 0.5 equivalent of
BF3·OEt2 at –78 °C, followed by aqueous workup. The ad-
MHz for 13C) instrument. Chemical shifts (d) are given in ppm rel-
ative to resonances of solvent (1H: 7.26 ppm for CHCl3; 13C: 77.0
ppm for CDCl3), coupling constants (J) are given in Hz. The multi-
plicities of signals were determined by the DEPT or the APT tech-
nique. DEPT: + = primary or tertiary (positive DEPT-signal); – =
secondary (negative DEPT-signal), Cquat = quaternary C-atom;
APT: + = primary or tertiary (positive APT-signal); – = secondary
or quaternary C-atom (negative APT-signal). IR spectra were re-
corded on a Bruker IFS 66 spectrometer. MS data were measured
on a Finnigan MAT 95 instrument (70 eV). HRMS measurement
duct 5-i-Pr was also obtained as the sole product when were performed on a Finnigan MAT 95 instrument using preselect-
ed ion peak matching at R = 10000 to be within 2 ppm. Chromato-
benzonitrile was added to the enolate formed from isopro-
graphic separations were carried out on Merck Silica 60 (0.063–
0.200 mm, 70–230 mesh ASTM). The dimensions of the columns
pylmagnesium chloride and 1-Cl.
The a-chloro-b-hydroxy esters 2 which are, in most cases,
diastereoselectively formed in this one-pot sequential
Michael addition-aldol reaction from 1-Cl, isopropylmag-
nesium chloride and an aldehyde, offer themselves as pre-
cursors to a,b-epoxy esters of the Darzens type 6. In fact,
when 2b-i-Pr in THF was treated at ambient temperature
with t-BuOK, it underwent cyclization to the diastereo-
merically pure a,b-epoxyester 6b-i-Pr, however, some p-
are given as ‘diameter × height’ of the silica column. TLC analyses
were carried out on Macherey–Nagel TLC plates (Alugram® Sil G/
UV254), with detection under UV light at 254 nm and development
with MOPS reagent (10% molybdophosphoric acid, solution in
EtOH), if not otherwise stated (e.g. 1% anisaldehyde in MeOH/
AcOH/H2SO4, 85:10:5). Melting points were measured on a Dr.
Tottoli (Büchi) apparatus and the values are uncorrected. Elemental
analyses were carried out at Mikroanalytisches Laboratorium, Insti-
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

474
S. Dalai et al.
PAPER
tut für Organische und Biomolekulare Chemie, Universität Göttin-
gen.
MS (DCI): m/z (%) = 690.9 (20) [2 × M + NH4]+, 354.5 (100) [M +
NH4]+.
Anal. Calcd for C19H25ClO3 (336.9): C, 67.75; H, 7.48. Found: C,
67.82; H, 7.36.
One-Pot Reaction of Methyl 2-Halo-2-cyclopropylideneacetate
(1) with Grignard Reagents and Benzaldehydes; General Pro-
cedure
(2S*,3R*)-Methyl 2-Chloro-2-(1-ethylcyclopropyl)-3-hydroxy-
3-phenylpropionate (2a-Et)
From 1-Cl (294 mg, 2.0 mmol), EtMgBr (2 M in Et2O, 1.1 mL, 2.2
mmol), and benzaldehyde (233 mg, 2.2 mmol), chromatographic
purification on silica gel [30 g, 3 × 10 cm, pentane–Et2O (5:1), Rf
0.60, p-anisaldehyde] yielded 2a-Et (180 mg, 32%) as a colorless
oil.
To a solution of 1 (147 mg of 1-Cl, 191 mg of 1-Br, each 1.00
mmol) in THF (10 mL) was slowly (within 10 min) added at 0 °C a
solution of the Grignard reagent (1.00 mmol). The mixture was
stirred for 30 min under rewarming to 20 °C, then cooled again, and
at 0 °C a solution of the respective aldehyde (1.05 mmol) in THF (2
mL) was added, then the mixture was stirred for an additional 30
min under rewarming to 20 °C. The mixture was cooled again to 0
°C, the reaction was quenched with sat. NH4Cl solution (4 mL), and
the mixture was stirred at 20 °C for 15 min. Et2O (20 mL) was add-
ed, the phases were separated, the aq phase was extracted with Et2O
(20 mL). The combined organic phase was dried over Na2SO4, and
the volatiles were removed in vacuo. Chromatographic purification
of the residue on silica gel yielded the products.
IR (film): 3530, 3030, 2970, 2945, 1721, 1453, 1269 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.01–0.07 (m, 1 H, c-Pr-H), 0.31–
0.37 (m, 1 H, c-Pr-H), 0.74 (t, 3J = 7.5 Hz, 3 H, CH3), 0.86–0.93 (m,
2 H, c-Pr-H), 1.63–1.88 (m, 2 H, CH2), 2.90–3.40 (br s, 1 H, OH),
3.84 (s, 3 H, OCH3), 5.59 (s, 1 H, OCH), 7.26–7.33 (m, 3 H, aryl-
H), 7.43–7.47 (m, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 15.4 (–, c-Pr-C), 16.5
(–, c-Pr-C), 18.2 (+, CH3), 31.2 (Cquat, c-Pr-C), 33.4 (–, CH2), 61.5
(+, OCH3), 82.9 (+, OCH), 88.6 (Cquat, ClC), 135.7 (+, 2 × C, aryl-
C), 136.5 (+, aryl-C), 136.9 (+, 2 × C, aryl-C), 146.4 (Cquat, Cipso),
180.8 (Cquat, C=O).
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-phenylpropionate (2a-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and benzaldehyde (111 mg, 1.05 mmol), chromato-
graphic purification on silica gel [20 g, 1.5 × 15 cm, pentane–Et2O
(3:1), Rf 0.30, p-anisaldehyde] yielded 2a-i-Pr (273 mg, 92%) as a
colorless oil.
MS (DCI): m/z (%) = 582.6 (75) [2 × M + NH4]+, 300.3 (100) [M +
NH4]+.
Anal. Calcd for C15H19ClO3 (282.8): C, 63.72; H, 6.77. Found: C,
63.76; H, 6.44.
IR (film): 3516, 2960, 2929, 2873, 1723, 1454, 1262, 1054, 702
cm–1.
1H NMR (250 MHz, CDCl3): d = –0.14–0.08 (m, 1 H, c-Pr-H),
0.16–0.26 (m, 2 H, c-Pr-H), 0.69 (d, 3J = 6.7 Hz, 3 H, CH3), 0.78 (d,
3J = 6.7 Hz, 3 H, CH3), 0.85–1.03 (m, 1 H, c-Pr-H), 2.42 (sept, 3J =
6.7, 6.97 Hz, 1 H, CH), 3.82 (s, 3 H, OCH3), 5.64 (s, 1 H, CH), 7.21–
7.51 (m, 5 H, aryl-H).
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-3-phenyl-2-(1-phenylcy-
clopropyl)propionate (2a-Ph)
From 1-Cl (147 mg, 1.00 mmol), PhMgCl (2 M in THF, 0.5 mL,
1.00 mmol), and benzaldehyde (111 mg, 1.10 mmol), chromato-
graphic purification on silica gel (20 g, 1.5 × 15 cm, pentane–Et2O
(3:1), Rf 0.30] and subsequent crystallization from pentane–Et2O
gave the pure product 2a-Ph (139 mg, 42%) as colorless crystals;
mp 105–107 °C.
13C NMR (62.9 MHz, DEPT, CDCl3): d = 5.1 (–, c-Pr-C), 8.5 (–, c-
Pr-C), 20.9 (+, CH3), 21.2 (+, CH3), 26.1 (+, CH), 28.0 (Cquat, c-
PrC), 53.1 (+, OCH3), 75.1 (+, CH), 81.8 (Cquat, ClC), 127.5 (+, 2 ×
C, aryl-C), 128.3 (+, aryl-C), 128.7 (+, 2 × C, aryl-C), 138.3 (Cquat
ipso), 172.4 (Cquat, C=O).
,
IR (KBr): 3549, 1729, 1320, 1182, 700 cm–1.
C
1H NMR (250 MHz, CDCl3): d = 0.88–0.94 (m, 2 H, c-Pr-H), 1.08–
1.16 (m, 1 H, c-Pr-H), 1.48–1.54 (m, 1 H, c-Pr-H), 3.75 (s, 3 H,
OCH3), 4.30 (br s, 1 H, OH), 4.79 (br s, 1 H, OCH), 7.23–7.37 (m,
8 H, aryl-H), 7.62–7.66 (m, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 10.8 (–, c-Pr-C), 14.3
(–, c-Pr-C), 31.8 (Cquat, c-Pr-C), 53.2 (+, OCH3), 77.5 (+, OCH),
79.9 (Cquat, ClC), 127.5 (+, 2 × C, aryl-C), 127.6 (+, 2 × C, aryl-C),
127.7 (+, aryl-C), 128.1 (+, aryl-C), 128.7 (+, 2 × C, aryl-C), 132.4
(+, 2 × C, aryl-C), 138.8 (Cquat, Cipso), 140.4 (Cquat, Cipso), 171.0
(Cquat, C=O).
MS (DCI): m/z (%) = 610.6 (< 1) [2 × M + NH4]+, 314.3 (100) [M
+ NH4]+.
Anal. Calcd for C16H21ClO3 (296.8): C, 64.75; H, 7.13. Found: C,
64.97; H, 6.86.
(2S*,3R*)-Methyl 2-Chloro-2-(1-cyclohexylcyclopropyl)-3-hy-
droxy-3-phenylpropionate (2a-c-Hex)
From 1-Cl (147 mg, 1.00 mmol), c-HexMgBr (2 M in Et2O, 0.5 mL,
1.00 mmol), and benzaldehyde (111 mg, 1.05 mmol), chromato-
graphic purification on silica gel [30 g, 3 × 10 cm, pentane–Et2O
(3:1), Rf 0.13, p-anisaldehyde] yielded 2a-c-Hex (91 mg, 27%) as a
colorless oil.
MS (DCI): m/z (%) = 678.6 (3) [2 × M + NH4]+, 348.3 (100) [M +
NH4]+.
IR (film): 3521, 2928, 1718, 1453, 1263, 701 cm–1.
Anal. Calcd for C19H19ClO3 (330.8): C, 68.98; H, 5.79. Found: C,
69.00; H, 5.51.
1H NMR (250 MHz, CDCl3): d = –0.02–0.07 (m, 1 H, c-Pr-H),
0.18–0.32 (m, 2 H, c-Pr-H), 0.45–0.60 (m, 1 H, c-Hex-H), 0.92–
1.93 (m, 11 H, c-Hex-H, c-Pr-H), 3.14 (br s, 1 H, OH), 3.84 (s, 3 H,
OCH3), 5.62 (s, 1 H, OCH), 7.26–7.34 (m, 3 H, aryl-H), 7.40–7.44
(m, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 5.9 (–, c-Pr-C), 7.1 (–, c-
Pr-C), 26.1 (–, CH2, c-Hex), 26.8 (–, CH2, c-Hex), 27.1 (–, CH2, c-
Hex), 28.0 (Cquat, c-Pr-C), 31.3 (–, CH2, c-Hex), 32.1 (–, CH2, c-
Hex), 36.5 (+, CH, c-Hex), 53.0 (+, OCH3), 75.3 (+, OCH), 82.4
(Cquat, ClC), 127.5 (+, 2 × C, aryl-C), 128.2 (+, aryl-C), 128.6 (+,
2 × C, aryl-C), 138.4 (Cquat, Cipso), 172.1 (Cquat, C=O).
Methyl 2-Chloro-3-hydroxy-3-phenyl-2-(1-phenylcyclopro-
pyl)propionate (2a-Ph)
To a solution of PhMgCl (2 M in Et2O, 0.55 mL, 1.1 mmol), in THF
(10 mL) was added CuCN (99 mg, 1.1 mmol) at –78 °C, the solution
was stirred for 15 min, then BF3·Et2O (100 mg, 0.70 mmol) and
1-Cl (147 mg, 1.00 mmol) were added and the solution was stirred at
–78 °C for 1 h at which point benzaldehyde (148 mg, 1.4 mmol) was
added and stirring was continued for 12 h at 20 °C. Water (10 mL)
and Et2O (20 mL) were added, layers were separated and the aq lay-
er was extracted with Et2O (2 × 10 mL). Drying over Na2SO4, re-
moval of the solvent in the vacuum and chromatographic
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

PAPER
Michael-Aldol Reactions of Methyl 2-Chloro-2-cyclopropylideneacetate
475
3
3
purification of the residue on silica gel [20 g, 1.5 × 20 cm, pentane–
Et2O (5:1), Rf 0.45] yielded the syn-isomer (39 mg, 12%) as a col-
orless oil and anti-isomer (77 mg, 23%) [pentane–Et2O, (5:1), Rf
0.30] as a colorless oil.
H), 5.10 (d, J = 3.7 Hz, 1 H, vinyl-H), 5.42 (d, J = 5.5 Hz, 1 H,
CH), 6.48 (dd, 3J = 17.0 Hz, 2J = 10.1 Hz, 1 H, vinyl-H), 7.27–7.37
(m, 3 H, aryl-H), 7.42–7.51 (m, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 11.0 (–, c-Pr-C), 11.9
(–, c-Pr-C), 27.3 (Cquat, c-Pr-C), 53.0 (+, OCH3), 77.2 (+, CH), 78.6
(Cquat, ClC), 114.4 (–, vinyl-C), 127.5 (+, 2 × C, aryl-C), 128.2 (+,
aryl-C), 128.6 (+, 2 × C, aryl-C), 138.1 (Cquat, Cipso), 138.7 (+, vinyl-
C), 170.2 (–, C=O).
anti-Isomer
Same as described above for (2S*,3R*)-2a-Ph.
syn-Isomer
MS (DCI): m/z (%) = 578 (7) [2 × M + NH4]+, 315 (60) [M + NH3
IR (film): 3523, 2961, 1734, 1456, 1264, 1069, 1031, 703 cm–1.
+ NH4]+, 298 (100) [M + NH4]+.
1H NMR (250 MHz, CDCl3): d = 0.80–0.91 (m, 1 H, c-Pr-H), 1.05–
1.18 (m, 1 H, c-Pr-H), 1.52–1.61 (m, 1 H, c-Pr-H), 1.67–1.79 (m, 1
H, c-Pr-H), 2.56 (d, 3J = 5.7 Hz, 1 H, OH), 3.54 (s, 3 H, OCH3), 5.24
(d, 3J = 5.7 Hz, 1 H, CH), 7.24–7.36 (m, 6 H, aryl-H), 7.39–7.43 (m,
2 H, aryl-H), 7.48–7.55 (m, 2 H, aryl-H).
anti-Isomer
IR (film): 3523, 3089, 3032, 2953, 1718, 1454, 1266, 1069, 911,
701 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.14–0.23 (m, 1 H, c-Pr-H), 0.38–
0.56 (m, 2 H, c-Pr-H), 1.18–1.28 (m, 1 H, c-Pr-H), 3.68 (br s, 1 H,
OH), 3.87 (s, 3 H, CH3), 4.98 (d, 3J = 17.0 Hz, 1 H, vinyl-H), 5.10
(d, 3J = 6.5 Hz, 1 H, vinyl-H), 5.52 (s, 1 H, CH), 6.14 (dd, 3J = 16.3
Hz, 2J = 10.5 Hz, 1 H, vinyl-H), 7.27–7.37 (m, 3 H, aryl-H), 7.42–
7.56 (m, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 9.84 (–, c-Pr-C), 13.86
(–, c-Pr-C), 26.5 (Cquat, c-Pr-C), 53.4 (+, OCH3), 75.1 (+, CHC),
78.3 (Cquat, ClC), 114.8 (–, vinyl-C), 127.3 (+, 2 × C, aryl-C), 128.2
(+, aryl-C), 128.7 (+, 2 × C, aryl-C), 137.6 (+, vinyl-C), 137.7 (Cquat
ipso), 172.1 (–, C=O).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 9.91 (–, c-Pr-C), 12.7
(–, c-Pr-C), 32.4 (Cquat, c-Pr-C), 52.3 (+, OCH3), 74.9 (+, OCH3),
82.2 (Cquat, ClC), 115.2 (+, aryl-C), 120.6 (+, aryl-C), 127.7 (+, 2 ×
C, aryl-C), 128.2 (+, 2 × C, aryl-C), 128.2 (+, aryl-C), 128.7 (+, 2 ×
C, aryl-C), 129.6 (+, aryl-C), 131.9 (+, 2 × C, aryl-C), 139.3 (Cquat
Cipso), 141.4 (Cquat, Cipso), 168.6 (Cquat, C=O).
,
MS (DCI): m/z (%) = 678.2 (12) [2 × M + NH4]+, 348.1 (100) [M +
NH4]+.
,
(2S*,3R*)-Methyl 2-Chloro-2-[1-(4-fluorophenyl)cyclopropyl]-
3-hydroxy-3-phenylpropionate (2a-4-FC6H4)
C
MS (DCI): m/z (%) = 578 (27) [2 × M + NH4]+, 298 (100) [M +
From 1-Cl (147 mg, 1.0 mmol), 4-F-PhMgCl (1 M in THF, 0.5 mL,
1.0 mmol), and benzaldehyde (111 mg, 1.05 mmol), chromato-
graphic purification on silica gel [25 g, 1.5 × 20 cm, pentane–Et2O
(5:1), Rf = 0.52] and subsequent crystallization from pentane–Et2O
gave 2a-4-FC6H4 (136 mg, 39%) as a colorless solid; mp 125–127
°C.
NH4]+.
Anal. Calcd for C15H17ClO3 (280.8): C, 64.17; H, 6.17. Found: C,
64.27; H, 5.88.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(4-methoxyphenyl)propionate (2b-i-Pr)
IR (KBr): 3548, 1731, 1217, 701, 557 cm–1.
From 1-Cl (800 mg, 5.46 mmol), i-PrMgCl (2 M in Et2O, 3.00 mL,
6.00 mmol), and 4-methoxybenzaldehyde (818 mg, 6.00 mmol),
chromatographic purification on silica gel [30 g, 3 × 10 cm, pen-
tane–Et2O (3:1), Rf 0.13, p-anisaldehyde] yielded 2b-i-Pr (1.29 g,
72%) as a colorless oil, which crystallized spontaneously; mp 95
°C.
1H NMR (300 MHz, CDCl3): d = 0.86–0.96 (m, 2 H, c-Pr-H), 1.03–
1.13 (m, 1 H, c-Pr-H), 1.45–1.54 (m, 1 H, c-Pr-H), 3.74 (s, 3 H,
OCH3), 4.40 (br s, 1 H, OH), 4.66 (br s, 1 H, OCH), 6.97–7.05 (m,
2 H, aryl-H), 7.26–7.29 (m, 6 H, aryl-H), 7.61–7.67 (m, 1 H, aryl-
H).
13C NMR (75.5 MHz, APT, CDCl3): d = 11.1 (–, c-Pr-C), 14.8 (–,
c-Pr-C), 31.0 (–, c-Pr-C), 53.4 (+, OCH3), 77.9 (+, OCH), 79.8 (–,
ClC), 114.6 (+, d, 2JC–F = 21.1 Hz, aryl-C), 127.7 (+, 2 × C, aryl-C),
128.2 (+, aryl-C), 128.6 (+, 2 × C, aryl-C), 134.2 (+, d, 3JC–F = 8.3
Hz, aryl-C), 136.23 (–, d, 4JC–F = 3.0 Hz, aryl-C), 138.7 (–, aryl-C),
162.1 (–, d, 1JC–F = 247 Hz, aryl-CF), 170.8 (–, C=O).
IR (KBr): 3505, 2968, 2947, 2841, 1715, 1613, 1516, 1252, 1034,
835 cm–1.
1H NMR (250 MHz, CDCl3): d = –0.12–0.10 (m, 1 H, c-Pr-H),
0.11–0.35 (m, 2 H, c-Pr-H), 0.68 (d, 3J = 6.4 Hz, 3 H, CH3), 0.77 (d,
3J = 6.4 Hz, 3 H, CH3), 0.85–1.03 (m, 1 H, c-Pr-H), 2.40 (sept, 3J =
6.4 Hz, 1 H, CH), 3.81 (s, 6 H, 2 × OCH3), 3.84 (s, 1 H, OH), 5.59
(s, 1 H, CH), 6.85 (d, 3J = 8.8 Hz, 2 H, aryl-H), 7.35 (d, 3J = 8.8 Hz,
2 H, aryl-H).
MS (DCI): m/z (%) = 714.2 (23) [2 × M + NH4]+, 366.1 (100) [M +
NH4]+.
Anal. Calcd for C19H18ClFO3 (348.8): C, 65.43; H, 5.20. Found: C,
65.43; H, 5.04.
13C NMR (62.9 MHz, DEPT, CDCl3): d = 5.1 (–, c-Pr-C), 8.5 (–, c-
Pr-C), 20.9 (+, CH3), 21.2 (+, CH3), 26.1 (+, CH), 28.1 (Cquat, c-Pr-
C), 53.0 (+, OCH3), 55.2 (+, OCH3), 74.7 (+, CH), 82.0 (Cquat, ClC),
112.8 (+, 2 × C, aryl-C), 129.8 (+, 2 × C, aryl-C), 130.5 (Cquat, Cipso),
159.5 (Cquat, Cipso), 172.5 (Cquat, C=O).
Methyl 2-Chloro-3-hydroxy-2-(1-vinylcyclopropyl)-3-phenyl-
propionate (2a-Vin)
From vinylmagnesium bromide (1.25 M in Et2O, 1.12 mL, 1.4
mmol), CuCN (126 mg, 1.4 mmol), BF3·OEt2 (100 mg, 0.70 mmol),
1-Cl (147 mg, 1.00 mmol) and benzaldehyde (148 mg, 1.4 mmol)
chromatographic purification on silica gel [20 g, 1.5 × 20 cm, pen-
tane–Et2O (5:1), Rf 0.28] yielded syn-isomer (55 mg, 20%) and anti-
isomer (122 mg, 44%) (pentane–Et2O, 5:1, Rf 0.21) as colorless oils.
MS (DCI): m/z (%) = 670.3 (50) [2 × M + NH4]+, 344.2 (100) [M +
NH4]+.
Anal. Calcd for C17H23ClO4 (326.8): C, 62.48; H, 7.09. Found: C,
62.53; H, 6.80.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(1,3-benzodioxole-5-yl)propionate (2c-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and piperonal (158 mg, 1.05 mmol), chromatographic
purification on silica gel [20 g, 3 × 10 cm, pentane–Et2O (2:1), Rf
0.31, p-anisaldehyde) yielded 2c-i-Pr (264 mg, 78%) as a colorless
solid; mp 113–115 °C.
syn-Isomer
IR (film): 3523, 3086, 3031, 2951, 1734, 1453, 1386, 1264, 1031,
916, 701 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.51–0.60 (m, 1 H, c-Pr-H), 0.79–
0.98 (m, 2 H, c-Pr-H), 1.13–1.23 (m, 1 H, c-Pr-H), 3.05 (d, 3J = 5.50
Hz, 1 H, OH), 3.74 (s, 3 H, CH3), 5.04 (d, 3J = 10.0 Hz, 1 H, vinyl-
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

476
S. Dalai et al.
PAPER
IR (KBr): 3544, 2975, 2872, 1712, 1440, 1248, 1041, 929 cm–1.
MS (DCI): m/z (%) = 790 (45) [2 × M + NH4]+, 404 (100) [M +
NH4]+, 369 (90).
1H NMR (250 MHz, CDCl3): d = 0.04–0.18 (m, 1 H, c-Pr-H), 0.22–
0.36 (m, 2 H, c-Pr-H), 0.68 (d, 3J = 7.0 Hz, 3 H, CH3), 0.80 (d, 3J =
7.0 Hz, 3 H, CH3), 0.95–1.02 (m, 1 H, c-Pr-H), 2.41 (sept, 3J = 7.0
Hz, 1 H, i-Pr-H), 3.38 (d, 3J = 5.7 Hz, 1 H, OH), 3.84 (s, 3 H, CH3),
5.59 (d, 3J = 5.7 Hz, 1 H, CH), 5.98 (s, 2 H, CH2), 6.72–6.94 (m, 2
H, aryl-H), 7.02 (s, 1 H, aryl-H).
Anal. Calcd for C19H27ClO6 (386.9): C, 58.99; H, 7.03. Found: C,
59.21; H, 6.88.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(pentafluorophenyl)propionate (2f-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and pentafluorobenzaldehyde (206 mg, 1.05 mmol),
chromatographic purification on silica gel [20 g, 3 × 10 cm, pen-
tane–Et2O (3:1), Rf 0.50, p-anisaldehyde] yielded 2f-i-Pr (302 mg,
78%) as a colorless solid; mp 74 °C.
13C NMR (62.9 MHz, DEPT, CDCl3): d = 5.25 (–, c-Pr-C), 8.50
(–, c-Pr-C), 20.9 (+, i-Pr-C), 21.2 (+, i-Pr-C), 26.1 (+, i-Pr-C), 28.0
(Cquat, c-Pr-C), 53.1 (+, OCH3), 74.8 (+, CH), 81.8 (Cquat, ClC),
101.0 (–, CH2), 107.2 (+, aryl-C), 109.0 (+, aryl-C), 122.4 (+, aryl-
C), 132.2 (Cquat, aryl-C), 147.0 (Cquat, aryl-C), 147.4 (Cquat, aryl-C),
172.4 (Cquat, C=O).
IR (KBr): 3389, 3032, 2992, 2962, 2880, 1753, 1658, 1528, 1500,
1237, 999, 946 cm–1.
MS (70 eV): m/z (%) = 340 (1) [M]+, 151 (100), 93 (64), 65 (66).
1H NMR (300 MHz, CDCl3): d = 0.40–0.54 (m, 3 H, c-Pr-H), 0.67
(d, 3J = 7.0 Hz, 3 H, CH3), 0.78 (d, 3J = 7.0 Hz, 3 H, CH3), 1.00–
1.08 (m, 1 H, c-Pr-H), 2.28 (sept, 3J = 7.0 Hz, 1 H, i-Pr-H), 3.83 (s,
3 H, CH3), 4.07 (d, J = 5.6 Hz, 1 H, OH), 5.80 (d, 3J = 5.6 Hz, 1 H,
CH).
13C NMR (75.5 MHz, APT, CDCl3): d = 6.94 (–, c-Pr-C), 8.71 (–,
c-Pr-C), 21.1 (+, i-Pr-C), 21.5 (+, i-Pr-C), 26.6 (+, i-Pr-C), 29.5 (–,
c-Pr-C), 53.6 (+, OCH3), 70.1 (+, CH), 80.7 (–, ClC), 113.5 (–, m,
aryl-C), 135.8 (–, m, aryl-C), 139.1 (–, m, aryl-C), 142.8 (–, m, aryl-
C), 143.6 (–, m, aryl-C), 146.9 (–, m, aryl-C), 170.6 (–, C=O).
Anal. Calcd for C17H21ClO5 (340.8): C, 59.91; H, 6.21. Found: C,
60.27; H, 5.96.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(4-dimethylaminophenyl)propionate (2d-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and 4-dimethylaminobenzaldehyde (156 mg, 1.05
mmol), chromatographic purification on silica gel [20 g, 3 × 10 cm,
pentane–Et2O (1:1), Rf 0.40, p-anisaldehyde] yielded 2d-i-Pr (270
mg, 80%) as a colorless solid; mp 88 °C.
IR (KBr): 3529, 2974, 2953, 2796, 1716, 1617, 1525, 1344, 1271,
945, 821 cm–1.
MS (DCI): m/z (%) = 790 (10) [2 × M + NH4]+, 404 (100) [M +
NH4]+.
1H NMR (250 MHz, CDCl3): d = 0.03–0.14 (m, 1 H, c-Pr-H), 0.20–
0.31 (m, 2 H, c-Pr-H), 0.67 (d, 3J = 6.9 Hz, 3 H, CH3), 0.78 (d, 3J =
6.9 Hz, 3 H, CH3), 0.90–0.98 (m, 1 H, c-Pr-H), 2.38 (sept, 3J = 6.9
Hz, 1 H, i-Pr-H), 2.98 (s, 6 H, NMe2), 3.19 (d, 3J = 5.8 Hz, 1 H, OH),
3.82 (s, 3 H, CH3), 5.55 (d, 3J = 5.8 Hz, 1 H, CH), 6.63–6.72 (m, 2
H, aryl-H), 7.24–7.32 (m, 2 H, aryl-H).
13C NMR (75.5 MHz, APT, CDCl3): d = 5.36 (–, c-Pr-C), 8.61 (–,
c-Pr-C), 21.0 (+, i-Pr-C), 21.3 (+, i-Pr-C), 26.1 (+, i-Pr-C), 28.4 (–,
c-Pr-C), 40.5 (+, NCH3), 53.0 (+, OCH3), 75.1 (+, CH), 82.7 (–,
ClC), 111.5 (+, 2 × C, aryl-C), 126.2 (–, aryl-C), 129.3 (+, 2 × C,
aryl-C), 150.5 (–, aryl-C), 172.4 (–, C=O).
Anal. Calcd for C16H16ClF5O3 (386.7): C, 49.69; H, 4.17. Found: C,
49.81; H, 3.96.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(2-fluoro-4-nitrophenyl)propionate (2g-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and 2-fluoro-4-nitrobenzaldehyde (177 mg, 1.05
mmol), chromatographic purification on silica gel [20 g, 3 × 10 cm,
pentane–Et2O (3:1), Rf 0.45, p-anisaldehyde] yielded 2g-i-Pr (299
mg, 83%) as a colorless solid; mp 98 °C.
IR (KBr): 3530, 3199, 2999, 2978, 2878, 1717, 1616, 1539, 1357,
1242, 876, 801 cm–1.
MS (DCI): m/z (%): 679 (2) [2 × M + H]+, 340 (38) [M + H]+, 150
(100).
1H NMR (300 MHz, CDCl3): d = 0.11–0.20 (m, 1 H, c-Pr-H), 0.42–
0.54 (m, 2 H, c-Pr-H), 0.62 (d, 3J = 7.0 Hz, 3 H, CH3), 0.83 (d, 3J =
7.0 Hz, 3 H, CH3), 0.95–1.02 (m, 1 H, c-Pr-H), 2.25 (sept, 3J = 7.0
Hz, 1 H, i-Pr-H), 3.74 (s, 3 H, CH3), 4.35 (br s, 1 H, OH), 6.42 (s, 1
H, CH), 7.26–7.31 (m, 1 H, aryl-H), 7.58 (m, 1 H, aryl-H), 7.80 (m,
1 H, aryl-H).
Anal. Calcd for C18H26ClNO3 (339.9): C, 63.61; H, 7.71; N, 4.12.
Found: C, 63.91; H, 7.46; N, 4.21.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(3,4,5-trimethoxyphenyl)propionate (2e-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and 3,4,5-trimethoxybenzaldehyde (206 mg, 1.05
mmol), chromatographic purification on silica gel [20 g, 3 × 10 cm,
pentane–Et2O (1:2), Rf 0.50, p-anisaldehyde] yielded 2e-i-Pr (278
mg, 72%) as a colorless solid; mp 105 °C.
13C NMR (75.5 MHz, APT, CDCl3): d = 7.88 (–, c-Pr-C), 8.35 (–,
c-Pr-C), 21.2 (+, i-Pr-C), 21.3 (+, i-Pr-C), 26.5 (+, i-Pr-C), 29.4 (–,
c-Pr-C), 53.4 (+, OCH3), 68.9 (+, CH), 81.5 (–, ClC), 111.9 (+, d,
2JC–F = 26.4 Hz, aryl-C), 119.4 (+, d, 3JC–F = 20.4 Hz, aryl-C), 129.9
3
4
(–, d, JC-F = 3.8 Hz, aryl-C), 132.0 (+, d, JC-F = 7.5 Hz, aryl-C),
2
1
150.3 (–, d, JC–F = 15.1 Hz, aryl-C), 161.5 (–, d, JC–F = 252 Hz,
IR (KBr): 3533, 3026, 2951, 2916, 2882, 1722, 1593, 1506, 1462,
1266, 1122, 846 cm–1.
aryl-C), 171.6 (–, C=O).
MS (DCI): m/z (%) = 736 (56) [2 × M + NH4]+, 377 (100) [M +
1H NMR (300 MHz, CDCl3): d = 0.05–0.13 (m, 1 H, c-Pr-H), 0.18–
0.28 (m, 2 H, c-Pr-H), 0.67 (d, 3J = 7.0 Hz, 3 H, CH3), 0.77 (d, 3J =
7.0 Hz, 3 H, CH3), 0.89–0.97 (m, 1 H, c-Pr-H), 2.38 (sept, 3J = 7.0
Hz, 1 H, i-Pr-H), 3.32–3.42 (br s, 1 H, OH), 3.80 (s, 3 H, CH3), 3.82
(s, 9 H, CH3), 5.54 (s, 1 H, CH), 6.67 (s, 2 H, aryl-H).
13C NMR (75.5 MHz, APT, CDCl3): d = 5.38 (–, c-Pr-C), 8.49 (–,
c-Pr-C), 21.0 (+, i-Pr-C), 21.2 (+, i-Pr-C), 26.2 (+, i-Pr-C), 28.1 (–,
c-Pr-C), 53.1 (+, OCH3), 56.1 (+, 2 × C, OCH3), 60.9 (+, OCH3),
75.2 (+, CH), 81.7 (–, ClC), 106.2 (+, 2 × C, aryl-C), 133.9 (–, aryl-
C), 138.1 (–, aryl-C), 152.4 (–, aryl-C), 172.5 (–, C=O).
NH4]+.
Anal. Calcd for C16H19ClFNO5 (359.8): C, 53.41; H, 5.32; N, 3.89.
Found: C, 53.58; H, 5.11; N, 3.97.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(4-fluorophenyl)propionate (2h-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and 4-fluorobenzaldehyde (129 mg, 1.05 mmol), chro-
matographic purification on silica gel [20 g, 3 × 10 cm, pentane–
Et2O (3:1), Rf 0.35, p-anisaldehyde] yielded 2h-i-Pr (252 mg, 80%)
as a colorless solid; mp 78 °C.
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

PAPER
Michael-Aldol Reactions of Methyl 2-Chloro-2-cyclopropylideneacetate
477
IR (KBr): 3556, 3002, 2981, 2955, 2877, 1716, 1604, 1511, 1267,
1218, 840 cm–1.
Anal. Calcd for C10H17ClO3 (220.7): C, 54.42; H, 7.76. Found: C,
54.67; H, 5.51.
1H NMR (250 MHz, CDCl3): d = –0.13–0.04 (m, 1 H, c-Pr-H),
0.12–0.33 (m, 2 H, c-Pr-H), 0.67 (d, 3J = 7.0 Hz, 3 H, CH3), 0.79 (d,
3J = 7.0 Hz, 3 H, CH3), 0.86–1.00 (m, 1 H, c-Pr-H), 2.38 (sept, 3J =
7.0 Hz, 1 H, i-Pr-H), 3.43 (d, 3J = 5.6 Hz, 1 H, OH), 3.83 (s, 3 H,
CH3), 5.63 (d, J = 5.6 Hz, 1 H, CH), 6.97–7.08 (m, 2 H, aryl-H),
7.37–7.46 (m, 2 H, aryl-H).
13C NMR (50.3 MHz, APT, CDCl3): d = 5.09 (–, c-Pr-C), 8.51 (–,
c-Pr-C), 20.9 (+, i-Pr-C), 21.2 (+, i-Pr-C), 26.1 (+, i-Pr-C), 28.0 (–,
c-Pr-C), 53.1 (+, OCH3), 74.4 (+, CH), 81.5 (Cquat, ClC), 114.4 (+,
d, 2JC–F = 21.6 Hz, 2 × C, aryl-C), 130.4 (+, d, 3JC–F = 8.0 Hz, 2 × C,
aryl-C), 134.1 (–, d, 4JC–F = 3.0 Hz, aryl-C), 162.7 (–, d, 1JC–F = 247
Hz, aryl-C), 172.6 (–, C=O).
(2S*,3R*)-2-Chloro-3-hydroxy-2-(1-isopropylcyclopropyl)suc-
cinic Acid 4-Ethyl Ester 1-Methyl Ester (2k-i-Pr)
From 1-Cl (147.0 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50
mL, 1.00 mmol), and ethylglyoxylate (224 mg, 50% solution in tol-
uene, 1.1 mmol), chromatographic purification on silica gel [20 g,
1.5 × 15 cm, pentane–Et2O (5:1), Rf 0.35] yielded 2i-i-Pr (211 mg,
72%) as a colorless oil.
3
IR (film): 3496, 2968, 1734, 1436, 1268, 1121, 1029, 763 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.39–0.46 (m, 1 H, c-Pr-H), 0.65–
0.74 (m, 1 H, c-Pr-H), 0.76 (d, 3J = 6.8 Hz, 3 H, CH3), 0.85 (d, 3J =
6.8 Hz, 3 H, CH3), 1.01–1.09 (m, 2 H, CH2), 1.27 (t, 3J = 7.0 Hz, 3
H, CH3), 2.39 (sept, 3J = 6.8 Hz, 1 H, i-Pr-H), 3.20 (d, 3J = 6.8 Hz,
1 H, OH), 3.81 (s, 3 H, OCH3), 4.15–4.32 (m, 2 H, CH2), 5.03 (d,
3J = 6.8 Hz, 1 H, CH).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 6.31 (–, c-Pr-C), 9.73
(–, c-Pr-C), 13.9 (+, CH3), 21.1 (+, CH, i-Pr-C), 21.7 (Cquat, c-Pr-C),
26.6 (+, CH), 30.2 (Cquat, c-Pr-C), 53.0 (+, OCH3), 62.7 (–, CH2),
MS (DCI): m/z (%) = 332 (62) [M + NH4]+, 296 (100) [M – H2O]+.
Anal. Calcd for C16H20ClFO3 (314.8): C, 61.05; H, 6.40. Found: C,
61.30; H, 6.21.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)-3-(4-nitrophenyl)propionate (2i-i-Pr)
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.50 mL,
1.00 mmol), and 4-nitrobenzaldehyde (159 mg, 1.05 mmol), chro-
matographic purification on silica gel [20 g, 3 × 10 cm, pentane–
Et2O (2:1), Rf 0.35, p-anisaldehyde] yielded 2i-i-Pr (250 mg, 73%)
as a colorless solid; mp 138 °C.
74.4 (+, CH), 80.3 (Cquat, ClC), 169.2 (Cquat, C=O), 171.2 (Cquat
C=O).
,
MS (DCI): m/z (%) = 602.6 (1) [2 × M + NH4]+, 310.3 (100) [M +
NH4]+.
Anal. Calcd for C13H21ClO5 (292.8): C, 53.34; H, 7.23. Found: C,
53.54; H, 7.11.
IR (KBr): 3580, 2972, 2950, 2877, 1729, 1515, 1346, 1250, 1078,
855 cm–1.
(2S*,3R*)-Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopro-
pyl)hexanoate (2l-i-Pr)
From 1-Cl (147.0 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.5 mL,
1.0 mmol), butyraldehyde (260 mg, 5 mmol), chromatografic puri-
fication on silica gel [20 g, 1.5 × 15 cm, pentane–Et2O (5:1), Rf 0.35]
yielded 2l-i-Pr (85mg, 32%) as a colorless oil.
1H NMR (250 MHz, CDCl3): d = –0.18–0.02 (m, 1 H, c-Pr-H),
0.16–0.39 (m, 2 H, c-Pr-H), 0.67 (d, 3J = 7.0 Hz, 3 H, CH3), 0.82 (d,
3J = 7.0 Hz, 3 H, CH3), 0.95–1.00 (m, 1 H, c-Pr-H), 2.46 (sept, 3J =
7.0 Hz, 1 H, i-Pr-H), 3.67 (d, 3J = 5.7 Hz, 1 H, OH), 3.85 (s, 3 H,
CH3), 5.78 (d, 3J = 5.7 Hz, 1 H, CH), 7.61 (m, 2 H, aryl-H), 8.19 (m,
2 H, aryl-H).
IR (film): 3530, 2962, 2873, 1717, 1467, 1260, 1123, 1079, 1033,
1013 cm–1.
13C NMR (62.9 MHz, DEPT, CDCl3): d = 5.08 (–, c-Pr-C), 8.66
(–, c-Pr-C), 20.8 (+, i-Pr-C), 21.2 (+, i-Pr-C), 26.2 (+, i-Pr-C), 27.8
(Cquat, c-Pr-C), 53.3 (+, OCH3), 74.1 (+, CH), 80.5 (Cquat, ClC),
122.5 (+, 2 × C, aryl-C), 129.8 (+, 2 × C, aryl-C), 145.4 (Cquat, aryl-
C), 147.7 (Cquat, aryl-C), 172.4 (Cquat, C=O).
MS (DCI): m/z (%) = 359 (5) [M + NH4]+, 210 (32), 208 (100), 139
(93).
1H NMR (250 MHz, CDCl3): d = 0.42–0.66 (m, 2 H, c-Pr-H), 0.75
(d, 3J = 3.6 Hz, 3 H, CH3), 0.79 (d, 3J = 3.6 Hz, 3 H, CH3), 0.87–
1.11 (m, 5 H), 1.38–1.56 (m, 2 H, CH2), 1.61–1.77 (m, 2 H, CH2),
2.12 (sept, 3J = 6.8 Hz, 1 H, i-Pr-H), 3.80 (s, 3 H, OCH3), 4.38–4.46
(m, 1 H, CH).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 7.16 (–, c-Pr-C), 8.13
(–, c-Pr-C), 14.1 (+, CH3), 19.0 (–, CH2), 21.2 (+, CH3), 21.4 (+,
CH3), 26.6 (+, CH, i-Pr), 28.0 (Cquat, c-Pr-C), 33.3 (–, CH2), 52.9 (+,
OCH3), 73.0 (+, CH), 81.8 (Cquat, ClC), 172.5 (Cquat, C=O).
Anal. Calcd for C16H20ClNO5 (341.8): C, 56.23; H, 5.90; N, 4.10.
Found: C, 56.38; H, 5.80; N, 4.00.
Methyl 2-Chloro-3-hydroxy-2-(1-isopropylcyclopropyl)propi-
onate (2j-i-Pr)
MS (DCI): m/z (%) = 280.3 (100) [M + NH4]+.
From 1-Cl (147 mg, 1.00 mmol), i-PrMgCl (2 M in Et2O, 0.5 mL,
1.0 mmol), paraformaldehyde (150 mg, 5 mmol of monomer) after
15 h, chromatographic purification on silica gel [20 g, 1.5 × 15 cm,
pentane–Et2O (3:1), Rf 0.35] yielded 2j-i-Pr (13 mg, 61%) as a col-
orless oil.
Anal. Calcd for C13H23ClO3 (262.8): C, 59.42; H, 8.82. Found: C,
59.34; H, 8.54.
Methyl Chloro(1-isopropylcyclopropyl)acetate (5-i-Pr)
From 1-Cl (294 mg, 2.0 mmol), i-PrMgCl (2 M in Et2O, 1.1 mL, 2.2
mmol) and aq sat. NH4Cl, chromatographic purification on silica
gel [20 g, 1.5 × 10 cm, pentane–Et2O (5:1), Rf 0.80] yielded 5-i-Pr
(373 mg, 98%) as a colorless oil.
IR (film): 3464, 2961, 2875, 1733, 1436, 1266, 1077, 1031, 733
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.48–0.61 (m, 2 H, c-Pr-H), 0.78
(d, 3J = 2.1 Hz, 3 H, CH3), 0.81 (d, 3J = 2.1 Hz, 3 H, CH3), 0.85–
0.93 (m, 2 H, c-Pr-H), 2.08 (sept, 3J = 6.8 Hz, 1 H, i-Pr-H), 2.37 (br
s, 1 H, OH), 3.71 (d, 3J = 12.3 Hz, 1 H, CH2), 3.81 (s, 3 H, CH3),
4.19 (d, 3J = 12.3 Hz, 1 H, CH2).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 7.76 (–, c-Pr-C), 8.33
(–, c-Pr-C), 21.2 (+, i-Pr-C), 27.8 (+, i-Pr-C), 29.1 (Cquat, c-Pr-C),
53.0 (+, OCH3), 67.3 (–, CH2), 80.6 (Cquat, ClC), 170.8 (–, C=O).
IR (film): 3085, 2960, 2875, 1758, 1434, 1168, 1015, 772 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.56–0.61 (m, 4 H, c-Pr-H), 0.85–
0.94 (m, 6 H, 2 × CH3), 1.64–1.72 (m, 1 H, CH), 3.73 (s, 3 H,
OCH3), 4.38 (s, 1 H, CH).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 10.4 (–, c-Pr-C), 11.9
(–, c-Pr-C), 19.5 (+, i-Pr-C), 20.0 (+, i-Pr-C), 28.1 (Cquat, c-Pr-C),
31.3 (+, i-Pr-C), 52.6 (+, CCl), 62.7 (+, OCH3), 169.3 (Cquat, C=O).
MS (DCI): m/z (%) = 458 (1) [2 × M+ NH4]+, 255 (13) [M+ NH3 +
MS (DCI): m/z (%): 225.3 (50) [M + NH3 + NH4]+, 208.2 (100) [M
NH4]+, 238 (100) [M + NH4]+.
+ NH4]+.
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

478
S. Dalai et al.
PAPER
Methyl Chloro(1-vinylcyclopropyl)acetate (5-Vin)
0.94 (m, 1 H, c-Pr-H), 2.42 (sept, 3J = 6.9 Hz, 1 H, CH), 3.78 (s, 3
H, OCH3), 4.31 (s, 1 H), 7.28–7.40 (m, 5 H, aryl-H).
13C NMR (75.5 MHz, APT, CDCl3): d = 7.7 (–, c-Pr-C), 9.3 (–, c-
Pr-C), 19.9 (+, CH3), 20.0 (+, CH3), 22.7 (–, c-Pr-C), 30.1 (+, CH),
52.5 (+, OCH3), 63.6 (+, CH), 66.6 (–, CO), 127.2 (+, 2 × C, aryl-
C), 127.9 (+, 2 × C, aryl-C), 128.0 (+, aryl-C), 134.3 (–, Cipso), 171.1
(–, C=O).
To a solution of vinylmagnesium bromide (4.78 mL, 9.56 mmol, 2
M) in THF (40 mL) was added CuCN (855 mg, 9.55 mmol) at –78
°C. The mixture was stirred for 15 min, then BF3·OEt2 (600 mL, 4.78
mmol) and 1-Cl (1.00 g, 6.82 mmol) were added, and the mixture
was stirred at –78 °C for 3 h. H2O (20 mL) was added at this tem-
perature and the mixture was allowed to warm to 20 °C. Extraction
of the aq phase with Et2O (3 × 30 mL), drying over Na2SO4, removal
of the solvent in vacuo and chromatographic purification of the res-
idue on silica gel [20 g, 1.5 × 20 cm, pentane–Et2O (100:1), Rf 0.42
(pentane–Et2O, 10:1)] yielded 5-Vin (957 mg, 80%) as a colorless
oil.
MS (DCI): m/z (%) = 538.5 (< 1) [2 × M + NH4]+, 278.2 (100) [M
+ NH4]+.
Anal. Calcd for C16H20O3 (260.3): C, 73.82; H, 7.74. Found: C,
73.69; H, 7.39.
IR (film): 3087, 3010, 2955, 1756 (C=O), 1699, 1653, 1641, 1436,
1289, 1195, 1168, 1014, 908, 808, 668 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.85–1.13 (m, 4 H, c-Pr-H), 3.78
(s, 3 H, OCH3), 4.01 (s, 1 H, CH), 5.02 (dd, 3J = 17.3 Hz, 2J = 0.7
Hz, 1 H, vinyl-H), 5.06 (dd, 3J = 10.6 Hz, 2J = 0.7 Hz, 1 H, vinyl-
H), 6.05 (dd, 3J = 17.3 Hz, 3J = 10.6 Hz, 1 H, vinyl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 14.8 (–, c-Pr-C), 15.1
(–, c-Pr-C), 26.3 (Cquat, c-Pr-C), 52.6 (+, CHCl), 64.3 (+, OCH3),
114.0 (–, vinyl-C), 136.8 (+, vinyl-C), 168.5 (Cquat, C=O).
Acknowledgment
This work was supported by the State of Niedersachsen and the
Fonds der Chemischen Industrie. We are grateful to Celanese AG
for a generous gift of chemicals. M.L. is indebted to the German Na-
tional Merit Foundation (Studienstiftung des deutschen Volkes) for
a student (2000–2002) as well as a doctoral fellowship (2002–2004)
and L.Z. is grateful to the Alexander von Humboldt foundation for
a Research Fellowship. The authors thank Dr. B. Knieriem, Göttin-
gen, for his careful proofreading of the final manuscript.
MS (70 eV): m/z (%) = 174 (< 1) [M]+, 173 (1) [M – H]+, 139 (100)
[M – Cl]+, 107 (12), 79 (35), 67 (10), 59 (8).
Anal. Calcd for C8H11ClO2 (174.6): C, 55.02; H, 6.35; Cl, 20.30.
Found: C, 55.09; H, 6.31; Cl, 20.24.
References
(1) (a) Part 119 in the series ‘Cyclopropyl Building Blocks for
Organic Synthesis’. (b) For part 118 see: Yucel, B.; Arve,
L.; de Meijere, A. Tetrahedron 2005, 61, 11355. (c) Part
117: Bräse, A.; Nüske, H.; Frank, D.; de Meijere, A. Eur. J.
Org. Chem. 2005, 4167.
(2) (a) Liese, T.; Splettstösser, G.; de Meijere, A. Angew.
Chem., Int. Ed. Engl. 1982, 21, 790; Angew. Chem. 1982, 94,
799. (b) Liese, T.; Seyed-Mahdavi, F.; de Meijere, A. Org.
Synth. 1990, 69, 148. (c) For an advanced synthesis of 1-Br
and 1-Cl see: Limbach, M.; Dalai, S.; de Meijere, A. Adv.
Synth. Catal. 2004, 346, 760.
(2R*,3R*)-Methyl 2-(1-Isopropylcyclopropyl)-3-(4-methoxy-
phenyloxiranyl)-2-carboxylate (6b-i-Pr)
To a solution of 2b-i-Pr (222 mg, 679 mmol) in THF (20 mL) was
added t-BuOK (80 mg, 713 mmol) at 20 °C, and the suspension was
stirred at this temperature for 3 h. Removal of all volatiles in vacuo
and chromatographic purification of the residue on silica gel [20 g,
3 × 20 cm, pentane–Et2O (3:1), Rf 0.75, MOPS] yielded 6b-i-Pr
(122 mg, 62%) as a colorless oil.
IR (film): 2957, 2874, 2837, 1734, 1614, 1516, 1436, 1251, 1038,
831 cm–1.
(3) For reviews see: (a) de Meijere, A. Bull. Soc. Chim. Belg.
1984, 93, 241. (b) de Meijere, A.; Wessjohann, L. Synlett
1990, 20. (c) de Meijere, A. In New Aspects of Organic
Chemistry II, Proceedings of the Fifth International Kyoto
Conference on New Aspects of Organic Chemistry (IKCOC
5, Kyoto, Nov. 11–15, 1991); Oshiro, Y., Ed.; Kodansha:
Tokyo, 1992, 181. (d) de Meijere, A.; Kozhushkov, S. I.;
Hadjiarapoglou, L. Top. Curr. Chem. 1999, 207, 149.
(4) (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
Rev. 2003, 103, 1213. (b) Nakamura, I.; Yamamoto, Y. Adv.
Synth. Catal. 2002, 344, 111.
1H NMR (250 MHz, CDCl3): d = 0.21–0.50 (m, 3 H, c-Pr-H), 0.58
(d, 3J = 7.0 Hz, 3 H, CH3), 0.81 (d, 3J = 7.0 Hz, 3 H, CH3), 0.85–
1.03 (m, 1 H, c-Pr-H), 2.65 (sept, 3J = 7.0, Hz, 1 H, i-Pr), 3.79 (s, 3
H, OCH3), 3.81 (s, 3 H, OCH3), 4.24 (s, 1 H, CH), 6.84 (d, 3J = 8.8
Hz, 2 H, aryl-H), 7.28 (d, 3J = 8.8 Hz, 2 H, aryl-H).
13C NMR (62.9 MHz, DEPT, CDCl3): d = 7.7 (–, c-Pr-C), 9.3 (–, c-
Pr-C), 19.9 (+, CH3, 2 × C), 22.5 (Cquat, c-Pr-C), 30.1 (+, CH), 52.4
(+, OCH3), 55.2 (+, OCH3), 63.4 (+, CH), 66.4 (Cquat, CO), 113.4 (+,
2 × C, aryl-C), 126.1 (Cquat, Cipso), 128.3 (+, 2 × C, aryl-C), 159.3
(Cquat, Cipso), 171.1 (Cquat, C=O).
(5) (a) Liese, T.; Teichmann, S.; de Meijere, A. Synthesis 1988,
25. (b) Seyed-Mahdavi, F.; Teichmann, S.; de Meijere, A.
Tetrahedron Lett. 1986, 27, 6185.
(6) (a) Spitzner, D.; Engler, A.; Liese, T.; Splettstößer, G.; de
Meijere, A. Angew. Chem., Int. Ed. Engl. 1982, 21, 791;
Angew. Chem. 1982, 94, 799. (b) Spitzner, D.; Engler, A.;
Wagner, P.; de Meijere, A.; Bengtson, G.; Simon, A.; Peters,
K.; Peters, E.-M. Tetrahedron 1987, 43, 3213.
MS (DCI): m/z (%) = 598.7 (1) [2 × M + NH4]+, 308.3 (100) [M +
NH4]+, 291.3 (46) [M + H]+.
Anal. Calcd for C17H22O4 (290.4): C, 70.32; H, 7.64. Found: C,
70.23; H, 7.35.
(2R*,3R*)-Methyl 2-(1-Isopropylcyclopropyl)-3-(phenyloxira-
nyl)-2-carboxylate (6a-i-Pr)
According to general procedure from 1-Br (191.0 mg, 1.00 mmol),
i-PrMgCl (2 M in Et2O, 0.50 mL, 1.00 mmol), and benzaldehyde
(111 mg, 1.05 mmol), chromatographic purification on silica gel
[20 g, 1.5 × 15 cm, pentane–Et2O (10:1), Rf 0.50, MOPS] yielded
6a-i-Pr (249 mg, 96%) as a colorless oil.
(c) Hadjiarapoglou, L.; Klein, I.; Spitzner, D.; de Meijere, A.
Synthesis 1996, 525. (d) de Meijere, A.; Teichmann, S.;
Seyed-Mahdavi, F.; Kohlstruk, S. Liebigs Ann. 1996, 1989.
(e) Wessjohann, L.; Giller, K.; Zuck, B.; Skattebøl, L.; de
Meijere, A. J. Org. Chem. 1993, 58, 6442.
(f) Hadjiarapoglou, L.; de Meijere, A.; Seitz, H.-J.; Klein, I.;
Spitzner, D. Tetrahedron Lett. 1994, 35, 3269. (g) de
Meijere, A.; Hadjiarapoglou, L. P.; Noltemeyer, M.; Gutke,
H.-J.; Klein, I.; Spitzner, D. Eur. J. Org. Chem. 1998, 441.
IR (film): 2959, 2875, 1738, 1453, 1268, 1038, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.24–0.41 (m, 3 H, c-Pr-H), 0.47
(d, 3J = 6.9 Hz, 3 H, CH3), 0.78 (d, 3J = 6.9 Hz, 3 H, CH3), 0.84–
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York

PAPER
Michael-Aldol Reactions of Methyl 2-Chloro-2-cyclopropylideneacetate
479
(7) (a) de Meijere, A.; Teichmann, S.; Yu, D.; Kopf, J.; Oly, M.;
(13) Recent examples: (a) Hara, O.; Sugimoto, K.; Makino, K.;
Hamada, Y. Synlett 2004, 1625. (b) Rao, H. S. P.;
Senthilkumar, S. P. J. Org. Chem. 2004, 69, 2591.
(c) Makino, K.; Hara, O.; Takiguchi, Y.; Katano, T.;
Asakawa, Y.; Hatano, K.; Hamada, Y. Tetrahedron Lett.
2003, 44, 8925. (d) Huang, X.; Xiong, Z.-C. Chem.
Commun. 2003, 14, 1714. (e) Yamamoto, Y.; Momiyama,
N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962.
(14) Recent examples: (a) Paulsen, H.; Antons, S.; Brandes, A.;
Lögers, M.; Müller, S. N.; Naab, P.; Schmeck, C.; Schneider,
S.; Stoltefuß, J. Angew. Chem. Int. Ed. 1999, 38, 3373;
Angew. Chem. 1999, 111, 3574. (b) Schneider, C.; Reese,
O. Angew. Chem. Int. Ed. 2000, 39, 2948; Angew. Chem.
2000, 112, 3074. (c) Kamimura, A.; Mitsudera, H.; Omata,
Y.; Matsuura, K.; Shirai, M.; Kakehi, A. Tetrahedron 2002,
58, 9817. (d) Huang, X.; Xie, M. H. Org. Lett. 2002, 4,
1331. (e) Huang, X.; Xie, M. H. J. Org. Chem. 2002, 67,
8895. (f) Arai, T.; Sasai, H.; Aoe, K.-I.; Okamura, K.; Date,
T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
104; Angew. Chem. 1996, 108, 103. (g) Halland, N.;
Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2004,
43, 1272; Angew. Chem. 2004, 116, 1292.
(15) (a) Satoh, T.; Kitoh, Y.; Onda, K.-I.; Takana, K.;
Yamakawa, K. Tetrahedron 1994, 50, 4957. (b) Evans, D.
A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392.
(16) (a) Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319. (b) Thibonnet, J.; Vu, V. A.; Berillon, L.; Knochel, P.
Tetrahedron 2002, 58, 4787.
(17) Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited as
supplementary publication no. CCDC-268832 with the
Cambridge Crystallographic Data Centre. Copies of the data
can be obtained free of charge on application to The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: +44 (1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
(18) Chandrasekhar, S.; Narsihmulu, C.; Reddy, M. R.; Reddy,
M. S. Tetrahedron Lett. 2003, 44, 2583.
von Thienen, N. Tetrahedron 1989, 45, 2957.
(b) Wessjohann, L.; Skattebøl, L.; de Meijere, A. J. Chem.
Soc., Chem. Commun. 1990, 574. (c) Giller, K.; Baird, M.
S.; de Meijere, A. Synlett 1992, 524. (d) Es-Sayed, M.;
Heiner, T.; de Meijere, A. Synlett 1993, 57. (e) Zorn, C.;
Goti, A.; Brandi, A.; Johnsen, K.; Kozhushkov, S. I.; de
Meijere, A. Chem. Commun. 1998, 903. (f) Nötzel, M. W.;
Tamm, M.; Labahn, T.; Noltemeyer, M.; Es-Sayed, M.; de
Meijere, A. J. Org. Chem. 2000, 65, 3850. (g) Nötzel, M.
W.; Labahn, T.; Es-Sayed, M.; de Meijere, A. Eur. J. Org.
Chem. 2001, 3025. (h) Nötzel, M. W.; Rauch, K.; Labahn,
T.; de Meijere, A. Org. Lett. 2002, 4, 839. (i) Zorn, C.;
Goti, A.; Brandi, A.; Johnsen, K.; Noltemeyer, M.;
Kozhushkov, S. I.; de Meijere, A. J. Org. Chem. 1999, 64,
755.
(8) (a) Wessjohann, L.; McGaffin, G.; de Meijere, A. Synthesis
1989, 359. (b) Wessjohann, L.; Krass, N.; Yu, D.; de
Meijere, A. Chem. Ber. 1992, 125, 867. (c) Es-Sayed, M.;
Gratkowski, C.; Krass, N.; Meyers, A. I.; de Meijere, A.
Synlett 1992, 962. (d) Es-Sayed, M.; G ratkowski, C.; Krass,
N.; Meyers, A. I.; de Meijere, A. Tetrahedron Lett. 1993, 34,
289. (e) Tamm, M.; Thutewohl, M.; Ricker, C. B.; Bes, M.
T.; de Meijere, A. Eur. J. Org. Chem. 1999, 2017.
(9) (a) Belov, V. N.; Funke, C.; Labahn, T.; Es-Sayed, M.; de
Meijere, A. Eur. J. Org. Chem. 1999, 1345. (b) Funke, C.;
Es-Sayed, M.; de Meijere, A. Org. Lett. 2000, 2, 4249.
(c) Limbach, M.; Dalai, S.; Janssen, A.; Es-Sayed, M.;
Magull, J.; de Meijere, A. Eur. J. Org. Chem. 2005, 610.
(10) Reviews see: (a) Gawley, R. E. Synthesis 1976, 777.
(b) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res.
2004, 37, 580.
(11) (a) Posner, G. H. Chem. Rev. 1986, 86, 831. (b) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131;
Angew. Chem. 1993, 105, 137. (c) Tietze, L. F. Chem. Rev.
1996, 96, 115.
(12) Recent examples: (a) Barrett, A. G. M.; Kamimura, A. J.
Chem. Soc., Chem. Commun. 1995, 17, 1755. (b) Tsukada,
N.; Nishimura, T. K.; Tsubouchi, H.; Ono, M.; Hayama, T.;
Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 2003, 44,
2323. (c) Tsukada, N.; Shimida, T.; Gyoung, Y. S.; Asao,
N.; Yamamoto, Y. J. Org. Chem. 1995, 60, 143.
(19) Sokolov, V.V.; Es-Sayed, M.; De Meijere, A. unpublished
results.
Synthesis 2006, No. 3, 471–479 © Thieme Stuttgart · New York