Thermal and hyperbaric addition of N,N- and N,O-binucleophiles on cycloalkylidenic bromo esters

Article abstract of DOI:10.1002/poc.493

The thermal and high-pressure (11 kbar) induced reaction between 2-bromo-2-(cycloalkylidene)acetates and N,O- and N,N-binucleophiles (such as ethylenediamines or aminoethanols) provides morpholin-2-ones and piperazin-2-ones. Thus, in contrast to simple primary amines, binucleophiles do not form spirocyclic derivatives. The expected Michael addition competes with a cascade reaction consisting of a migration of the double bond followed by the substitution of the newly established allylic halogen and a lactonization (lactamization), and eventually ended by a back-migration of the double bond. Copyright

Full text of DOI:10.1002/poc.493

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2002; 15: 590–598
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.493
Thermal and hyperbaric addition of N,N- and N,O-
binucleophiles on cycloalkylidenic bromo esters†
Alexandre Y. Rulev‡ and and Jacques Maddaluno*
Laboratoire des Fonctions Azote es et Oxyge ne es Complexes de I'IRCOF, UMR 6014 CNRS, Universite de Rouen, 76821 Mont St Aignan
Cedex, France
Received 16 November 2001; revised 30 January 2002; accepted 6 February 2002
ABSTRACT: The thermal and high-pressure (11 kbar) induced reaction between 2-bromo-2-(cycloalkylidene)ace-
tates and N,O- and N,N-binucleophiles (such as ethylenediamines or aminoethanols) provides morpholin-2-ones and
piperazin-2-ones. Thus, in contrast to simple primary amines, binucleophiles do not form spirocyclic derivatives. The
expected Michael addition competes with a cascade reaction consisting of a migration of the double bond followed by
the substitution of the newly established allylic halogen and a lactonization (lactamization), and eventually ended by a
back-migration of the double bond. Copyright  2002 John Wiley & Sons, Ltd.
KEYWORDS: high pressure; hetero-Michael addition; cascade reaction; migration
INTRODUCTION
biologically important heterocycles and natural analogs
of interest owing to their multifunctional reactivity.4 The
hetero-Michael addition provides efficiently and with
good diastereoselectivities the corresponding b-amino
esters, which are good templates for pseudo-peptide
chemistry, for instance.5 Interestingly, the presence of a
leaving group at the a-position of the ester triggers a
direct spiroaziridination.6 The possibilities opened up by
this reaction for the construction of other spirohetero-
cycles prompted us to investigate the use of binucleo-
philes.7 In principle, these can undergo a conjugated
addition of their amino group, leading to an intermediate
a-halo-b-amino ester that could cyclize through an
intramolecular nucleophilic substitution (Fig. 1).
The activation of organic reactions relies most of the time
on two very general methods, heat and catalysis, and,
occasionally, photochemistry. Ultrasound, microwaves
or high pressure (the so-called ‘extreme’ conditions) can
also, in special circumstances, offer a helpful alternative
to the classical techniques.1 The latter is particularly well
suited to cases where bulky or fragile reagents/products
are needed and can therefore become helpful in solving
problems encountered along complex synthetic path-
ways.2
In this context, we have recently been interested in the
applications of the high pressure-promoted hetero-
Michael addition of amines to tri- or tetrasubstituted
electron-deficient olefins. The effect of high pressure on
the (hetero) Michael addition is very well known and has
long been exploited. The large negative activation
volume value associated with these reactions leads not
only to their spectacular acceleration but also to a
dramatic increase in their regio- and stereoselectivities.3
a-Halo-a,b-unsaturated carbonyl compounds are good
substrates for these reactions and, as such, constitute a
class of simple building blocks in the synthesis of
In such a strategy, primary amines can become
troublesome since they are likely to add and then
*Correspondence to: J. Maddaluno, Laboratoire des Fonctions
Azote´es et Oxyge´ne´es Complexes de I’IRCOF, UMR 6014 CNRS,
Universite´ de Rouen, 76821 Mont St Aignan Cedex, France.
E-mail: jmaddalu@crihan.fr
†Presented at the 8th European Symposium on Organic Reactivity
(ESOR-8), Cavtat (Dubrovnik), Croatia, September 2001.
‡Current address: Favorsky Institute of Chemistry, Siberian Branch of
the Russian Academy of Sciences, 1 Favorsky St., 664033 Irkutsk,
Russia.
Contract/grant sponsor: Conseil Re´gional de Haute-Normandie.
Figure 1
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

THERMAL AND HYPERBARIC ADDITION OF BINUCLEOPHILES
591
product is probably formed in a sequence of reactions in
which the double bond first deconjugates to an endo-
cyclic position, yielding an allylic bromine, rapidly
substituted by the amine; the second amino group would
then convert the ester intramolecularly into a lactam. The
back-migration of the double bond into its original
exocyclic position leads to a secondary enamine,
tautomer of the cyclic imine (4). Under 11 kbar, in the
same solvent but at room temperature and after 3.5 days,
the same piperazinone (3a) is obtained in a better yield of
52% (entry 2), without any isomerization into 4. Thus,
the final migration of the double bond appears to be
favored by a temperature increase or to be slowed by
pressure. We next decided to examine the case of a
primary/secondary diamine, resorting to N-methylethy-
lenediamine (2b). The corresponding regioisomeric
piperazinones (3b,c) were obtained in higher yields,
under both thermal and hyperbaric conditions (entries 3
and 4). The selectivity of the addition was relatively high
(>85%) and, expectedly, in favor of a quicker substitu-
tion of the allylic bromine by the secondary (more
nucleophilic) amine. We finally moved to N,N'-dimethyl-
ethylenediamine (2c). At reflux of ethanol the same
sequence of reactions takes place, providing 3d in fair
yield (entry 5). Similarly, the reaction between 2c and the
corresponding six-membered ring substrate methyl
cyclohexylidenebromoacetate (1b) gave, in methanol,
the N,N-dimethylpiperazinone 5 (entry 6).
Scheme 1
substitute the halogen, yielding the corresponding
spiroaziridines, as previously established in various
cases.6 On the other hand, secondary amines are known
to be poor nucleophiles in conjugated additions, at least
under thermal conditions.5a We therefore examined both
thermal and hyperbaric versions of this reaction and
present our results here.
Thus, the high pressure-induced spiroaziridination of
bromo esters 1, observed previously with various primary
amines in alcohols, appears to strongly depend on the
structure of the amine, the nucleophilic and basic
properties of the diamines entering in competition in
this case.
We next considered aminoethanols 6 as possible
binucleophiles, in an attempt to take advantage of an
eventual concerted proton transfer from the hydroxyl
proton during the hetero-Michael step (the importance
of this proton transfer step was clearly emphasized in
Ref. 5c). The reaction was first performed between ester
1a and N-methylaminoethanol (6a) under similar
thermal (refluxing ethanol, 1 equiv NEt3) or hyperbaric
(11 kbar, EtOH, room temperature) conditions. In both
cases, the deconjugation–substitution–reconjugation se-
quence occurred, providing the cyclopentylidenic 1,3-
RESULTS AND DISCUSSION
We first considered ethylenediamine (2a), the simplest
diamine, that was reacted with ethyl cyclopentylidene-
bromoacetate (1a), a substrate known to undergo the
conjugate addition,6b in the presence of 1 equiv. of
triethylamine (Scheme 1 and Table 1). At reflux of
ethanol and at atmospheric pressure, no spiropiperazine
was observed; instead, a mixture of cyclopentenylpiper-
azinone (3a) and cyclopentyldihydropirazinone (4) was
recovered in mediocre yields (entry 1). The primary
Table 1. Thermal and/or hyperbaric reaction between esters 1 and diamines 2 (chromatographic yields)
Entry
Ester
Amine
Conditionsa
Products (yield, %)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1b
2a
2a
2b
2b
2c
2c
EtOH, 80°C, 1 bar, 24 h
EtOH, RT, 11 kbar, 86 h
EtOH, 80°C, 1 bar, 24 h
EtOH, RT, 11 kbar, 43 h
EtOH, 80°C, 1 bar, 24 h
MeOH, 75°C, 1 bar, 168 h
3a (24) ‡ 4 (18)
3a (56)
3b (54) ‡ 3c (9)
3b (62) ‡ 3c (9)
3d (53)
5 (71)
a
RT = room temperature.
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

592
A. Y. RULEV AND J. MADDALUNO
gated (and unlactonized) precursor 7b is obtained.
Actually, the products ratio is much less influenced by
the nitrogen substituent under high pressure (entry 4). In
the hyperbaric case, replacing triethylamine by a second
equivalent of 5b is also of little consequence (entry 5),
while replacing methanol by a 9:1 mixture of methylene
chloride (DCM) and tert-butyl alcohol (to combine a
very fluid solvent and a non-nucleophilic proton donor)
inhibits the reaction (entry 6). Interestingly, in this last
case, N-benzyloxazolidine, probably resulting from the
side-condensation of DCM and 6b under high pressure,
was isolated in 15% yield (with respect to 6b).The
critical influence of methanol on this reaction, which has
been emphasized before,5b,c,6 is once more obvious in
this case.
Finally, the sensitivity of this reaction to the ester
structure was also evaluated, repeating the experiments
of entries 1 and 2 on bromo ester 1b. The thermal reaction
(in methanol to avoid transesterification) gives access to
the cyclohexenylic 1,3-dihydro-[1,4]oxazinone 10, the
six-membered ring stabilizing the endocyclic double
bond (entry 7). By contrast, in the hyperbaric version 1b
undergoes a conjugate addition of methanol and provides
the methyl ether 11 (entry 8), as already observed with
other secondary amines.6a Replacing this solvent by
DCM leads to 10 only in very low yields, almost 80% of
the starting material being recovered after 48 h at 11 kbar
(entry 9). This suggests that neither a concerted nor an
intermolecular proton transfer from the hydroxyl group
of the amino alcohol takes place efficiently.
Scheme 2
This study on amino alcohols was completed by
varying the nucleophilicity/electrophilicity of the part-
ners. First, 2-aminophenol, a known inhibitor of
tyrosinase,8 was heated in refluxing ethanol with 1a and
triethylamine. Despite its lower nucleophilicity, this
aniline reacts as the aminoethanols 5 do, providing
amino ester 12 along with the corresponding benzoxa-
zinone 13 in 55 and 20% yield, respectively (Scheme 3).
The very nucleophilic N-benzylhydroxylamine9 was also
reacted with 1a. Under high pressure, the same reaction
suite as above takes place and the double bond remains
dihydro-[1,4]oxazinone (9a) in fair to good yields
(Scheme 2 and Table 2, entries 1 and 2). In the high-
pressure process, the final lactonization step was
incomplete and about 10% amino alcohol 8a was
recovered (entry 2), in a comparable 70% overall yield.
Replacing the N-methyl by an N-benzylaminoethanol
(6b) changed only the base-catalyzed double bond
migration step. Hence, entry 3 shows that under
conditions identical with those of entry 1, a quasi-
equimolar mixture of oxazinone 9b and its unconju-
Table 2. Thermal and/or hyperbaric reaction between esters 1 and aminoethanols 6 (chromatographic yields)
Entry
Ester
Amine (equiv.)
Conditions
Products (yield, %)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
6a (1)
6a (1)
6b (1)
6b (1)
6b (2)
6b (2)
6a (1)
6a (1)
6a (1)
EtOH, NEt3, 80°C, 1 bar, 24 h
EtOH, NEt3, RT, 11 kbar, 48 h
EtOH, NEt3, 80°C, 1 bar, 24 h
EtOH, RT, NEt3, 11 kbar, 72 h
EtOH, RT, 11 kbar, 72 h
CH2Cl2, t-BuOH, RT, 11 kbar, 96 h
MeOH, NEt3, 75°C, 1 bar, 56 h
MeOH, NEt3, RT, 11 kbar, 64 h
CH2Cl2, NEt3, RT, 11 kbar, 48 h
9a (71)
8a (12) ‡ 9a (57)
7 (25) ‡ 9b (30)
8b (4) ‡ 9b (66)
8b (11) ‡ 9b (53)
9b (4)a
10a (72)
11 (39)b
10a (13)c
a
Together with 87% starting material 1a and 15% N-benzyloxazolidine.
Together with 21% starting material 1b.
Together with 78% starting material 1b.
b
c
Copyright  2002 John Wiley & Sons, Ltd.
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THERMAL AND HYPERBARIC ADDITION OF BINUCLEOPHILES
593
Scheme 4
Michael addition of benzylaminoethanol be observed,
in low yield.
We finally decided to swap the order of the steps,
according to the strategy depicted in Fig. 2. An a,b-
dibromo ester could first undergo a nucleophilic sub-
stitution in the a-position, followed by a dehydrohalo-
genation to generate a double bond that could, in turn,
behave as a substrate for a final intramolecular hetero-
Michael addition.12 This was achieved on dibromo esters
19, both compounds being intermediates en route to
bromo esters 1 (Scheme 5).
Both esters 19 were treated with N,N'-dimetylami-
noethylenediamine (2c) or N-benzylaminoethanol (6b).
The results are collected in Table 3. No thermal
experiments were run in this case since the dehydrohalo-
genation is the only reaction to take place. It turns out that
under high pressure, the bromine b-elimination is also the
first event to occur, converting 19 in a-bromo-a,b-
unsaturated esters 1. After 1 h under 11 kbar, this is almost
Scheme 3
intracyclic, yielding the a-hydroxyamino ester 14 (47%)
(Scheme 3).
Increasing the electrophilicity of the substrate was
another way of boosting the reactivity. We thus
considered the a,b-unsaturated bromoketone 15, pre-
pared following the route described for 1.6 When reacted
with N-benzylaminoethanol 6b under high pressure
(Scheme 4), this bromoketone undergoes the deconjuga-
tion–substitution described above. Surprisingly in this
case, the intramolecular addition of the alcohol to the
ketone leads to a perfectly stable hemiacetal, viz.
cyclopentenylmethylmorpholinol (16), in 75% yield
(and with a high diastereoselectivity of about 10:1).
The strained 2-chloro-2-cyclopropylidene acetate 17, a
useful building block extensively studied by de Meijere
and co-workers,10 could also be considered as an
activated substrate for a conjugated addition.11 Reacting
this compound with aminoethanol 6b under our hyper-
baric conditions finally provides the expected a-chloro-b-
amino ester 18 that did not lactonize (Scheme 4).
However, the yield was moderate (40%) and several
unidentified side-products were also obtained.
In conclusion to this part, it appears that the amino
alcohols behave similarly to diamines in this reaction,
giving similar products under thermal and hyperbaric
conditions.
A deconjugation–substitution sequence,
eventually followed by a back-migration of the double
bond to an exocyclic position and by a final lactonization
step, occurs in most cases. Only with the highly activated
chlorocyclopropylidene acetate 17 could the hetero-
Figure 2
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

594
A. Y. RULEV AND J. MADDALUNO
Scheme 6
Scheme 5
the only transformation observed with both the diamine
and the amino alcohol (entries 1 and 3), while after 3 days
the usual sequence is completed and the same condensation
products as described above are obtained (entries 2 and 4).
Working in methanol led, in the case of 18b, to the
competitive conjugate addition of the solvent (entries 5 and
7). The replacement of this alcohol by a DCM–t-BuOH
mixture (9:1), as mentioned above, stopped the sequence at
its very first step, providing ester 1b in high yield (entry 6).
It is worth pointing out the efficiency of the b-elimination,
which does not seem to be inhibited by pressure. This was
checked compressing esters 19a at 11 kbar in ethanol with
triethylamine and recovering 1a,b in 41–71% yield after
1 h at room temperature.
We also decided to examine the action of a primary
amine on such dibromo esters. Placing 19b in methanol
under 11 kbar in the presence of 1 equiv. of N-
methylethylenediamine (2b) at room temperature pro-
vided the unexpected strained spiroaziridine 20 in low
yield (28%) after 72 h (Scheme 6). The mechanism of
this reaction has not been detailed; one can suspect,
however, that 19b converts into 1b which, in turn,
undergoes the hetero-Michael addition, followed by the
spiroaziridination and the final lactamization. The more
or less concerted aspect of this reaction is to be
emphasized since this reaction does not take place when
2b and 1a are put under 11 kbar (Table 1, entry 4). On the
other hand this sequence makes more sense, in our
opinion, than a double nucleophilic substitution of the
two bromines (one of which being on a tertiary carbon)
by the primary amine.
This last reaction illustrates the well-known propensity
of high pressures to favor highly compact structures and
processes leading to the formation of a maximum number
of bonds.
CONCLUSION
The spiroaziridination reaction between 2-bromo-2-
(cycloalkylidene)acetates and primary amines cannot be
extended to other spiroheterocycles resorting to simple
neutral binucleophiles. Indeed, the N,O- and N,N-
binucleophiles that we considered (ethylenediamines
and aminoethanols) under thermal or hyperbaric (11
kbar) conditions provide in all cases morpholin-2-ones
and piperazin-2-ones. The expected hetero-Michael
addition apparently competes with a cascade beginning
by a migration of the double bond followed by a
substitution of the allylic halogen and a lactonization
(lactamization), and eventually ended by a back-migra-
tion of the double bond. Enhancing the nucleophilicity of
the amine or the electrophilicity of the substrate did not
change the course of this reaction. No substantial
difference between the thermal and hyperbaric versions
of the reaction could be observed during this work, only
the distribution of the products being slightly altered. A
relatively large set of unusual and attractive a-amino
Table 3. Hyperbaric reaction (11 kbar, RT) between dibromo esters 19 and 1 equiv. of diamine 2c or aminoethanol 6b in the
presence of 1 equiv. of NEt3 (chromatographic yields)
Entry
Ester
Amine
Conditions
Products (yield,%)
1
2
3
4
5
6
7
19a
19a
19a
19a
19b
19b
19b
2c
2c
6b
6b
2c
2c
6b
EtOH, 1 h
1a (41) ‡ 3d (35)
EtOH, 67 h
3d (84)
EtOH, 1 h
EtOH, 67 h
MeOH, 72 h
CH2Cl2, t-BuOH, 65 h
MeOH, 72 h
1a (71) ‡ 7 (5) ‡ 9b (5)
8b (11) ‡ 9b (60)
5 (34) ‡ 11 (46)
1b (94)
10b (6) ‡ 11 (52)a
a
Together with 10% of
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

THERMAL AND HYPERBARIC ADDITION OF BINUCLEOPHILES
595
esters, lactones and lactams has nevertheless been
obtained through this approach. In addition, the control
of the absolute configuration of the asymmetric center
created by this sequence would be of special interest.
Results in this direction will be published in due course.
phile (1.0–1.5 mmol) and, eventually, triethylamine (1.0–
1.5 mmol) in methanol/ethanol (3–4 g) or in a 9:1 mixture
of methylene chloride and tert-butanol was compressed
to 11 kbar at room temperature or brought to reflux under
atmospheric pressure for a suitable time (see Tables 1–3).
After returning to atmospheric pressure, the solvent was
evaporated. The residue was chromatographed (CH2Cl2–
MeOH for 3–5 and pentane–Et2O for 7–14) to yield the
corresponding products. The following compounds were
thus prepared.
EXPERIMENTAL
1H and 13C NMR spectra were measured on Bruker AM-
200 and Avance 300 spectrometers; coupling constants
(J) are given in Hz. MS analyses (EI, 70 eV) were
performed on an ATI-Unicam Automass apparatus.
High-resolution mass spectra (HRMS) were recorded
with a Jeol JMS AX-500 spectrometer. IR spectra were
measured on a Perkin-Elmer 16 PC FT-IR spectrometer.
High-pressure reactions were performed in a Unipress
piston-cylinder apparatus for pressures up to 14 kbar. The
silica gel used for flash chromatography was obtained
from SDS (230–400 mesh). Diethyl ether and THF were
distilled from sodium–benzophenone. Methylene chror-
2-Cyclopent-1-en-1-yl tetrahydropyrazin-2(1H)-one
(3a). 1H NMR (CDCl3), ꢀ ppm: 1.75–2.00 (m, 2H);
1.80 (br s, 1H); 2.30–2.45 (m, 4H); 2.85–3.15 (m, 2H);
3.20–3.40 (m, 2H); 4.14 (s, 1H); 5.70 (s, 1H); 6.84 (br s,
1H). 13C NMR (CDCl3), ꢀ ppm: 23.70, 32.74, 32.90,
40.87, 43.43, 60.24, 130.02, 141.70, 171.41. IR (KBr,
cmÀ1): 1669 (br s, C
166 (37, M ), 137 (21), 109 (40), 94 (67), 81 (100). Anal.
Calcd for C9H14N2O: C 65.03; H 8.49; N 16.85. Found: C
64.78; H 8.45; N 16.62%.
=
C, C=
O), 3273 (NH). MS (m/z):
‡
˚
ide, methanol and ethanol were dried over 3 A molecular
sieves and then distilled. Ethyl cyclopentylidenebromo-
acetate (1a), methyl 4-tert-butylcyclohexylidenebromo-
acetate (1b) and dibromo esters 19 were prepared as
reported previously.6 Methyl 2-chloro-2-(cyclopropyli-
dene)acetate (17) was obtained from Professor Armin de
Meijere (University of Go¨ttingen, Germany). Cyclopen-
tylidenepropanone was prepared following Villieras and
Rambaud’s convenient procedure.13 Ketone 15 was
prepared in 62% yield from cyclopentylidenepropanone
in a similar fashion to 1a,b.6
2-Cyclopent-1-en-1-yl-4-methyltetrahydropyrazin-
2(1H)-one (3b) and 2-cyclopent-1-en-1-yl-1-methyl-
tetrahydropyrazin-2(1H)-one (3c). H NMR (CDCl3),
1
ꢀ ppm: 1.75–1.95 (m, 2H); 2.19 (for 4-Me isomer), 2.91
(for 1-Me isomer) (2 s, 3H); 2.10–2.40 (m, 4H); 2.43 (td,
J = 11.0, 4.0 Hz, 1H); 2.80–2.90 (m, 2H); 3.10–3.20 (m,
2H); 3.38 (s, 1H); 3.42 (td, J = 11.0, 4.0 Hz, 1H); 5.70
(for 4-Me isomer), 5.62 (for 1-Me isomer) (2 s, 1H); 6.72
(for 4-Me isomer), 6.82 (for 1-Me isomer) (br s, 1H). 13
C
NMR (CDCl3), ꢀ ppm: 23.71, 31.71, 32.54, 43.91, 41.25,
51.04, 69.37, 132.45, 140.75, 170.82. IR (KBr, cmÀ1):
1-Bromo-1-cyclopentylidenepropanone (15). 1H
NMR (CDCl3), ꢀ ppm: 1.50–1.65 (m, 2H); 1.65–1.80
(m, 2H); 2.34 (s, 3H); 2.37 (t, J = 7.2 Hz, 2H); 2.61 (t,
J = 7.2 Hz, 2H). 13C NMR (CDCl3), ꢀ ppm: 25.58, 28.84,
36.96, 40.43, 30.98, 114.81, 164.55, 195.78. IR (v,
1636 (C
=
C), 1668 (br s, C
=
O), 3195 (NH). MS (m/z):
‡
180 (50, M ), 109 (74), 94 (93), 44 (100). Anal. Calcd for
C10H16N2O: C 66.64; H 8.95; N 15.54. Found: C 66.45;
H 8.86; N 15.29%.
cmÀ1): 1589 (C
(58, M ); 161, 159 (20), 123 (72), 79 (100). Anal. Calcd
for C8H11BrO: C 47.32; H 5.46. Found: C 47.32; H
5.58%.
=
C); 1678 (C
=
O). MS (m/z): 204, 202
2-Cyclopent-1-en-1-yl-1,4-dimethyltetrahydropyra-
zin-2(1H)-one (3d). 1H NMR (CDCl3), ꢀ ppm: 1.70–1.95
(m, 2H); 2.17 (s, 3H); 2.10–2.40 (m, 4H); 2.45 (td,
J = 11.0, 4.0 Hz, 1H); 2.89 (s, 3H); 2.85–2.95 (m, 1H);
3.07 (qd, J = 11.0, 3.4 Hz, 1H); 3.35 (s, 1H); 3.47 (td,
J = 11.0, 4.4 Hz, 1H); 5.67 (br s, 1H). 13C NMR (CDCl3),
ꢀ ppm: 23.71, 31.96, 32.51, 34.84, 44.01, 48.50, 51.20,
‡
1
Ethyl (1-bromocyclopentyl) bromoacetate (19a). H
NMR (CDCl3), ꢀ ppm: 1.26 (t, J = 7.2 Hz, 3H); 1.65–2.45
(m, 8H); 4.21 (q, J = 7.2 Hz, 2H); 4.81 (s, 1H). 13C NMR
(CDCl3), ꢀ ppm: 14.56, 23.61, 24.39, 39.21, 42.76, 53.04,
69.65, 132.00, 141.09, 167.98. IR (KBr, cmÀ1): 1650 (br
‡
s, C
=
C, C
=
O). MS (m/z): 194 (24, M ), 165 (23), 94
62.75, 75.28, 168.36. IR (KBr, cmÀ1): 1747 (C
(m/z): 313 (2, M À 1), 233 (80), 125 (98), 79 (100).
Anal. Calcd for C9H14Br2O2: C 34.42; H 4.49. Found: C
34.32; H 4.54%.
=O). MS
(70), 42 (100). Anal. Calcd for C11H18N2O: C 68.01; H
9.34; N 14.42. Found: C 67.90; H 9.28; N 14.42%.
‡
3-Cyclopentyl-2H-oxazin-2-one (4). 1H NMR (CDCl3),
ꢀ ppm: 1.50–1.70 (m, 5H); 1.75–1.95 (m, 3H); 3.30–3.45
(m, mask., 1H); 3.36 (td, J = 6.2, 2.9 Hz, 2H); 3.71 (t,
J = 6.2 Hz, 2H); 7.14 (br s, 1H). 13C NMR (CDCl3),
ꢀ ppm: 25.98, 30.72, 39.23, 47.95, 42.45, 43.91, 158.86,
General procedure for the reaction of esters 1a,b
with the binucleophiles
169.20. IR (KBr, cmÀ1): 1620 (C
3229 (NH). MS (m/z): 166 (15, M ), 125 (60), 110 (38),
=
N), 1685 (C
=O),
‡
A solution of an ester 1a,b (1–1.5 mmol) and binucleo-
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

596
A. Y. RULEV AND J. MADDALUNO
‡
97 (100). Anal. Calcd for C9H14N2O: C 65.03; H 8.49; N
16.85. Found: C 64.21; H 8.37; N 16.69%.
M ), 272 (70), 230 (65), 205 (80), 91 (100). Anal. Calcd
for C18H25NO3: C 71.26; H 8.31; N 4.62. Found: C 71.46;
H 8.49; N 4.77%.
3-[4-(tert-Butyl)cyclohex-1-en-1-yl]-1,4-dimethyl-
tetrahydropyrazin-2(1H)-one (5) (1:1 mixture of the
two diastereomers). H NMR (CDCl3), ꢀ ppm: 0.73,
4-Methyl-3-cyclopentylidenemorpholin-2-one (9a).
1H NMR (CDCl3), ꢀ ppm: 1.55–1.75. (m, 4H); 2.30–
2.40 (m, 2H); 2.55 (s, 3H); 2.55–2.75 (m, 2H); 3.00–3.10
(m, 2H); 4.20–4.25 (m, 2H). 13C NMR (CDCl3), ꢀ ppm:
26.28, 26.78, 33.23, 33.99, 42.35, 51.57, 64.75, 129.33,
1
0.74 (2 s, 9H); 0.90–1.30 (m, 2H); 1.60–2.05 (m, 5H);
2.08, 2.10 (2 s, 3H); 2.30–2.45 (m, 1H); 2.75–2.83 (m,
1H); 2.83, 2.84 (2 s, 3H); 2.90–3.00 (m, 2H); 3.45 (td,
J = 11.6, 4.5 Hz, 1H); 5.55–5.65 (m, 1H). 13C NMR
(CDCl3), ꢀ ppm: 24.32, 24.41, 25.70, 27.06, 27.23, 27.28,
27.54, 27.58, 32.50, 32.59, 34.83, 43.85, 44.01, 44.24,
44.42, 48.60, 48.66, 51.44, 51.54, 75.66, 76.28, 129.17,
149.24, 165.05. IR (KBr, cmÀ1): 1615 (C
=
C), 1729
‡
(C=
O). MS (m/z): 181 (45, M ), 108 (100), 94 (60), 42
(70). Anal. Calcd for C10H15NO2: C 66.27; H 8.34; N
7.73. Found: C 66.19; H 8.29; N 7.56%.
129.28, 134.81, 135.14, 168.40, 168.64. IR (KBr, cmÀ1):
‡
1654 (br s, C
=C, C
=
O). MS (m/z): 264 (17, M ), 128
4-Benzyl-3-cyclopentylidenemorpholin-2-one (9b).
1H NMR (CDCl3), ꢀ ppm: 1.60–1.80 (m, 4H); 2.42 (br
t, J = 6.5 Hz, 2H); 2.60 (br t, J = 6.5 Hz, 2H); 2.83 (br t,
J = 4.8 Hz, 2H); 3.96 (s, 2H); 4.12 (br t, J = 4.8 Hz, 2H);
7.20–7.40 (m, 5H). 13C NMR (CDCl3), ꢀ ppm: 26.29,
26.89, 33.42, 33.77, 47.78, 58.97, 64.65, 127.87, 128.50,
(65), 99 (100), 57 (93). Anal. Calcd for C16H28N2O: C
72.68; H 10.67; N 10.59. Found: C 72.77; H 10.92; N
10.50%.
Ethyl 2-cyclopent-1-en-1-yl-2-[(hydroxyethyl)(ben-
1
zyl)amino]acetate (7). H NMR (CDCl3), ꢀ ppm: 1.27
129.00, 138.27, 129.05, 150.91, 165.26. IR (KBr, cmÀ1):
‡
(t, J = 7.3 Hz, 3H); 1.86 (quint, J = 7.3 Hz, 2H); 2.10–
3.05 (m, 6H); 3.40–3.60 (m, 2H); 3.67 (d, A part of an AB
system, J = 14.2 Hz, 1H); 3.89 (d, B part of an AB
system, J = 14.2 Hz, 1H); 4.05 (s, 1H); 4.19 (q,
J = 7.3 Hz, 2H); 5.61 (s, 1H); 7.20–7.35 (m, 5H). 13C
NMR (CDCl3), ꢀ ppm: 14.76, 23.75, 32.89, 34.73, 52.85,
55.74, 59.51, 60.88, 64.42, 127.63, 129.02, 131.23,
139.79, 128.91, 139.71, 172.65. IR (KBr, cmÀ1): 1636
1616 (C
=
C), 1732 (C
=
O). MS (m/z): 257 (36, M ), 166
(50), 91 (100). Anal. Calcd for C16H19NO2: C 74.68; H
7.44; N 5.44. Found: C 74.52; H 7.51; N 5.22%.
3-[4-(tert-Butyl)cyclohex-1-en-1-yl]-4-methylmor-
pholin-2-one (10a) (1:1 mixture of the two diaster-
eomers). 1H NMR (CDCl3), ꢀ ppm: 0.79, 0.80 (2 s, 9H);
1.00–1.30. (m, 2H); 1.80–2.20 (m, 5H); 2.15, 2.18 (2 s,
3H); 2.50–2.65 (m, 1H); 2.80–2.85 (m, 1H); 3.20, 3.21 (2
s, 1H); 4.33 (ddd, J = 10.7, 3.2, 1.8 Hz, 1H); 4.53 (td,
J = 11.4, 3.2 Hz, 1H); 5.75–5.85 (m, 1H). 13C NMR
(CDCl3), ꢀ ppm: 24.28, 24.38, 25.63, 27.31, 27.35, 27.37,
27.56, 27.60, 32.58, 32.63, 43.48, 43.66, 44.21, 44.31,
51.50, 51.42, 68.62, 75.18, 75.85, 130.43, 130.46,
(C=C), 1733 (C=O), 3448 (OH). MS (m/z): 303 (4,
‡
M ), 272 (60), 230 (98), 120 (55), 91 (100). Anal. Calcd
for C18H25NO3: C 71.26; H 8.31; N 4.62. Found: C 71.43;
H 8.38; N 4.28%.
Ethyl
2-cyclopentylidene-2-[(2-hydroxyethyl)
(methyl)amino]acetate (8a). 1H NMR (CDCl3),
ꢀ ppm: 1.25 (t, J = 7.1 Hz, 3H); 1.55–1.70. (m, 4H);
2.44 (t, J = 6.2 Hz, 2H); 2.50 (s, 3H); 2.60 (t, J = 6.2 Hz,
2H); 2.89 (t, J = 5.2 Hz, 2H); 2.92 (br s, 1H); 3.45–3.55
(m, 2H); 4.15 (q, J = 7.1 Hz, 2H). 13C NMR (CDCl3),
ꢀ ppm: 14.80, 25.89, 27.37, 33.19, 33.56, 40.01, 57.54,
59.51, 60.39, 132.85, 158.74, 167.09. IR (KBr, cmÀ1):
133.61, 133.86, 169.29, 169.56. IR (KBr, cmÀ1): 1682
‡
(C=
C), 1723 (C
=
O). MS (m/z): 251 (2, M ), 226 (8),
207 (64), 178 (50), 122 (100), 94 (70). Anal. Calcd for
C15H25NO2: C 71.67; H 10.02; N 5.57. Found: C 71.58;
H 10.04; N 5.44%.
1634 (C
=
C), 1704 (C
=
O), 3451 (OH). MS (m/z): 227
3-[4-(tert-Butyl)cyclohex-1-en-1-yl]-4-benzylmor-
pholin-2-one (10b) (1:1 mixture of the two
diastereomers)
‡
(13, M ), 196 (90), 81 (80), 42 (100). Anal. Calcd for
C12H21NO3: C 63.41; H 9.31; N 6.16. Found: C 63.45; H
9.28; N 6.44%.
1H NMR (CDCl3), ꢀ ppm: 0.78, 0.79 (2 s, 9H); 1.00–1.30
(m, 2H); 1.70–2.20 (m, 5H); 2.38 (qd, J = 12.0, 3.4 Hz,
1H); 2.75–2.85 (m, 1H); 2.97 (d, A part of an AB system,
J = 13.6 Hz, 1H); 3.53, 3.54 (2 s, 1H); 3.92 (dd, B part of
an AB system, J = 18.7, 13.6 Hz, 1H); 4.15–4.25 (m, 1H);
4.31 (td, J = 11.0, 3.0 Hz, 1H); 5.78–5.87 (m, 1H); 7.15–
7.35 (m, 5H). 13C NMR (CDCl3), ꢀ ppm: 24.62, 26.20,
27.67, 28.13, 27.84, 27.87, 32.86, 32.92, 44.50, 44.56,
47.63, 58.88, 59.16, 69.26, 73.90, 74.50, 128.02, 128.04,
129.35, 129.44, 131.40, 131.44, 138.41, 138.48, 129.17,
133.98, 134.27, 169.71, 169.97. IR (KBr, cmÀ1): 1678
Ethyl 2-cyclopentylidene-2-[(2-hydroxyethyl)(ben-
zyl)amino]acetate (8b). 1H NMR (CDCl3), ꢀ ppm:
1.26 (t, J = 7.2 Hz, 3H); 1.40–1.65. (m, 4H); 2.32 (t,
J = 7.0 Hz, 2H); 2.56 (t, J = 7.0 Hz, 2H); 2.91 (br s, 1H);
2.96 (t, J = 5.0 Hz, 2H); 3.44 (br s, 2H); 3.92 (s, 2H); 4.16
(q, J = 7.2 Hz, 2H); 7.15–7.30 (m, 5H). 13C NMR
(CDCl3), ꢀ ppm: 14.82, 25.93, 27.24, 33.25, 34.15,
55.41, 58.15, 60.36, 60.63, 127.51, 128.66, 129.41,
139.81, 131.14, 159.95, 167.54. IR (KBr, cmÀ1): 1631
(C=C), 1701 (C=O), 3446 (OH). MS (m/z): 303 (4,
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

THERMAL AND HYPERBARIC ADDITION OF BINUCLEOPHILES
597
‡
(C
=
C), 1744 (C
=
O). MS (m/z): 327 (5, M ), 283 (54),
1.60–1.95 (m, 2H); 2.17–2.35 (m, mask., 3H); 2.40–2.50
(m, 1H); 2.70 (dd, J = 12.0, 4.1 Hz, 1H); 2.80 (dd, A part
of an AB system, J = 13.5 Hz, 1H); 3.19 (s, 1H); 3.59 (dd,
J = 12.0, 3.8 Hz, 1H); 3.80 (dd, B part of an AB system,
J = 13.5 Hz, 1H); 3.98 (td, J = 12.0, 4.1 Hz, 1H); 4.50 (br
s, 1H); 5.67 (s, 1H); 7.15–7.30 (m, 5H). 13C NMR
(CDCl3), ꢀ ppm: major isomer: 24.50, 25.27, 32.32,
32.69, 52.84, 59.42, 60.23, 96.15, 127.82, 129.36,
134.16, 139.28, 129.05, 141.68; minor isomer: 24.90,
24.93, 32.32, 32.65, 52.84, 59.99, 60.40, 95.99, 127.94,
192 (97), 149 (86), 91 (99), 57 (100). Anal. Calcd for
C21H29NO2: C 77.03; H 8.93; N 4.28. Found: C 76.87; H
9.02; N 4.38%.
Ethyl
no)acetate (12)
2-cyclopent-1-en-1-yl-2-(2-hydroxyanili-
1H NMR (CDCl3), ꢀ ppm: 1.26 (t, J = 7.1 Hz, 3H); 1.89
(quint, J = 7.3 Hz, 2H); 2.25–2.50 (m, 4H); 4.22 (q,
J = 7.1 Hz, 2H); 4.68 (s, 1H); 5.79 (s, 1H); 6.50–6.80 (m,
4H). 13C NMR (CDCl3), ꢀ ppm: 14.58, 23.57, 32.85,
33.05, 58.74, 62.04, 113.46, 115.15, 119.20, 121.37,
135.78, 145.06, 129.68, 140.04, 173.47. IR (KBr, cmÀ1):
129.48, 134.55, 138.78, 129.05, 141.68. IR (KBr, cmÀ1):
‡
1641 (C=
C), 3463 (OH). MS (m/z): 273 (6, M ), 255 (6),
182 (20), 91 (100). Anal. Calcd for C17H23NO2: C 74.69;
H 8.48; N 5.12. Found: C 74.73; H 8.74; N 5.22%.
1647 (C
=
C), 1738 (C
=
O), 3413 (OH, NH). MS (m/z):
Methyl 2-cyclopropyl-2-[(2-hydroxyethyl)(benzyl)-
amino]chloroacetate (18). H NMR (CDCl3), ꢀ ppm:
‡
1
261 (13, M ), 188 (100), 109 (25). Anal. Calcd for
C15H19NO3: C 68.94; H 7.33; N 5.36. Found: C 68.86; H
7.19; N 5.19%.
0.70–1.20. (m, 4H); 1.97 (br s, 1H); 2.80 (br t, 2H), 3.24
(m, 2H); 3.71 (s, 3H); 3.77 (d, A part of an AB system,
J = 14.0 Hz, 1H); 3.88 (d, B part of an AB system,
J = 14.0 Hz, 1H); 4.60 (s, 1H); 7.10–7.30 (m, 5H). 13C
NMR (CDCl3), ꢀ ppm: 15.35, 17.30, 48.21, 53.61, 55.25,
58.76, 60.09, 61.54, 127.96, 128.77, 129.19, 140.52,
3-Cyclopentyl-2H-1,4-benzoxazin-2-one (13)
1H NMR (CDCl3), ꢀ ppm: 1.55–2.20 (m, 8H); 3.54
(quint, J = 8.0 Hz, 1H); 7.20–7.75 (m, 4H). 13C NMR
(CDCl3), ꢀ ppm: 26.21, 31.02, 43.51, 116.62, 125.64,
129.23, 130.62, 131.57, 146.67, 153.43, 161.14. IR (KBr,
169.87. IR (KBr, cmÀ1): 1752 (C
(m/z): 261 (7, M À HCl), 229 (14), 91 (100). Anal.
Calcd for C15H20ClNO3: C 60.50; H 6.77; N 4.70. Found:
C 61.29; H 7.07; N 5.55%.
=
O), 3432 (OH). MS
‡
cmÀ1): 1743 (br s, C
=
N, C
=
O). MS (m/z): 215 (32,
‡
M ), 146 (100). Anal. Calcd for C13H13NO2: C 72.54; H
6.09; N 6.51. Found: C 72.38; H 6.05; N 6.32%.
Spirolactam 20 (10:1 mixture of the two diastereo-
mers). 1H NMR (CDCl3), ꢀ ppm: 0.80 (s, 9H); 0.90–1.50
(m, 6H); 1.65–1.90 (m, 3H); 2.21, 2.23 (2 s, 1H); 2.89,
2.90 (2 s, 3H); 2.80–3.00 (m, 2H); 3.10–3.35 (m, 1H);
3.69 (td, J = 12.0, 4.5 Hz, 1H). 13C NMR (CDCl3),
ꢀ ppm: major isomer: 26.50, 26.60, 27.50, 28.08, 32.79,
34.20, 38.33, 42.03, 49.44, 43.37, 48.03, 48.11, 167.66;
minor isomer: 25.75, 25.85, 27.50, 29.73, 32.88, 34.20,
Ethyl 2-cyclopent-1-en-1-yl-2-(N-hydroxy-N-ben-
zylamino)acetate (14)
1H NMR (CDCl3), ꢀ ppm: 1.20 (t, J = 7.2 Hz, 3H); 1.70–
1.90 (m, 2H); 2.25–2.45 (m, 4H); 3.53 (d, A part of an AB
system, J = 13.8 Hz, 1H); 3.93 (d, B part of an AB
system, J = 13.8 Hz, 1H); 4.12 (qd, J = 7.2, 2.1 Hz, 2H);
4.14 (s, 1H); 5.45 (br s, 1H); 5.82 (s, 1H); 7.15–7.35 (m,
5H). 13C NMR (CDCl3), ꢀ ppm: 14.58, 23.53, 32.71,
32.81, 60.84, 61.34, 72.48, 127.68, 129.76, 132.97,
138.42, 128.62, 137.92, 170.94). IR (KBr, cmÀ1): 1649
37.97, 42.78, 49.54, 42.96, 47.55, 47.72, 167.78. IR
‡
(KBr, cmÀ1): 1654 (br s, C
=
O). MS (m/z): 250 (55, M ),
235 (97), 193 (65), 165 (71), 86 (99), 57 (100). Anal.
Calcd for C15H26N28O: C 71.96; H 10.47; N 11.19.
Found: C 71.03; H 10.67; N 11.27%.
Methyl 2-[4-(tert-butyl)cyclohex-1-en-1-yl]-2-[(hy-
droxyethyl)(benzyl)amino]acetate (21) (1:1 mixture
of two diastereomers). 1H NMR (CDCl3), ꢀ ppm: 0.77,
0.78 (2 s, 9H); 1.00–2.30 (m, 8H); 2.70–2.95 (m, 2H);
3.30–3.60 (m, 4H); 3.64, 3.65 (2 s, 2H); 3.80–3.90 (m,
2H); 5.50 (br s, 1H); 7.10–7.30 (m, 5H). 13C NMR
(CDCl3), ꢀ ppm: 24.54, 24.81, 27.64, 27.67, 29.51, 30.07,
27.78, 27.84, 32.86, 44.30, 44.48, 52.02, 52.03, 52.84,
53.44, 55.93, 56.16, 59.75, 60.03, 69.09, 70.64, 127.86,
128.62, 128.80, 129.17, 129.36, 140.11, 140.35, 129.88,
(C=C), 1725 (C=O), 3443 (OH). MS (m/z): 275 (8,
‡
M ), 202 (100), 186 (67), 91 (76). Anal. Calcd for
C16H21NO3: C 69.79; H 7.69; N 5.09. Found: C 70.05; H
7.85; N 5.28%.
4-Benzyl-3-cyclopent-1-en-1-yl-2-methylmorpholin-
2-ol (16). H NMR (CDCl3), ꢀ ppm: major isomer: 1.20
1
(s, 3H); 1.60–1.95 (m, 2H); 2.08 (td, J = 12.0, 4.1 Hz,
1H); 2.17–2.35 (m, 3H); 2.40–2.50 (m, 1H); 2.55 (dd,
J = 12.0, 2.4 Hz, 1H); 2.80 (dd, A part of an AB system,
J = 13.5 Hz, 1H); 3.03 (s, 1H); 3.46 (dd, J = 12.0, 3.0 Hz,
1H); 3.80 (dd, B part of an AB system, J = 13.5 Hz, 1H);
3.86 (td, J = 12.0, 3.0 Hz, 1H); 4.50 (br s, 1H); 5.77 (s,
1H); 7.15–7.30 (m, 5H); minor isomer: 1.18 (s, 3H);
133.78, 133.85, 173.58, 173.74. IR (KBr, cmÀ1): 1737
‡
(C=
O), 3443 (OH). MS (m/z): 359 (1, M ), 328 (39),
300 (90), 192 (100), 149 (78), 91 (71), 57 (80). Anal.
Calcd for C22H33NO3: C 73.50; H 9.25; N 3.90. Found: C
73.55; H 9.35; N 3.98%.
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598

598
A. Y. RULEV AND J. MADDALUNO
3-Benzyloxazolidine. 1H NMR (CDCl3), ꢀ ppm: 2.91 (t,
J = 6.8 Hz, 2H); 3.64 (s, 2H); 3.74 (t, J = 6.8 Hz, 2H);
4.24 (s, 3H) 7.15–7.35 (m, 5H). 13C NMR (CDCl3),
ꢀ ppm: 52.39, 58.46, 63.69, 86.95, 127.70, 128.85,
129.20, 139.24. IR (KBr, cmÀ1): 1006, 1057, 1674
(saturated ring). MS (m/z): 163 (20, M ), 162 (53), 91
(100). Anal. Calcd for C10H13NO: C 73.59; H 8.03; N
8.58. Found: C 73.38; H 7.88; N 8.47%.
Classical Conditions, Van Eldik R, Hubbard CD (eds). John Wiley
& Sons: New York, 1997; 163–188; (g) Ciobanu M, Matsumoto K.
Liebigs Ann./Recl. 1997; 623; (h) Jenner G. In High Pressure
Molecular Science, Winter R, Jonas J (eds). Kluwer: Dordrecht,
1999; 313–330; (h) Kla¨rner FG, Wurche F. J. Prakt. Chem. 2000;
342: 609.
3. (a) Jenner G. New J. Chem. 1995; 19: 173; (b) Jenner G.
Tetrahedron 1996; 52: 13557; (c) Jenner G. J. Phys. Org. Chem.
1999; 12: 619; (d) Jenner G. Tetrahedron Lett. 2001; 42: 4807.
4. Rulev AY. Russ. Chem. Rev. 1998; 67: 279.
5. (a) Pfau M. Bull. Soc. Chim. Fr. 1967; 1118; (b) d’Angelo J,
Maddaluno J. J. Am. Chem. Soc. 1986; 108: 8112; (c) Dumas F,
Mezrhab B, d’Angelo J, Riche C, Chiaroni A. J. Org. Chem. 1996;
61: 2293; (d) Romanova NN, Gravis AG, Shaidullina GM,
Leshcheva IF, Bundel’ YG. Mendeleev Commun. 1997; 235; (d)
Cardillo G, Tomasini C. Chem. Soc. Rev. 1996; 117; (e) Juaristi E.
Enantioselective Synthesis of b-Amino Acids. Wiley-VCH: New
York, 1997.
‡
Acknowledgements
A.Y.R. is grateful to the CNRS for a research associate
position (August–December 1999). Our high-pressure
research program and equipment are supported by grants
from the Conseil Re´gional de Haute-Normandie
(France). We also warmly thank Professor Armin de
Meijere (University of Go¨ttingen, Germany) for provid-
ing a sample of methyl 2-chloro-2-(cyclopropylidene)-
acetate (17).
6. (a) Rulev AY, Maddaluno J, Ple´ G, Plaquevent JC, Duhamel L. J.
Chem. Soc., Perkin Trans. 1 1998; 1397; (b) Rulev AY,
Maddaluno J. Eur. J. Org. Chem. 2001; 2569.
7. (a) de Meijere A, Teichmann S, Dahai Yu, Kopf J, Oly M, von
Thienen N. Tetrahedron 1989; 45: 2957; (b) de Meijere A,
Wessjohann L. Synlett 1990; 20; (c) Belov VN, Funke C, Labahn
T, Es-Sayed M, de Meijere A. Eur. J. Org. Chem. 1999; 1345; (d)
No¨tzel MW, Tamm M, Labahn T, Noltemeyer M, Es-Sayed M, de
Meijere A. J. Org. Chem. 2000; 65: 3850; (e) Funke C, Es-Sayed
M, de Meijere A. Org. Lett. 2000; 2: 4249; (f) No¨tzel MW, Labahn
T, Es-Sayed M, de Meijere A. Eur. J. Org. Chem. 2001; 3025.
8. (a) Toussaint O, Lerch K. Biochemistry 1987; 26: 8567; (b)
Maddaluno JF, Faull KF. Experientia 1988; 44: 885.
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Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 590–598