Spiroaziridination of cycloalkylidene esters under high pressure

Article abstract of DOI:10.1002/1099-0690(200107)2001:13<2569::AID-EJOC2569>3.0.CO;2-1

The reaction between primary amines and 2-bromo-2-(cycloalkylidene)acetates in alcohol under high pressure provides the expected spiroaziridines in good yields and diastereomeric excesses. With bulky or aromatic amines, this reaction competes with the migration of the double bond, which, migrating from an exo to an endocyclic position, provides an intermediate allylic α-bromo ester, immediately converted into an α-amino ester. It was also possible to develop a tandem version, applying the same high pressure conditions to a 1,4-bis-cyclohexylidene acetate. The corresponding bisspiroaziridine was obtained in good yield and moderate de. However, this reaction did not succeed with 2-chloro-2-(cyclopropylidene)acetate, which produced only glutaric acid derivatives in low yields.

Full text of DOI:10.1002/1099-0690(200107)2001:13<2569::AID-EJOC2569>3.0.CO;2-1

FULL PAPER
Spiroaziridination of Cycloalkylidene Esters under High Pressure
Alexandre Rulev[b] and Jacques Maddaluno*[a]
Keywords: Amines / High pressure chemistry / Michael additions / Spiro compounds
The reaction between primary amines and 2-bromo-2-(cyclo- into an α-amino ester. It was also possible to develop a tan-
alkylidene)acetates in alcohol under high pressure provides
dem version, applying the same high pressure conditions to
the expected spiroaziridines in good yields and diastereom- a 1,4-bis-cyclohexylidene acetate. The corresponding bis-
eric excesses. With bulky or aromatic amines, this reaction
competes with the migration of the double bond, which, mi-
spiroaziridine was obtained in good yield and moderate de.
However, this reaction did not succeed with 2-chloro-2-
grating from an exo to an endocyclic position, provides an (cyclopropylidene)acetate, which produced only glutaric acid
intermediate allylic α-bromo ester, immediately converted
derivatives in low yields.
Introduction
tivation could make this route viable.[12] High pressure is
indeed known to help in overcoming steric problems[13] and
to give access to tetrasubstituted centers bearing amino
functions through direct addition of primary amines to β,β-
disubstituted α,β-unsaturated esters.[14] Such a reaction is
totally inefficient under atmospheric pressure.[5,12,14] Here
we wish to present the developments we have made on our
original results in an effort to define the scope and limita-
tions of this method more accurately.
The biological potential of α- and β-amino acids and es-
ters continually fuels the interest of organic chemists in syn-
thetic methods that offer access to precursors of such func-
tional patterns.[1] The possibilities opened by the regioselec-
tive ring-fission of aziridine-2-carboxylates to provide both
α- and β-functionalized amino esters illustrate why this
group of heterocycles is regarded as such a versatile tool in
modern organic synthesis.[2] One classical route to aziridine-
2-carboxylates consists of the hetero-Michael addition of
primary amines to α,β-unsaturated-α-halo esters. This
straightforward and general access is efficient and compat-
ible with a large variety of functionalities.[3] However, one
of its limitations is the sensitivity of the conjugate additions
to steric factors.[4] This well known phenomenon was re-
ported as early as 1967 for amine addition to unsaturated
esters.[5] Consequently, it has been possible to prepare aziri-
dines incorporating a tetrasubstituted carbon atom only in
a restricted number of cases, using different methods
(nitrene[6] or carbene[7] addition, addition of ammonia onto
α,β-dibromo esters,[3d] photolysis of 2-(dialkylamino)cy-
clohex-2-enone,[8] or Payne-type[9] or iminium[10] rearrange-
ments). To the best of our knowledge, only in two recent
cases has the hetero-Michael addition successfully been ap-
plied to the synthesis of such highly substituted aziridines.
Resorting to an activated substrate, methyl 2-chloro-2-
cyclopropylideneacetate, De Meijere and colleagues ob-
tained the expected azaspiropentanecarboxylate under ther-
mal conditions, but only in relatively low yield.[11] We were
able to show that, in the case of 2-bromo-2-(4Ј-tert-butyl-
cyclohexylidene)acetate and benzylamine, high pressure ac-
Results and Discussion
We first extended our reaction conditions to six common
primary amines[15] and to the five-membered and six-mem-
bered ring haloacetates 1 (Scheme 1). The starting esters
were prepared from the corresponding cycloalkanones by
means of a WittigϪHorner/bromination/dehydrobromin-
ation sequence reported previously.[12] The hetero-Michael
step was then performed, following the previously optim-
ized experimental procedure (11 kbar, alcohol, room tem-
perature) and the results from this are listed in Table 1. Es-
ter 1a was used in methanol and 1b in ethanol, to avoid
transesterification phenomena.
The results in Table 1 show that spiroaziridination took
place for both five-membered and six-membered rings, pro-
vided that the primary amine used was sufficiently nucleo-
philic and not too bulky. Thus, entries 1, 2, 4, 5, and 6
represent fair to good yields in 2 and 3. The presence of the
tert-butyl group on the cyclohexylidene ester results in the
formation of diastereomers, with selectivities in the 90%
range being observed (entries 1Ϫ4). Use of a chiral amine
such as (S)-α-methylbenzylamine (entry 4) produced spi-
roaziridine 2d as a mixture of four different diastereomers,
the ratio of which was potentially subject to influence both
by the axial/equatorial selectivity of the addition and by
induction by the chiral center of the amine. In reality, the
NMR spectrum of the crude mixture of 2d showed that the
first type of selectivity had remained in the 90% range,
[a]
´
´ ´
Laboratoire des Fonctions Azotees et Oxygenees Complexes de
´
l’IRCOF, UMR 6014 CNRS, Universite de Rouen,
76821 Mont St Aignan, France
Fax: (internat.) ϩ33 2 3552 2971
E-mail: jmaddalu@crihan.fr
[b]
Permanent address: Favorsky Institute of Chemistry, Siberian
Branch of Russian Academy of Sciences,
1 Favorsky St., 664033, Irkutsk, Russia
Eur. J. Org. Chem. 2001, 2569Ϫ2576
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0713Ϫ2569 $ 17.50ϩ.50/0
2569

A. Rulev, J. Maddaluno
FULL PAPER
The reaction between 1b and aniline (entry 7) provided
the α-amino ester 9c, probably because a migration of the
double bond occurred first, and was immediately followed
by a nucleophilic substitution of the allylic bromine by the
aniline (Scheme 2). Depending on the exact experimental
conditions, this latter compound tended to reconjugate
through a second migration of the double bond back to its
original position, affording the apparent ipso-substitution
product: the enamino ester 10c. We were indeed able to es-
tablish in one case that 9 is the kinetic product while 10 is
the thermodynamic one: subjection of pure 9e (R3 ϭ iPr)
to the conditions of the reaction (EtOH, 1 equiv. iPrNH2,
11 kbar, room temp.) for 62 h produced a 3:1 mixture of
10e and 9e.
This reaction was also sensitive to the bulkiness of the
carbon α to the nitrogen atom. For instance, use of isoprop-
ylamine instead of n-propylamine (entry 9) resulted in a
mixture of the expected aziridine together with the two
products originating from the double bond migration
Scheme 1
Table 1. Hetero-Michael addition of 2 equiv. of primary amines to cycloalkylidene acetates under high pressure (11 kbar)
Entry
Ester
R3
Time (h)
Solvent Product
Yield (de)%
Side products
1
2
3
1a
1a
1a
Bn
nPr
Ph
96
36
65
MeOH
MeOH
2a
2bc
83 (91)
70 (91)
9 (?)[b]
Ϫ
4 (17%)
6 (44%) ϩ 8c (25%)
MeOH[a]
4
5
6
7
8
9
10
1a
1b
1b
1b
1b
1b
1b
PhCHMe
Bn
nPr
Ph
PhCHMe
iPr
Ph2CH
40
48
48
65
40
65
48
MeOH
EtOH
EtOH
EtOH[a]
EtOH
EtOH
EtOH
2d
3a
3b
Ϫ
Ϫ
3e
Ϫ
78 (?)[c]
Ϫ
57 (Ϫ)[d]
9a (12%)
5 (8%)
78 (Ϫ)[d]
0
9c (22%) ϩ 10c (50%)
0
16 (Ϫ)[d]
0
9d (56%)[e]
9e (19%) ϩ 10e (48%)
9f (10%)[e]
[a]
[b]
Reaction run in the presence of 1 equiv. of aniline ϩ 1 equiv. of NEt3. Ϫ de not determined (only one isomer was recovered after
[c]
[d]
flash chromatography). Ϫ
asymmetric center created. Ϫ Together with starting material 1b (30% for entry 8, 69% for entry 10).
Only one pair of diastereoisomers was detected in the crude reaction mixture by NMR. Ϫ
Only one
[e]
while the asymmetric induction was extremely low. This dis-
appointing result is not too surprising in view of related
experiments dealing with the addition of chiral amines to
crotonates.[5b] The nucleophilic character of some of the
amines used in excess in these reactions tends partly to
transform the aziridino esters 2b and 3b into the corres-
ponding amides 4 and 5, as previously emphasized by de
Meijere[11] and ourselves.[12]
Conversely, a decrease in the amine nucleophilicity is also
of consequence: use of aniline instead of an alkylamine re-
sults, in the case of 1a, in the addition of methanol, provid-
ing the β-methoxy-α-bromo ester 6 (Scheme 1 and Table 1)
in fair yield and good diastereoisomeric excess (90% from
NMR spectroscopic data). In contrast, the side product 8c,
also detected in this reaction, the origin of which is discus-
sed below, did not exhibit any diastereomeric excess, as re-
ported in our previous paper.[12] Interestingly, under com-
parable experimental conditions, ethanol hardly added to
1a, producing the corresponding β-ethoxyester in only
12% yield.[16]
Scheme 2
2570
Eur. J. Org. Chem. 2001, 2569Ϫ2576

Spiroaziridination of Cycloalkylidene Esters under High Pressure
FULL PAPER
within the ring as described above (Scheme 2). With less of cis and trans isomers of 17 was obtained, but this time
nucleophilic or more cumbersome amines (such as aniline, careful flash chromatography on silica gel allowed us to
α-methylbenzylamine, or diphenylmethylamine, entries 7, 8, isolate very pure samples of each isomer.
and 10), the aziridination no longer took place, the two
deconjugation/substitution products 9 and 10 being reco-
vered in various ratios, together with significant amounts
of starting material 1b.
To extend our investigations further, we also considered
the case of methyl 2-chloro-2-(cyclopropylidene)acetate 1c,
the activated substrate previously studied by de Meijere and
colleagues.[11] No aziridination could be observed when the
above conditions were applied to this substrate; treatment
of 1c with 2 equiv. benzylamine in methanol provided only
the unexpected N-benzylglutaramide methyl ester 13, in
15% yield (Scheme 3). To avoid possible opening of the azir-
idine by the nucleophiles present in the medium, we re-
peated the reaction in ethanol (vide supra), with only one
equivalent of benzylamine. Only diethyl glutarate 14 was
recovered this time, in 19% yield. We interpret these rather
Scheme 4
These were separately subjected to compression in the
presence of benzylamine in methanol at 11 kbar. As shown
in Scheme 5, double aziridination took place in fair to good
isolated yields (48% for the cis isomer, 63% for the trans
one), the products 18 being obtained as a 50:50 mixture of
two major diastereoisomers plus two minor ones. Interest-
ingly, it appeared on the basis of simple TLC observation
that the major diastereomers obtained from the diester cis-
17 corresponded to the minor diastereomers obtained from
the diester trans-17 and vice versa. The ratio between the
major diastereomers and the minor ones was about 5:1, as
puzzling results in terms of the sequence depicted in
Scheme 3. It is known that the putative intermediate spi-
roaziridine resulting from the cyclization of chloro ester 11
rearranges in basic methanolic solution into cyclobutenam-
ino ester 12. This stable product has indeed already been
obtained by addition of benzylamine to 1c and has been
fully characterized.[11]
1
determined from H NMR integration.
Scheme 3
Actually, 12 can be obtained in about 75% yield under
our conditions, provided that only one equivalent of amine
is used, in a nonalcoholic solvent such as a 50:50 mixture
of acetonitrile and THF.[17] We assume that, depending on
the conditions, the tautomeric imino ester form of 12 can
eventually undergo an addition of either benzylamine or
ethanol to give an intermediate imidate or amidine that
would hydrolyze upon workup into the corresponding
amide or ester appendage.
Finally, we also explored the possibilities opened by a
tandem version of this reaction, using dibromodiester 17.
This latter was prepared by means of a double Wittig reac-
tion between cyclohexanedione 15 and (methoxycarbonyl-
methylene)triphenylphosphorane (Scheme 4).[18] As de-
scribed, the expected diester 16 was obtained (as a 50:50
inseparable mixture of cis and trans isomers), together with
Scheme 5
These results can be explained by considering the stereo-
the corresponding mono ester. Pure 16 was then bromin- chemical consequences of the tandem aspect of the reac-
ated in chloroform and the crude tetrabromodiester sub- tion. Up to four (racemic) stereoisomers can indeed be ex-
jected to base-induced dehydrobromation, using the condi- pected from this bis-addition, the attack of the nitrogen on
tions previously optimized for 1a.[12] Again, a 50:50 mixture the exocyclic double bond taking place either in a syn or
Eur. J. Org. Chem. 2001, 2569Ϫ2576
2571

A. Rulev, J. Maddaluno
FULL PAPER
in an anti fashion with respect to the first one (Scheme 5).
Assuming that i) the first addition has no or little influence
on the second one (the newly formed aziridine being in a
remote ‘‘para’’ position with respect to the remaining
double bond), ii) the proton source in the protonation step
immediately following the addition is the methanol and that
it adds mainly anti to the incoming amine (Figure 1), as
established in a closely related example,[19] and iii) the intra-
molecular nucleophilic substitution closing the aziridine
ring is almost perfectly of the SN2 type, as generally ac-
cepted (Figure 1), one may then predict that the two major
isomers result from the syn and anti second additions (pro-
ducing 18a and 18b, in which the ester groups are syn, when
starting from cis-17, and 18c and 18d, in which they are
trans, when starting from trans-17). In the framework of
these hypothesis, the two minor diastereomers may, in both
cases, derive from a small amount of syn protonation, pos-
sibly occurring through competitive intramolecular proton
transfer from the newly formed secondary amine. Competi-
tion between syn and anti proton transfers following the
addition of a neutral nucleophile has been implicated in at
least one case, with thiophenol and an α,β-unsaturated
amides, by Miyata and colleagues.[20]
Experimental Section
1H and 13C NMR spectra were measured in deuterochloroform on
Bruker AM 200 and 300 FT spectrometers, coupling constants (J)
are given in Hz. Low resolution MS and GC/MS analyses (EI,
70 eV) were performed on an ATI-Unicam Automass instrument.
High resolution mass spectra (HRMS) were recorded with a Jeol
JMS AX 500 spectrometer. IR spectra were measured on a
PerkinϪElmer 16 PC FT-IR spectrometer. High pressure reactions
were performed in a Unipress piston cylinder apparatus, for pres-
sures up to 14 kbar. The silica gel used for flash chromatography
was from the SDS company (230Ϫ400 mesh).
THF was distilled from sodium/benzophenone. Dichloromethane,
methanol, and ethanol were dried over 3-A molecular sieves and
then distilled.
˚
Methyl 2-bromo-2-(4-tert-butylcyclohexylidene)acetate (1a) was
prepared as reported previously.[12] The ethyl cyclopentylideneacet-
ate was obtained from cyclopentanone by means of
a
WittigϪHorner reaction.[21] The ester 1b was prepared from ethyl
cyclopentylideneacetate in similar fashion to 1a, in 72% yield.
Ethyl 2-Bromo-2-cyclopentylideneacetate (1b): Oil. IR (KBr): ν˜ ϭ
1615 (CϭC), 1708 (CϭO) cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.25
1
(t, J ϭ 7.1 Hz, 3 H, CH3); 1.60Ϫ1.70 (m, 2 H), 1.70Ϫ1.80 (m, 2
H, 3-CH2, 4-CH2); 2.47 (t, J ϭ 7.2 Hz, 2 H), 2.71 (t, J ϭ 7.1 Hz,
2 H, 2-CH2, 5-CH2); 4.18 (q, J ϭ 7.1 Hz, 2 H, CH2O). Ϫ 13C NMR
(CDCl3): δ ϭ 14.61 (CH3); 25.58, 28.41 (C3, C4); 36.19, 40.07 (C2,
C5); 62.08 (CH2O); 105.83 (ϭCBr); 163.46 (C1); 165.96 (CϭO). Ϫ
MS: m/z (%) ϭ 234, 232 (80) [Mϩ]; 206, 204 (60), 79 (100). Ϫ
C9H13BrO2 (233.1): calcd. C 46.36; H 5.62; found C 46.34; H 5.54.
General Procedure for the Treatment of Esters 1a and 1b with
Amines: A solution of the ester 1a or 1b (1 mmol) and amine
(2.0Ϫ2.5 mmol) in the corresponding alcohol (3Ϫ4 g) was allowed
to stand under 11 kbar pressure at room temp. for a suitable time
(see Table 1). After reversion to atmospheric pressure, the solvent
was evaporated. The residue was chromatographed (pentane/Et2O)
to yield the corresponding reaction products. The following com-
pounds were prepared in this manner.
Figure 1. Proposed detailed mechanism for the anti protonation
and spiroaziridination following the hetero-Michael addition reac-
tion.
Spiroaziridine 2a: Oil. All spectroscopic data in agreement with the
literature (ref.[12]).
Spiroaziridine 2b: Oil. IR (KBr): ν˜ ϭ 1724, 1750 (CϭO) cmϪ1. Ϫ
1H NMR (CDCl3): major isomer: δ ϭ 0.83 (s, 9 H, t-C4H9); 0.92
(t, J ϭ 7.5 Hz, 3 H, CH3CH2CH2N); 1.00Ϫ1.90 [m, 11 H, CH and
CH2 (cyclohex.) and CH3CH2CH2N]; 1.97 (s, 1 H, CHN); 2.47 (AB
system, 2 H, NCH2); 3.71 (s, 3 H, OCH3); minor isomer: δ ϭ 0.80
(s, 9 H, t-C4H9); 0.87 (t, J ϭ 7.0 Hz, 3 H, CH3CH2CH2N);
1.00Ϫ1.80 (m, 11 H, CH and CH2 (cyclohex.) and CH3CH2CH2N);
1.91 (s, 1 H, CHN); 2.09 (qd, J ϭ 9.0, 6.4 Hz, 1 H, NCH2); 2.81
(qd, J ϭ 9.4, 5.4 Hz, 1 H, NCH2); 3.65 (s, 3 H, OCH3). Ϫ 13C
NMR (CDCl3): major isomer: δ ϭ 12.15 (CH3); 23.55 (CH2CH3);
26.38 (C3); 27.38 (C5); 27.93 [C(CH3)3]; 29.39 (C6); 32.19
[C(CH3)3]; 32.70 (C2); 48.17 (C4); 48.93 (CHN); 51.06 (C1); 52.20
(OCH3); 53.97 (NCH2); 171.48 (CϭO); minor isomer: δ ϭ 12.25
(CH3); 23.61 (CH2CH3); 25.98 (C3); 26.44 (C5); 27.89 [C(CH3)3];
28.55 (C6); 32.56 [C(CH3)3]; 32.85 (C2); 47.89 (C4); 49.28 (CHN);
Conclusion
The results presented in this paper indicate that the spi-
roaziridination reaction we have previously described for
cyclohexylidene α-bromo esters can be extended to cyclo-
pentylidene and bis-spirocyclohexylidene ones, but not to
cyclopropylidene bromo esters. Most conventional nucleo-
philic primary amines are also within the scope of this reac-
tion. However, with poorly nucleophilic or bulky amines,
the system undergoes a competitive double bond isomeriz-
ation reaction, which yields α,β- or β,γ-unsaturated α-am- 49.73 (C1); 52.24 (OCH3); 54.49 (NCH2); 171.37 (CϭO). Ϫ MS:
m/z (%) ϭ 267 (7) [Mϩ], 252 (25), 208 (60), 166 (50), 57 (100). Ϫ
C16H29NO2 (267.4): calcd. C 71.87; H 10.93; N 5.24; found C
71.87; H 11.02; N 5.12.
ino esters (depending on the cycloalkyl ring size). This
‘‘side’’ reaction offers an interesting means of access to un-
usual compounds that may be considered as nonproteog-
enic amino acids. Further developments in this area are cur-
rently in progress and will be reported in due time.
Spiroaziridine 2c: Oil. IR (KBr): ν˜ ϭ 1726, 1752 (CϭO) cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.79 (s, 9 H, t-C4H9); 1.00Ϫ1.90 [m, 9 H,
2572
Eur. J. Org. Chem. 2001, 2569Ϫ2576

Spiroaziridination of Cycloalkylidene Esters under High Pressure
FULL PAPER
CH2 and CH (cyclohex.)]; 2.68 (s, 1 H, CHN); 3.76 (s, 3 H, OCH3); H, CH3CH2CH2N); 1.20Ϫ1.95 [m, 13 H, CH2 and CH (cyclohex.)
6.75Ϫ7.20 (m, 5 H, C6H5). Ϫ 13C NMR (CDCl3): δ ϭ 26.73 (C3); and CH3CH2CH2N]; 2.13 (minor isomer), 2.17 (major isomer) (2
27.38 (C5); 28.28 [C(CH3)3]; 32.31 [C(CH3)3]; 33.24 (C6); 35.72 s, 1 H, CHN); 2.70 (AB system, 2 H, CH2N); 3.42 (quint, J ϭ
(C2); 48.24 (C4); 48.58 (CHN); 52.93 (OCH3); 53.27 (C1); 120.93, 6.7 Hz, 2 H, CH2NCO). Ϫ 13C NMR (CDCl3): major isomer: δ ϭ
123.26, 129.41, 149.06 (C6H5); 171.48 (CϭO). Ϫ MS: m/z (%) ϭ 11.79 (CH3); 12.31 (CH3); 23.44 (CH2CH3); 23.96 (CH2CH3); 26.34
301 (2) [Mϩ], 300 (6), 242 (100), 158 (20), 104 (45), 77 (78), 57 (99). (C3); 27.26 (C5); 27.89 [C(CH3)3]; 29.96 (C6); 32.85 (C2); 32.87
Ϫ C19H27NO2 (301.4): calcd. C 75.71; H 9.03; N 4.65; found C [C(CH3)3]; 40.81 (CH2N), 48.47 (C4); 50.12 (C1); 51.51 (CHN);
75.73; H 10.02; N 4.28.
53.09 (NCH2); 170.13 (CϭO); minor isomer: 11.79 (CH3); 12.38
(CH3); 23.42 (CH2CH3); 23.96 (CH2CH3); 25.96 (C3); 27.26 (C5);
27.80 [C(CH3)3]; 28.87 (C6); 32.46 [C(CH3)3]; 32.85 (C2); 40.81
(CH2N), 47.81 (C4); 49.20 (C1); 51.18 (CHN); 53.75 (NCH2);
170.07 (CϭO). Ϫ MS: m/z (%) ϭ 294 (7) [Mϩ], 208 (100), 166 (23).
Ϫ C18H34N2O (294.5): calcd. C 73.42; H 11.64; N 9.51; found C
73.12; H 11.61; N 9.17.
Spiroaziridine 2d: Solid, M.p. ϭ 81 °C. Ϫ IR (KBr): ν˜ ϭ 1726,
1
1747 (CϭO) cmϪ1. Ϫ H NMR (CDCl3, mixture of the two major
diastereomers): δ ϭ 0.65, 0.73 (2 s, 9 H, t-C4H9); 1.24, 1.27 (2 d,
J ϭ 6.4 Hz, 3 H, CH3CH); 1.00Ϫ1.80 (m, 9 H, CH2 and CH (cyclo-
hex.)]; 1.88, 2.02 (2 s, 1 H, CHN); 3.20Ϫ3.35 (m, 1 H, CHCH3);
3.58, 3.71 (2 s, 3 H, OCH3); 7.05Ϫ7.35 (m, 5 H, C6H5). Ϫ 13C
NMR (CDCl3): first isomer: δ ϭ 24.94 (CH3CH); 26.59 (C3); 27.67
(C5); 28.14 [C(CH3)3]; 32.52 [C(CH3)3]; 30.04 (C6); 32.90 (C2);
48.18 (C4); 48.56 (CHN); 52.55 (OCH3); 52.67 (C1); 62.09
(CHCH3); 126.90, 127.29, 128.82, 145.55 (C6H5); 171.73 (CϭO);
second isomer: δ ϭ 25.21 (CH3CH); 26.69 (C3); 27.75 (C5); 28.20
[C(CH3)3]; 32.77 [C(CH3)3]; 29.63 (C6); 32.99 (C2); 48.08 (C4);
48.48 (CHN); 52.37 (OCH3); 52.88 (C1); 60.86 (CHCH3); 127.05,
127.46, 128.95, 145.15 (C6H5); 171.35 (CϭO). Ϫ MS: m/z (%) ϭ
329 (3) [Mϩ], 270 (15), 224 (98), 180 (32), 105 (99), 81 (88), 57
(100). Ϫ C21H31NO2 (329.5): calcd. C 76.55; H 9.48; N 4.25; found
C 76.58; H 9.72; N 4.52.
Spiroaziridine 5: Oil. IR (KBr): ν˜ ϭ 1668 (br. s, CϭO), 3382 (NH)
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.84 (t, J ϭ 7.5 Hz, 3 H,
CH3CH2CH2N); 0.88 (t, J ϭ 7.2 Hz, 3 H, CH3CH2CH2N);
1.40Ϫ1.75 [m, 12 H, CH2 (cyclopent.) and CH3CH2CH2N]; 1.93
(s, 1 H, CHN); 2.10 (dt, J ϭ 11.7, 7.5 Hz, 1 H, NCH2); 2.45 (dt,
J ϭ 11.7, 7.5 Hz, 1 H, NCH2); 3.00Ϫ3.20 (m, 2 H, CH2NCO); 6.63
(br.s, 1 H, NH). Ϫ 13C NMR (CDCl3): δ ϭ 11.81, 12.30
(CH3CH2CH2N); 23.60 (CH3CH2CH2N); 25.20, 26.20 (C3, C4);
27.53, 32.48 (C2, C5); 40.76 (NCH2); 51.44 (CHN); 54.70 (CN);
55.35 (CH2NCO); 170.62 (CϭO). Ϫ MS: m/z (%) ϭ 224 (22) [Mϩ],
138 (100), 96 (60). Ϫ C13H24N2O (224.3): calcd. C 69.60; H 10.78;
N 12.49; found C 68.02; H 10.68; N 12.20.
Spiroaziridine 3a: Oil. IR (KBr): ν˜ ϭ 1717, 1744 (CϭO) cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.19 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O);
1.50Ϫ1.90 (m, 8 H, CH2 (cyclopent.)]; 2.14 (s, 1 H, CHN); 3.63 (s,
2 H, PhCH2); 4.05Ϫ4.20 (m, 2 H, (CH2O); 7.05Ϫ7.35 (m, 5 H,
C6H5). Ϫ 13C NMR (CDCl3): δ ϭ 14.93 (CH3); 25.20, 26.18 (C3,
C4); 27.52, 32.78 (C2, C5); 49.83 (CHN); 56.16 (C1); 57.95
(NCH2); 61.25 (CH2O); 127.26, 127.80, 128.80, 139.54 (C6H5);
171.00 (CϭO). Ϫ MS: m/z (%) ϭ 259 (4) [Mϩ], 168 (68), 140 (34);
91 (100). Ϫ C16H21NO2 (259.3): calcd. C 74.10; H 8.16; N 5.40;
found C 74.27; H 8.22; N 5.24.
Methyl Anilino(4-tert-butylcyclohex-1-en-1-yl)acetate (8c): Oil. IR
1
(KBr): ν˜ ϭ 1738 (CϭO), 3405 (NH) cmϪ1. Ϫ H NMR (CDCl3):
δ ϭ 0.77, 0.78 (2 s, 9 H, t-C4H9); 1.00Ϫ2.20 [m, 7 H, CH2 and CH
(cyclohex.)]; 3.68 (s, 3 H, OCH3); 4.37 (s, 1 H, CHN); 4.47 (br. s.,
1 H, NH); 5.82 (s, 1 H, ϭCH); 6.45Ϫ6.65 (m, 3 H, C6H5);
7.00Ϫ7.15 (m, 2 H, C6H5). Ϫ 13C NMR (CDCl3): δ ϭ 24.52, 24.66
(C5); 26.90 (C6); 27.48, 27.55 (C3); 27.82 [(CH3)3C]; 32.84
[C(CH3)3]; 44.30, 44.55 (C4); 53.11, 53.16 (OCH3); 62.81 (CHN);
113.98, 114.04, 118.48, 129.84, 147.18 (C6H5); 126.61, 128.02 (C2);
134.19, 134.50 (C1); 173.33, 173.38 (CϭO). Ϫ MS: m/z (%) ϭ 301
(6) [Mϩ], 300 (25); 242 (59); 158 (37); 93 (84); 77 (100). Ϫ
C19H27NO2 (301.4): calcd. C 75.71; H 9.03; N 4.65; found C 74.55;
H 9.62; N 4.82.
Spiroaziridine 3b: Oil. IR (KBr): ν˜ ϭ 1717, 1747 (CϭO) cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 7.5 Hz, 3 H, CH3CH2CH2N);
1.23 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.45Ϫ1.85 [m, 10 H, CH2
(cyclopent.) and CH3CH2CH2N]; 1.99 (s, 1 H, CHN); 2.15, 2.45
(AB system, 2 H, NCH2); 4.11, 4.15 (2 q, J ϭ 7.2 Hz, 2 H, CH2O).
Ethyl Benzylamino(cyclopent-1-en-1-yl)acetate (9a): Oil. IR (KBr):
ν˜ ϭ 1732 (CϭO), 3338 (NH) cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.20
(t, J ϭ 7.2 Hz, 3 H, CH3); 1.75Ϫ1.85 (m, 2 H, 4-CH2); 1.90 (br. s.,
1 H, NH); 2.20Ϫ2.35 (m, 4 H, 3-CH2 and 5-CH2); 3.65 (AB system,
2 H, PhCH2); 3.92 (s, 1 H, CHN); 4.12 (q, J ϭ 7.2 Hz, 2 H, CH2O);
5.62 (s, 1 H, ϭCH); 7.10Ϫ7.30 (m, 5 H, C6H5). Ϫ 13C NMR
(CDCl3): δ ϭ 14.97 (CH3); 23.80 (C4); 32.92, 33.03 (C3, C5); 52.26
(CH2N); 61.56 (CH2O); 62.19 (CHN); 127.73, 129.04, 129.45,
141.15 (C6H5); 129.02 (ϭCH); 140.38 (C1); 173.69 (CϭO). Ϫ MS:
m/z (%) ϭ 259 (0.2) [Mϩ], 186 (94); 91 (100). Ϫ C16H21NO2 (259.3):
calcd. C 74.10; H 8.16; N 5.40; found C 74.84; H 8.86; N 5.56.
Ϫ
13C NMR (CDCl3):
δ ϭ 12.15 (CH3CH2CH2N); 14.79
(CH3CH2O); 23.41 (CH3CH2CH2N); 25.03, 25.96 (C3, C4); 26.93,
32.56 (C2, C5); 49.64 (CHN); 55.41 (C1); 56.41 (NCH2); 61.04
(OCH2); 171.25 (CϭO). Ϫ MS: m/z (%) ϭ 211 (15) [Mϩ], 138 (71),
95 (100). Ϫ C12H21NO2 (211.3): calcd. C 68.21; H 10.02; N 6.63;
found C 67.65; H 10.08; N 6.65.
Spiroaziridine 3e: Oil. IR (KBr): ν˜ ϭ 1719, 1746 (CϭO) cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.04 (d, J ϭ 6.4 Hz, 3 H, CH3CH); 1.08
(d, J ϭ 6.4 Hz, 3 H, CH3CH); 1.20 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O);
1.50Ϫ1.85 [m, 8 H, CH2 (cyclopent.)]; 1.98 (s, 1 H, CHN);
1.90Ϫ2.00 (m, 1 H, CHCH3); 4.12, 4.15 (2 q, J ϭ 7.2 Hz, 2 H,
CH2O). Ϫ 13C NMR (CDCl3): δ ϭ 15.02 (CH3CH2O); 22.70, 22.78
(CH3CH); 25.24, 26.23 (C3, C4); 26.77, 33.18 (C2, C5); 48.79
(CHN); 54.53 (CHCH3); 56.66 (C1); 61.24 (CH2O); 171.47 (CϭO).
Ϫ MS: m/z (%) ϭ 211 (13) [Mϩ], 210 (12); 168 (11); 149 (75); 71
(63); 57 (67); 43 (100). Ϫ C12H21NO2 (211.3): calcd. C 68.21; H
10.02; N 6.63; found C 67.85; H 10.09; N 6.71.
Ethyl Cyclopent-1-en-1-yl(propylamino)acetate (9b): This com-
pound was not obtained under the above hyperbaric conditions,
which provided only spiroaziridines 3b and 5 (see Table 1). It was,
however, prepared under thermal conditions comparable to those
described in ref. 12. Oil. IR (KBr): ν˜ ϭ 1648 (CϭC), 1736 (CϭO),
1
3334 (NH) cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.85 (t, J ϭ 7.5 Hz, 3
H, CH3CH2CH2N); 1.20 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O);
1.35Ϫ1.50 (m, 2 H, CH3CH2CH2N); 1.70 (br. s., 1 H, NH);
Spiroaziridine 4: Oil. IR (KBr): ν˜ ϭ 1670 (br.s, CϭC, CϭO), 3382
1
(NH) cmϪ1. Ϫ H NMR (CDCl3): mixture of two diastereomers: 1.75Ϫ1.90 (m, 2 H, 4-CH2); 2.20Ϫ2.35 (m, 4 H, 3-CH2 and 5-CH2);
δ ϭ 1.07 (major isomer), 1.09 (minor isomer) (2 s, 9 H, t-C4H9); 2.35Ϫ2.50 (m, 2 H, CH2N); 3.88 (s, 1 H, CHN); 4.12 (q, J ϭ
1.11 (t, J ϭ 7.5 Hz, 3 H, CH3CH2CH2N); 1.13 (t, J ϭ 7.5 Hz, 3 7.2 Hz, 2 H, CH2O); 5.61 (s, 1 H, ϭCH). Ϫ 13C NMR (CDCl3):
Eur. J. Org. Chem. 2001, 2569Ϫ2576
2573

A. Rulev, J. Maddaluno
FULL PAPER
δ ϭ 12.38 (CH3CH2CH2N); 14.91 (CH3CH2O); 23.76 (C4); 23.88 MS: m/z (%) ϭ 335 (0.3) [Mϩ], 262 (32); 167 (100). Ϫ C22H25NO2
(CH3CH2CH2N); 32.82, 32.95 (C3, C5); 50.44 (CH2N); 63.12 (335.4): calcd. C 78.77; H 7.51; N 4.18; found C 78.69; H 7.75;
(CHN); 61.44 (CH2O); 129.06 (C2); 141.26 (C1); 173.85 (CϭO). Ϫ N 4.46.
MS: m/z (%) ϭ 211 (6) [Mϩ], 167 (27); 149 (100); 97 (72); 71 (99).
Ϫ C12H21NO2 (211.3): calcd. C 68.21; H 10.02; N 6.63; found C
68.15; H 10.88; N 6.73.
Ethyl Anilino(cyclopentylidene)acetate (10c): Oil. IR (KBr): ν˜ ϭ
1644 (CϭC), 1703 (CϭO), 3379 (NH) cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ 1.16 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.50Ϫ1.60 (m, 2 H),
1.65Ϫ1.75 (m, 2 H, 3-CH2 and 4-CH2); 2.30 (t, J ϭ 7.2 Hz, 2 H),
2.78 (t, J ϭ 7.2 Hz, 2 H, 2-CH2 and 5-CH2); 4.10 (q, J ϭ 7.2 Hz,
2 H, CH2O); 5.17 (br. s, 1 H, NH); 6.45Ϫ6.70 (m, 3 H, C6H5);
7.00Ϫ7.15 (m, 2 H, C6H5). Ϫ 13C NMR (CDCl3): δ ϭ 14.89 (CH3);
26.11, 27.72 (C3, C4); 33.56, 34.62 (C2, C5); 61.17 (CH2O); 114.89,
119.21, 129.60, 145.88 (C6H5); 122.41 (C1); 157.29 (ϭC-N); 166.68
(CϭO). Ϫ MS: m/z (%) ϭ 245 (35) [Mϩ], 244 (37); 215 (14); 198
(12); 170 (100); 104 (58); 77 (98). Ϫ C15H19NO2 (245.3): calcd. C
73.44; H 7.87; N 5.71; found C 73.33; H 7.82; N 5.83.
Ethyl Anilino(cyclopent-1-en-1-yl)acetate (9c): Oil. IR (KBr): ν˜ ϭ
1
1733 (CϭO), 3398 (NH) cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.19 (t,
J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.75Ϫ1.90 (m, 2 H, 4-CH2);
2.20Ϫ2.35 (m, 4 H, 3-CH2 and 5-CH2); 4.14 (q, J ϭ 7.2 Hz, 2 H,
CH2O); 4.43 (br. s, 1 H, NH); 4.62 (s, 1 H, CHN); 5.73 (s, 1 H, ϭ
CH); 6.50Ϫ6.70 (m, 3 H, C6H5); 7.05Ϫ7.15 (m, 2 H, C6H5). Ϫ 13C
NMR (CDCl3): δ ϭ 14.86 (CH3); 23.84 (C4); 33.04, 33.11 (C3, C5);
58.37 (CHN); 62.08 (CH2O); 114.10, 118.73, 129.87, 147.21 (C6H5);
129.97 (C2); 140.47 (C1); 172.54 (CϭO). Ϫ MS: m/z (%) ϭ 245 (9)
[Mϩ], 244 (9); 172 (100); 77 (44). Ϫ C15H19NO2 (245.3): calcd. C
73.44; H 7.87; N 5.71; found C 73.21; H 7.98; N 5.79.
Ethyl Cyclopentylidene(isopropylamino)acetamide (10e): Oil. IR
(KBr): ν˜ ϭ 1640 (CϭC), 1690 (CϭO), 3340 (NH) cmϪ1. Ϫ 1H
NMR (CDCl3): δ ϭ 0.99 (d, J ϭ 6.4 Hz, 6 H, CH3CH); 1.25 (t,
J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.55Ϫ1.70 (m, 4 H, 3-CH2 and 4-
CH2); 2.25Ϫ2.35 (m, 2 H), 2.55Ϫ2.65 (m, 2 H, 2-CH2 and 5-CH2);
2.68 (br. s., 1 H, NH); 3.12 (quint, J ϭ 6.4 Hz, 1 H, CH3CH); 4.15
(q, J ϭ 7.2 Hz, 2 H, CH2O). Ϫ 13C NMR (CDCl3): δ ϭ 15.00
(CH3CH2O); 24.18 (CH3CH); 26.59, 27.83 (C3, C4); 33.48, 33.66
(C2, C5); 48.06 (CH3CH); 61.07 (CH2O); 128.76 (C1); 143.90 (ϭ
CϪN); 167.33 (CϭO). Ϫ MS: m/z (%) ϭ 211 (28) [Mϩ], 168 (15);
119 (10); 86 (98); 84 (94); 49 (98); 48 (100). Ϫ C12H21NO2 (211.3):
calcd. C 68.21; H 10.02; N 6.63; found C 67.96; H 9.92; N 6.49.
Ethyl Cyclopent-1-en-1-yl(α-methylbenzylamino)acetate (9d): Oil.
IR (KBr): first isomer: ν˜ ϭ 1650 (CϭC), 1732 (CϭO), 3331 (NH);
second isomer: n ϭ 1651 (CϭC), 1734 (CϭO), 3336 (NH) cmϪ1
.
1
Ϫ H NMR (CDCl3): first diastereomer: δ ϭ 1.19 (t, J ϭ 7.2 Hz,
3 H, (CH3CH2O); 1.27 (d, J ϭ 6.4 Hz, 3 H, CH3CH); 1.70Ϫ1.85
(m, 2 H, 4-CH2); 1.88 (br. s., 1 H, NH); 2.10Ϫ2.35 (m, 4 H, 3-CH2
and 5-CH2); 3.64 (q, J ϭ 6.4 Hz, 1 H, CH3CH); 3.65 (s, 1 H, CHN);
4.12 (dq, J ϭ 7.2, 1.9 Hz, 2 H, CH2O); 5.52 (s, 1 H, ϭCH);
7.10Ϫ7.30 (m, 5 H, C6H5); second diastereomer: δ ϭ 1.13 (t, J ϭ
7.2 Hz, 3 H, CH3CH2O); 1.29 (d, J ϭ 6.8 Hz, 3 H, CH3CH);
1.70Ϫ1.90 (m, 2 H, 4-CH2); 2.01 (br. s., 1 H, NH); 2.10Ϫ2.35 (m,
4 H, 3-CH2 and 5-CH2); 3.63 (q, J ϭ 6.8 Hz, 1 H, CH3CH); 3.83
(s, 1 H, CHN); 4.03 (dq, J ϭ 7.2, 1.9 Hz, 2 H, CH2O); 5.51 (s, 1
H, ϭCH); 7.10Ϫ7.30 (m, 5 H, C6H5). Ϫ 13C NMR (CDCl3): first
isomer: δ ϭ 14.97 (CH3CH2O); 23.67 (C4); 33.02, 33.39 (C3, C5);
25.66 (CH3CH); 57.04 (CH3CH); 60.63 (CHN); 61.37 (CH2O);
127.55, 127.70, 129.05, 145.59 (C6H5); 128.19 (C2); 141.66 (C1);
174.47 (CϭO); second isomer: δ ϭ 14.81 (CH3CH2O); 23.78 (C4);
32.22, 32.95 (C3, C5); 24.51 (CH3CH); 55.74 (CH3CH); 60.19
(CHN); 61.47 (CH2O); 127.52, 127.68, 129.03, 145.57 (C6H5);
130.10 (C2); 140.98 (C1); 173.38 (CϭO). Ϫ MS: m/z (%) ϭ 273 (3)
[Mϩ], 258 (8); 201 (80); 97 (100). Ϫ C17H23NO2 (273.4): calcd. C
74.69; H 8.48; N 5.12; found C 74.92; H 8.73; N 5.32.
Isomerization of Cyclopent-1-en-1-yl(isopropylamino)acetate 9e into
Ethyl Cyclopentylidene(isopropylamino)acetate (10e): A solution of
ester 9e (8 mg), isopropylamine (9 mg), and triethylamine (20 mg)
in ethanol (1 mL) was allowed to stand at 11 kbar at room temper-
ature for 62 h. After a return to atmospheric pressure, the solvent
and amines were evaporated to yield a mixture (1:3) of the initial
substrate 9e and its conjugated isomer 10e, according to 1H NMR.
Preparation of Dibromo Diester 17: A solution of Br2 (1.6 g,
10 mmol) in CHCl3 (15 mL) was added at 0 °C, over a period of
0.5 h, to a solution of diester 16 (1.1 g, 5 mmol) in CHCl3 (10 mL).
When the addition was complete, the solution was allowed to warm
slowly to room temperature, and stirred at room temp. for 4 h.
After evaporation of the solvent, the residue was dissolved in acet-
one (50 mL) and the solution was refluxed at the presence of
K2CO3 (1.4 g) for 8 h. After filtration and evaporation of the solv-
ent, the two isomers of diester 17 were isolated by flash chromato-
graphy (pentane/Et2O, 7:1) in 76% overall yield. Both are solids
(M.p. cis isomer: 117Ϫ118 °C, trans isomer: 130Ϫ131 °C) Ϫ IR
(KBr): cis isomer: ν˜ ϭ 1594 (CϭC), 1704 (CϭO) cmϪ1; trans iso-
Ethyl Cyclopent-1-en-1-yl(isopropylamino)acetate (9e): Oil. IR
(KBr): ν˜ ϭ 1651 (CϭC), 1735 (CϭO), 3330 (NH) cmϪ1. Ϫ 1H
NMR (CDCl3): δ ϭ 0.98 (d, J ϭ 6.0 Hz, 6 H, CH3CH); 1.20 (t,
J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.75Ϫ1.90 (m, 3 H, 4-CH2 and NH);
2.15Ϫ2.35 (m, 4 H, 3-CH2 and 5-CH2); 2.66 (quint, J ϭ 6.0 Hz, 1
H, CH3CH); 4.01 (s, 1 H, CHN); 4.12 (q, J ϭ 7.2 Hz, 2 H, CH2O);
5.61 (s, 1 H, ϭCH). Ϫ 13C NMR (CDCl3): δ ϭ 14.91 (CH3CH2O);
23.09, 23.77 (CH3CH); 23.72 (C4); 32.73, 32.98 (C3, C5); 46.95
(CH3CH); 60.46 (CHN); 61.48 (CH2O); 129.12 (C2); 141.28 (C1);
174.08 (CϭO). Ϫ MS: m/z (%) ϭ 211 (8) [Mϩ], 167 (18); 149 (69);
94 (48); 57(100). Ϫ C12H21NO2 (211.3): calcd. C 68.21; H 10.02; N
6.63; found C 67.92; H 10.01; N 6.62.
1
mer: ν˜ ϭ 1590 (CϭC), 1705 (CϭO) cmϪ1. Ϫ H NMR (CDCl3):
cis isomer: δ ϭ 2.62 [s, 4 H, CH2 (cyclohex.)]; 2.79 [s, 4 H, CH2
(cyclohex.)], 3.74 (s, 6 H, OCH3); trans isomer: δ ϭ 2.52 [t, J ϭ
6.5 Hz, 4 H, CH2 (cyclohex.)], 2.86 [t, J ϭ 6.5 Hz, 4 H, CH2 (cyclo-
hex.)]; 3.75 (s, 6 H, OCH3). Ϫ 13C NMR (CDCl3): cis isomer: δ ϭ
30.69 (C2, C3); 33.39 (C5, C6); 53.52 (OCH3); 108.57 (ϭCBr);
153.41 (C1, C4); 164.58 (CϭO); trans isomer: δ ϭ 29.38 (C3, C6);
33.81 (C2, C5); 53.26 (OCH3); 108.60 (ϭCBr); 153.07 (C1, C4);
164.28 (CϭO). Ϫ MS: m/z (%) ϭ 382 (15) [Mϩ]; 350 (28), 322 (52)
272, 271 (89), 191 (77), 103 (76), 59 (100). Ϫ C12H14Br2O4 (382.0):
calcd. C 37.73; H 3.69; Ϫ found C 37.97; H 3.73.
Ethyl Cyclopent-1-en-1-yl[(diphenylmethyl)amino]acetate (9f): Oil.
IR (KBr): ν˜ ϭ 1732 (CϭO), 3332 (NH) cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.18 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O); 1.75Ϫ1.90 (m,
2 H, 4-CH2); 2.20Ϫ2.35 (m, 5 H, 3-CH2, 5-CH2 and NH); 3.83 (s,
1 H, CHN); 4.12 (q, J ϭ 7.2 Hz, 2 H, CH2O); 4.70 (s, 1 H, CHPh2);
5.54 (s, 1 H, ϭCH); 7.10Ϫ7.50 (m, 10 H, C6H5). Ϫ 13C NMR
Reaction between Diester 17 and Benzylamine: A solution of trans
(CDCl3): δ ϭ 14.96 (CH3); 23.79 (C4); 33.05 (C3, C5); 60.64 diester 17 (191 mg, 0.5 mmol) and benzylamine (219 mg, 2 mmol)
(CHN); 61.50 (CH2O); 65.38 (CHPh2); 127.80, 128.14, 129.14, in a mixture of MeOH/CH2Cl2 (1:1, 4 g) was pressurized at 11 kbar
143.72, 144.46 (C6H5); 128.18 (C2); 141.31 (C1); 173.92 (CϭO). Ϫ
at room temperature for 70 h. After a return to atmospheric pres-
2574
Eur. J. Org. Chem. 2001, 2569Ϫ2576

Spiroaziridination of Cycloalkylidene Esters under High Pressure
sure, the solvent was removed and the residue was chromato-
FULL PAPER
c) Reaction in Acetonitrile/THF: the same reaction was performed
graphed (pentane/Et2O, 1:3) to give a mixture of two major (1:1) in a 1:1 acetonitrile/THF mixture under the conditions described
and two minor (1:1) diastereomers 18 (137 mg). Overall yield 63%.
above. After return to atmospheric pressure, the solvents were evap-
1
orated under reduce pressure to yield, according to H NMR, the
Dispiro Compound 18: Solid. IR (KBr): major isomers: ν˜ ϭ 1743
enamino ester 12 described earlier.[11]
1
(CϭO) cmϪ1; minor isomers: n ϭ 1744 (CϭO) cmϪ1. Ϫ H NMR
(CDCl3): major isomers: δ ϭ 1.50Ϫ1.90 [m, 8 H, CH2 (cyclohex.)];
2.13, 2.14 (2 s, 2 H, CHN); 3.63, 3.64 (2 s, 6 H, OCH3) 3.60Ϫ3.90
(AB system, 4 H, CH2Ph); 7.10Ϫ7.35 (m, 10 H, C6H5); minor iso-
mers: δ ϭ 1.50Ϫ1.95 [m, 8 H, CH2 (cyclohex.)]; 2.12, 2.14 (2 s, 2
H, CHN); 3.61, 3.65 (2 s, 6 H, OCH3) 3.60Ϫ3.90 (AB-system, 4 H,
CH2Ph); 7.10Ϫ7.35 (m, 10 H, C6H5). Ϫ 13C NMR (CDCl3): major
isomers: δ ϭ 27.71, 28.24 (C5, C6); 30.34, 30.46 (C2, C3); 48.56,
48.63 (CHN); 49.95, 50.23 (C1, C4); 52.47 (OCH3); 55.93 (PhCH2);
127.40, 127.77, 127.83, 128.82, 139.01, 139.07 (C6H5); 170.62,
170.72 (CϭO); minor isomers: δ ϭ 27.05, 27.49 (C5, C6); 31.05,
31.14 (C2, C3); 48.41, 48.53 (CHN); 50.05, 50.32 (C1, C4); 52.44
(OCH3); 55.93 (PhCH2); 127.38, 127.83, 127.90, 128.79, 128.81,
139.02, 139.07 (C6H5); 170.74, 170.79 (CϭO). Ϫ MS: m/z (%) ϭ
435 (2) [M ϩ 1]ϩ, 434 (2) [Mϩ], 375 (3), 330 (4), 257 (13), 178 (25),
91 (100). Ϫ C26H30N2O4 (434.5): calcd. C 71.87; H 6.96; N 6.45;
found C 71.74; H 7.14; N 6.39.
Acknowledgments
A. R. is grateful to the CNRS for a research associate position
(Aug. Ϫ Dec. 1999). We also wish to thank Prof. Armin de Meijere
(University of Göttingen, Germany) for samples of methyl 2-
chloro-2-(cyclopropylidene)acetate, Dr. Jean-Yves Valnot and Dr.
Isabelle Chataigner (IRCOF), and Prof. Jean d’Angelo (Univ. Paris
XI) for their productive comments.
[1]
[1a]
See for instance:
D. C. Cole, Tetrahedron 1994, 50,
9517Ϫ9582; G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996,
117Ϫ128. Ϫ [1b] E. Juaristi, Enantioselective Synthesis of β-Am-
[1c]
ino Acids, Wiley VCH, New York, 1997. Ϫ
N. N. Ro-
manova, A. G. Gravis, G. M. Shaidullina, I. F. Leshcheva, Y.
G. BundelЈ, Mendeleev Commun. 1997, 235Ϫ236.
[2]
[3]
The same reaction conditions using cis diester 17 (191 mg,
0.5 mmol) and benzylamine produced a mixture of four diastereo-
mers 18 (105 mg) in 48% overall yield.
D. Tanner, Angew. Chem. Int. Ed. Eng. 1994, 33, 599Ϫ619.
See for instance: [3a] G. Bouteville, Y. Gelas-Mialhe, R. Vessiere,
[3b]
Bull. Soc. Chim. Fr. 1971, 3264Ϫ3270. Ϫ
L. Wartski, C.
Wakselman, A. Sierra-Escudero, Bull. Soc. Chim. Fr. 1972,
[3c]
Reaction between Methyl 2-Chloro-2-(cyclopropylidene)acetate 1c
and Benzylamine. ؊ a) Reaction in Methanol: A solution of ester
1c (219 mg, 1.5 mmol) and benzylamine (321 mg, 3 mmol) in meth-
anol (3.5 mL) was pressurized at 11 kbar at room temperature for
48 h. After a return to atmospheric pressure, the solvent was re-
moved in vacuo and the residue was chromatographed on silica gel
(CH2Cl2/MeOH, 95:5) to give 13 (55 mg, 15%) as the only isol-
able product.
1478Ϫ1482. Ϫ
Heterocycl. Chem. 1974, 11, 347Ϫ349. Ϫ
E. Touraud, R. Vessiere, Can. J. Chem. 1982, 60, 2830Ϫ2851.
Y. Gelas-Mialhe, R. Hierle, R. Vessiere, J.
[3d]
Y. Gelas-Mialhe,
[3e]
Ϫ
J. Expert, Y. Gelas-Mialhe, R. Vessiere, J. Heterocycl.
Chem. 1985, 22, 1285Ϫ1289.
[4]
S. Martin, Tetrahedron 1980, 36, 419Ϫ460.
[5] [5a]
[5b]
M. Pfau, Bull. Soc. Chim. Fr. 1967, 1117Ϫ1125. Ϫ
J.
dЈAngelo, J. Maddaluno, J. Am. Chem. Soc. 1986, 108,
8112Ϫ8114.
[6]
M. Carducci, S. Fioravanti, M. A. Loreto, L. Pellacani, P. A.
Terdella, Tetrahedron Lett. 1996, 37, 3777Ϫ3778
Methyl 5-(Benzylamino)-5-oxopentanoate (13): Oil. IR (KBr): ν˜ ϭ
1649 (CϭO), 1737 (CϭO), 3295 (NH) cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ 1.88 (m, 2 H, 3-CH2); 2.18 (m, 2 H, 4-CH2); 2.28 (m, 2 H, 2-
CH2); 3.56 (s, 3 H, OCH3); 4.30 (s, 1 H, CH2Ph); 4.33 (s, 1 H,
CH2Ph); 6.14 (br. s, 1 H, NH); 7.10Ϫ7.30 (m, 5 H, C6H5). Ϫ 13C
NMR (CDCl3): δ ϭ 21.45, 33.66, 35.91 (CH2); 52.16 (OCH3);
128.02, 128.32, 129.24, 138.92 (C6H5); 172.67, 174.26 (CϭO). Ϫ
MS: m/z (%) ϭ 235 (28) [Mϩ], 204 (25); 175 (45); 106 (100); 91
(99). Ϫ C13H17NO3 (235.3): calcd. C 66.36; H 7.28; N 5.95; found
C 66.35; H 7.52; N 6.09.
[7] [7a]
M. N. Rao, A. G. Holkar, N. R. Ayyangar, Tetrahedron
Lett. 1989, 30, 4717Ϫ4720. Ϫ [7b] M. N. Rao, A. G. Holkar, N.
R. Ayyangar, Tetrahedron Lett. 1990, 31, 3343Ϫ3346. Ϫ
M. Mohan, B. S. Uphade, V. R. Choudhary, T. Ravindrana-
[7c]
J.
than, A. Sudalai, Chem. Commun. 1997, 1429Ϫ1430.
[8] [8a]
J. Cossy, J. P. Pete, Tetrahedron Lett. 1980, 21, 2947Ϫ2948.
[8b]
Ϫ
C. Meyer, J. P. Pete, O. Piva, Recl. Trav. Chim. Pays-Bas
1995, 114, 492Ϫ497.
[9]
J. Moulines, P. Charpentier, J. P. Bats, A. Nuhrich, A. M. Lami-
dey, Tetrahedron Lett. 1992, 33, 487Ϫ490.
E. Vedejs, S. Dax, G. R. Martinez, C. K. McClure, J. Org.
Chem. 1987, 52, 3470Ϫ3472.
M. Tamm, M. Thutewohl, C. B. Ricker, M. T. Bes, A. de Mei-
jere, Eur. J. Org. Chem. 1999, 2017Ϫ2024.
A. Y. Rulev, J. Maddaluno, G. Ple, J. C. Plaquevent, L. Du-
hamel, J. Chem. Soc., Perkin Trans. 1 1998, 1397Ϫ1401.
W. G. Dauben, J. M. Gerdes, Tetrahedron Lett. 1983, 24,
3841Ϫ3844.
J. Maddaluno, Ph.D. thesis, Univ. Paris VI, 1986.
Recent results by Reiser’s group have, however, shown that sec-
ondary amines can also behave as nucleophiles in conjugated
additions, provided that the hyperbaric reaction is performed
at 60 °C: O. Reiser, Poster # 39 at the European High Pressure
Research Group meeting, Kloster Banz (Germany), Aug. 30th
Ϫ Sept. 2nd 2000.
A. Y. Rulev, J. Maddaluno, unpublished data. The addition
of methanol to β-monosubstituted α,β-unsaturated esters takes
place at atmospheric pressure, as described by F. Dumas et
al. (ref.[19]).
[10]
[11]
[12]
[13]
b) Reaction in Ethanol: The same procedure was followed, but using
ethanol as solvent. Similar workup and chromatography on silica
gel (pentane/Et2O, 3:1) gave 11-Et (37 mg, 19%) and diethyl pen-
tanedioate 14 (35 mg, 19%). The isolated Michael adduct 11-Et was
unstable at room temp. and when stored in a solution of CDCl3 it
underwent decomposition in a few days. The spectral characteriza-
tion data for compound 11 were identical with those described earl-
ier.[22]
´
[14]
[15]
Ethyl 2-[1-(Benzylamino)cyclopropyl]-2-chloroacetate (11-Et): IR
1
(KBr): ν˜ ϭ 1750 (CϭO), 3340 (NH) cmϪ1. Ϫ H NMR (CDCl3):
δ ϭ 0.70Ϫ1.00 [m, 4 H, CH2 (cycloprop.)]; 1.25 (t, J ϭ 7.2 Hz, 3
H, CH3CH2O); 3.81 (d, J ϭ 12.8 Hz, ‘‘A’’ part of an AB system, 1
H, CH2Ph); 3.92 (d, J ϭ 12.8 Hz, ‘‘B’’ part of an AB system, 1 H,
CH2Ph); 4.19 (q, J ϭ 7.2 Hz, 2 H, CH2O); 4.34 (s, 1 H, CHCl);
7.10Ϫ7.30 (m, 5 H, C6H5). Ϫ 13C NMR (CDCl3): δ ϭ 14.73 (CH3);
15.26, 15.44 (CH2); 42.53 (Cquat); 50.92 (CH2N); 62.92 (OCH2);
63.58 (CHCl); 127.82, 128.82, 129.04, 140.34 (C6H5); 169.04 (Cϭ
O). Ϫ MS: m/z (%) ϭ 232 (28) [Mϩ Ϫ Cl]; 186 (44); 91 (100).
[16]
[17]
A solvent mixture compatible with the hetero-Michael addition
of amines (ref.[14]).
Eur. J. Org. Chem. 2001, 2569Ϫ2576
2575

A. Rulev, J. Maddaluno
FULL PAPER
[18]
[21]
[22]
M. R. Bryce, H. M. Coates, J. Cooper, L. C. Murphy, J. Org.
J. Volinsky, K. L. Erickson, J. Org. Chem. 1965, 30,
2208Ϫ2211.
Chem. 1984, 49, 3399Ϫ3401.
[19]
F. Dumas, B. Mezrhab, J. dЈAngelo, J. Org. Chem. 1996, 61,
H. Urata, H. Maekawa, S. Takahashi, T. Fuchikami, J. Org.
Chem. 1991, 56, 4320Ϫ4322.
2293Ϫ2304.
[20]
O. Miyata, T. Shinada, I. Ninomiya, T. Naito, Tetrahedron
Received November 6, 2000
Lett. 1991, 32, 3519Ϫ3522.
[O00563]
2576
Eur. J. Org. Chem. 2001, 2569Ϫ2576