Synthesis of N-protected β-aminocyclopropanedicarboxylates and their ring transformation to N-benzhydryl-3-alkoxycarbonyl-4,4-dialkyl-pyrrolidin-2- ones

Article abstract of DOI:10.1055/s-2005-869850

An easy and short synthesis of new N-protected β- aminocyclopropanedicarboxylates, a rather unexplored class of highly activated conformationally constrained β-amino acid derivatives, is described. Michael-induced ring closure (MIRC) of diphenylmethyliden

Full text of DOI:10.1055/s-2005-869850

LETTER
1521
Synthesis of N-Protected b-Aminocyclopropanedicarboxylates and
Their Ring Transformation to N-Benzhydryl-3-alkoxycarbonyl-4,4-dialkyl-
pyrrolidin-2-ones
Synthesis of
N
v
-Protected
b
e
-Aminocyc
n
lopropanedicarbox
M
ylates angelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Gent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 31 January 2005
ethyl 1-methyl pyridine-1,2(2H)-dicarboxylate,8 and the
Abstract: An easy and short synthesis of new N-protected b-ami-
photochemical rearrangement of 2-diphenylmethyliden-
nocyclopropanedicarboxylates, a rather unexplored class of highly
amino-2-methylcyclopropane-1-carboxylates to the cor-
activated conformationally constrained b-amino acid derivatives, is
described. Michael-induced ring closure (MIRC) of diphenylmeth-
responding 1-pyrrolines.9
ylidenamine to 2-bromoalkylidenemalonates leads to 3,3-dialkyl-2-
(diphenylmethylidenamino)cyclopropane-1,1-dicarboxylates, the
of N-protected 2-aminocyclopropane-1,1-dicarboxylates,
reactivity of which with hydrides was investigated, yielding 3-
In the present article results are disclosed on the synthesis
a class of highly activated b-ACCs, of which only few re-
lated compounds have been synthesised, i.e. b-purinyl,10
b-imidazolyl,11 b-nitro,12 and b-N,N-(bistrimethylsilyl-
oxy)aminocyclopropanedicarboxylates.13 Furthermore,
the synthetic use of the newly prepared b-aminocyclopro-
panedicarboxylates as interesting building blocks for
functionalised g-lactams is described. 3-(Alkoxycarbon-
yl)pyrrolidin-2-ones are highly desirable targets in organ-
ic synthesis, as they exhibit physiological activities, e.g.
scytalone dehydratase inhibition.14 Moreover, they also
have been used in the synthesis of other interesting com-
pounds, e.g. the antidepressant rolipram,15 dienophilic
pyrrolin-2-ones,16 3-alkylpyrrolidin-2-ones,17 3-alkylpyr-
rolinium salts,18 ene-pyrrolidine carbamates useful in rad-
ical cyclisations19 and intramolecular Diels–Alder
cyclisations,20 g-lactam-constrained amino acids21 and
dipeptides,22 cyclic five-membered non-proteinogenic
amino acids,23,24 5,6-dihydropyrrolo[2,3-d]pyrimidines,25
octahydropyrrolo[2,3-b]pyrroles,26 fused oxazolidino-
nes,27 polyheterocyclic systems,28–30 and polymers.31
(alkoxycarbonyl)pyrrolidin-2-ones.
Key words: Michael-induced ring closure, rearrangement, cyclo-
propanes, b-amino acids, N-heterocycles
One of the most conformationally constrained classes of
b-amino acids are 2-aminocyclopropanecarboxylic acids
(b-ACCs) 1, which readily undergo ring opening to g-
oxo-carboxylates 2, due to the 1,2-push-pull substitution
on the cyclopropane ring (Scheme 1).1 Therefore, an ap-
propriate N-protecting group has to be introduced during
the synthesis of b-aminocyclopropanecarboxylic acid
derivatives, and special procedures are necessary to incor-
porate these donor-acceptor cyclopropanes (D-A cyclo-
propanes) into b-peptide structures, which has limited
their use.2 Besides their incorporation in b-peptide struc-
tures, it can be envisioned that the intrinsic characteristic
of b-ACCs to ring open could be used as an advantage in
the synthesis of N-heterocyclic compounds under appro-
priate conditions. However, contrary to D-A cyclopro-
panes with an oxygen substituent as donor,1a only
relatively few examples of the heterocyclic synthetic use
of ring-opening of b-ACCs are known. Moreover, often
further functionalisation in the b-ACC structure is re-
quired to make the synthesis of the N-heterocycle possi-
NH2
O
R
H2O
H2N
CO2H
H
CO2H
H
CO2H
R
R
1
2
Scheme 1
ble. These examples include hydrolysis of
a
cyclopropanated enaminocarboxanilide to a pyrrolidone,3
transformation of ring-opened 3-acyl-2-aminocyclopro-
pane-1-carboxylates to tetrahydrocyclopenta[b]pyrroles
and tetrahydroindoles,4 electrocyclic ring enlargement of
cyclopropanated uridines to 1,3-diazepinediones,5 ring
transformation of b-ACC derivatives during the synthesis
of the alkaloid ( )-eburnamonine,6,7 thermal rearrange-
ment of 6-ethyl 2-methyl 2-azabicyclo[3.1.0]hex-3-ene-
2,6-dicarboxylate in the presence of CuBr to ethyl N-
methoxycarbonylpyrrole-2-acetate or gas pyrolysis to 2-
Under appropriate reaction conditions, in analogy with
other nucleophiles, e.g. methoxide, cyanide, thiolates, hy-
dride, phosphites,32 4-formylimidazole,11 or aminopu-
rines,10 diphenylmethylidenamine proved to be a suitable
nucleophile for the Michael-induced ring-closure (MIRC)
of dialkyl 2-bromoalkylidenemalonates 3, prepared via a
Knoevenagel condensation of the corresponding aldehyde
and malonate, followed by radical allylic bromination
(Scheme 2). Treatment of dialkyl 2-bromoalkylidene-
malonates 3 with one equivalent of diphenylmethyliden-
amine and triethylamine in tert-butyl alcohol under reflux
conditions, for a period of time as indicated by con-
sumption of the starting material on TLC, resulted in
SYNLETT 2005, No. 10, pp 1521–1526
1
7
.0
6
.2
0
0
5
Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869850; Art ID: G04005ST
© Georg Thieme Verlag Stuttgart · New York

1522
S. Mangelinckx, N. De Kimpe
LETTER
Ph
the formation of 3,3-dialkyl-2-(diphenylmethylidenami-
no)cyclopropane-1,1-dicarboxylates 4a–d in moderate to
good isolated yield.33,34 With this methodology, for the
first time 2-aminocyclopropane-1,1-dicarboxylates come
available with an easily deprotectable group on nitrogen.
Extensive chromatography was necessary to separate
compounds 4 from benzophenone 6, present in the reac-
tion mixtures and formed on column due to hydrolysis of
some residual diphenylmethylidenamine. Benzophenone
6 together with g-oxodicarboxylate 5 were also formed in
good yield upon acid hydrolysis of 4a (Scheme 3). In the
synthesis of cyclopropane 4c, an additional treatment with
potassium tert-butoxide in tert-butyl alcohol under reflux
conditions overnight was necessary to complete the steri-
cally hindered ring-closure after the initial Michael addi-
tion of diphenylmethylidenamine.
Ph
N
O
CO2Me
CO2Me
O
1) 10% HCl (aq)
+
CO2Me
H
Ph
Ph
2) CH2Cl2
94%
CO2Me
4a
5
6
Scheme 3
able side products besides cyclopropanes 4 and 1-pyrrol-
ine 8, which made the isolation of the cyclopropanes 4
impossible.
With the 3,3-dialkyl-2-(diphenylmethylidenamino)cyclo-
propane-1,1-dicarboxylates 4a–d in hand, their reactivity
under reducing conditions was investigated with cyclo-
propane 4a as preliminary substrate (Table 1). At first, re-
duction was attempted using sodium borohydride in
methanol, since the diphenylmethylidenamino moiety
normally is reduced under these conditions.37 However,
refluxing cyclopropane 4a in methanol with one molar
equivalent of sodium borohydride resulted in an almost
1:1 mixture of starting material and 1-pyrroline 8 (entry
1). Apparently, heating of cyclopropane 4a with sodium
borohydride lead to formation of 1-pyrroline 8, while so-
dium borohydride is not a strong enough reducing agent in
this case, confirmed by the absence of reaction at room
temperature (entry 2). Therefore, sodium cyanoborohy-
dride under acidic conditions was used in further experi-
ments as a stronger reducing system at room temperature.
When 2.5 molar equivalents of sodium cyanoborohydride
was used, a clean and complete ring transformation of the
starting cyclopropane 4a to N-benzhydryl-3-methoxycar-
bonyl-4,4-dimethylpyrrolidin-2-one (12a) was observed
(entry 3). In the same way, g-lactams 12b,c were formed,
whereas reduction of cyclopropane 4d resulted in a 2:1
mixture of g-aminodiester 11d and g-lactam 12d
(Scheme 5).38,39 The formation of g-lactams 12 can be ex-
plained by first reduction of the imino function via the
corresponding protonated iminium ion, followed by
spontaneous ring-opening of the intermediate 2-aminocy-
clopropane-1,1-dicarboxylates 9 to the g-iminodicarbox-
ylates 10. Further reduction then occurs by the excess of
hydride and the resulting g-aminodiesters 11 cyclise to the
corresponding lactams 12, with the cyclization being
slower with diethyl ester 11d. When the reduction of
cyclopropane 4a with sodium cyanoborohydride was not
allowed to proceed long enough, the intermediate g-
aminodiester 11a together with the lactam 12a could be
detected in the reaction mixture. A complex mixture of
aminodiester 11a together with starting compound 4a and
heterocycles 8 and 12a was formed when the reduction
was performed using sodium borohydride in combination
with cerium(III) chloride (Luche’s reagent, entry 6).40
Ph
4a,b,d:
Ph
R1
N
1 equiv Ph2C=NH
1 equiv Et3N
t-BuOH, ∆, 16–85 h
R1
R2 Br
CO2R3
CO2R3
CO2R3
R2 CO2R3
4c:
1) 1 equiv Ph2C=NH
1 equiv Et3N
t-BuOH, ∆, 24 h
2) 0.7 equiv t-BuOK
1 equiv Et3N
3a (R1 = R2 = R3 = Me)
4a (61%)
4b (39%)
4c (65%)
4d (67%)
3b (R1 = R2 = Et, R3 = Me)
3c (R1,R2 = (CH ) , R3 = Me)
2 5
3d (R1 = R2 = Me, R3 = Et)
t-BuOH, ∆, 14 h
Scheme 2
When methanol was used instead of tert-butyl alcohol for
the cyclization of 2-bromoalkylidenemalonate 3a an im-
portant side reaction occurred, which resulted in less for-
mation of cyclopropane 4a (Scheme 4). After prolonged
heating, compound 7 was isolated, resulting from ring-
opening of cyclopropane 4a under the given reaction con-
ditions, followed by nucleophilic attack of methanol (path
a). Besides 7, also a significant amount of 1-pyrroline 8
was observed in the reaction mixture.35 The formation of
the latter can be explained via an azavinylcyclopropane–
cyclopentene rearrangement similar to the thermal rear-
rangement of comparable N-cyclopropylimines to 1-pyr-
rolines (path b).9,36 Ring expansions of N-arylidene-
cyclopropylamines often require harsh conditions such as
vacuum pyrolysis above 350 °C.9a However, ring expan-
sion rates increase significantly if substituents are present
at the cyclopropane ring.9a,36b Therefore, it seems reason-
able that the methyl substituents and the ester functions in
N-(diphenylmethylidene)cyclopropylamine (4a) reduce
the activation energy for ring expansion. However, for N-
cyclopropylimines with an electron-withdrawing group at
C-2, formed by irradiation of imine carbene complexes
with alkenes, the rearrangement has only been reported
under photochemical conditions.9c In the conversion of 2-
bromoalkylidenemalonates 3 to cyclopropanes 4, increas-
ing the amount of diphenylmethylidenamine or the use of
other bases like potassium carbonate or potassium tert-
butoxide, or other solvents like dimethylformamide or
acetonitrile only led to the formation of more unidentifi-
The use of only a small excess of sodium cyanoborohy-
dride (entry 4) or one molar equivalent of the sterically
more demanding sodium triacetoxyborohydride (entry 5)
only lead to mixtures of starting product 4a and pyrroli-
din-2-one 12a without any evidence for the formation of
Synlett 2005, No. 10, 1521–1526 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Protected b-Aminocyclopropanedicarboxylates
1523
Table 1 Overview on the Reduction of Cyclopropane 4a
Entry
Reaction conditions
Yield (%)a,b
47 (4a) + 53 (8)
100 (4a)
1
2
3
4
5
6
1 equiv NaBH4, MeOH, D, 20 h
0.33 equiv NaBH4, MeOH, 0 °C to r.t., 14 h
2.5 equiv NaCNBH3, 1.2 equiv HOAc, MeOH, r.t., 17 h
0.34 equiv NaCNBH3, 1.2 equiv HOAc, MeOH, r.t., 3 h
1 equiv NaBH(OAc)3, HOAc–THF, –78 °C to r.t., 22 h
2 equiv NaBH4, 0.5 equiv CeCl3, MeOH, –78 °C to r.t., 21 h
100 (12a, 88)
86 (4a) + 14 (12a)
38 (4a) + 62 (12a)
23 (4a) + 15 (12a) + 26 (8) + 36 (11a)c
a Ratio of reaction products based on integrations of 1H NMR spectra of the reaction mixtures.
b Isolated yield.
c Not isolated, identification based on signals of the 1H NMR spectrum of the reaction mixture.
Ph
Ph
Ph
N
Ph
MeO
N
CO2Me
MeOH
path a
path b
CO2Me
CO2Me
CO2Me
7 (19%)
Ph
CO2Me
CO2Me
3a
1 equiv Ph2C=NH
Ph
N
Br
1 equiv Et3N
MeOH, ∆, 7 d
Ph
CO2Me
CO2Me
4a
Ph
N
N
Ph
Ph
CO2Me
CO2Me
CO2Me
8
CO2Me
Scheme 4
Ph
Ph
Ph
Ph
2.5 equiv
NaCNBH3
CO2R3
CO2R3
N
Ph
CO2R3
CO2R3
Ph
H
Ph
R1
N
HN
Ph
CO2R3
O
+
Ph
N
Ph
N
CO2R3
R1
1.2 equiv
HOAc
MeOH, r.t.,
4–48 h
R1
H
R1 R2
CO2R3
R1 R2
R2
R2 CO2R3
R2 CO2R3
11a–c (–)
11d (45%)
12a (88%)
12b (94%)
12c (78%)
12d (23%)
4a–d
9a–d
10a–d
Scheme 5
Ph
the intermediate g-iminodicarboxylate 10a. Clearly, the
reduction of the starting imino moiety of cyclopropane 4a
is slower then the ring-opening of the aminocyclopropane
9a and the subsequent reduction of the g-iminodicarbox-
ylate 10a. This can be explained by steric hindrance
during the reduction of the diphenylmethylidenamino
moiety and the strong tendency of the highly activated
D-A-cyclopropane ring to ring open by the two electron-
withdrawing ester functions of 2-aminocyclopropane-1,1-
dicarboxylate (9a). In an attempt to make the b-ACC
derivate 4a less prone towards ring-opening, a decarbox-
ylation reaction was attempted under Krapcho conditions,
which yielded, however, the 1-pyrroline 8 in moderate
isolated yield (Scheme 6).
Ph
N
1 equiv NaCl
DMSO/H2O, ∆, 23 h
Ph
N
Ph
CO2Me
CO2Me
CO2Me
CO2Me
8 (67%)
4a
Scheme 6
In conclusion, a short synthesis of functionalised b-ami-
nocyclopropanecarboxylates via a Michael-induced ring
closure was described. These compounds proved very
sensitive towards different ring-opening reactions, but
upon reduction under the appropriate conditions a clean
Synlett 2005, No. 10, 1521–1526 © Thieme Stuttgart · New York

1524
S. Mangelinckx, N. De Kimpe
LETTER
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and efficient transformation was accomplished towards
4,4-dialkyl-3-(methoxycarbonyl)pyrrolidin-2-ones which
are useful building blocks in heterocyclic chemistry.
Acknowledgment
The authors are indebted to the ‘Institute for the Promotion of
Innovation through Science and Technology in Flanders (IWT-
Vlaanderen)’ for financial support of this research.
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(33) General Experimental Procedure.
t-BuOH was dried by distillation over CaH2. To a mixture of
malonate 3 (10 mmol) and anhyd t-BuOH (15 mL) was
added diphenylmethylidenamine (10 mmol) and Et3N (10
mmol). The reaction mixture was stirred at reflux
temperature (4a: 16 h; 4b, 4d: 85 h; 4c: 24 h). For 4c, 0.7
equiv of t-BuOK were added and the reaction mixture was
stirred at reflux temperature overnight. The reaction mixture
Synlett 2005, No. 10, 1521–1526 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Protected b-Aminocyclopropanedicarboxylates
1525
was then evaporated, diluted with dry Et2O (40 mL), filtered
and concentrated. The pure cyclopropanes 4 were obtained
by flash column chromatography (neutral Al2O3, hexane–
Et2O, 2:1) and recrystallisation (Et2O–hexane) for 4a;
repeated flash column chromatography (basic Al2O3,
hexane–Et2O, 9:1) for 4b–d.
166 (57), 165 (78), 104 (39), 77 (38). Anal. Calcd for
C23H27NO5: C, 69.50; N, 3.52. Found: C, 69.38; N, 3.44.
Dimethyl 4,4-Dimethyl-2,2-diphenyl-2,4-dihydro-3H-
pyrrole-3,3-dicarboxylate (8).
White crystals. Rf (silica gel, petroleum ether–EtOAc,
7:3) = 0.22. Mp 112.6–113.6 °C. 1H NMR (300 MHz,
CDCl3): d = 1.27 (s, 6 H), 3.46 (s, 6 H), 7.12–7.26 (m, 6 H),
7.64 (br d, J = 7.71 Hz, 4 H), 7.71 (s, 1 H). 13C NMR (75
MHz, CDCl3): d = 23.6, 51.9, 55.7, 75.2, 89.1, 126.8, 127.4,
128.9, 143.4, 169.7, 170.8. IR (KBr): n = 1737, 1719, 1652
cm–1. MS (ES, pos. mode): m/z (%) = 366 (100) [M + H+].
Anal. Calcd for C22H23NO4: C, 72.31; N, 3.83. Found: C,
72.07; N, 3.75.
(34) All compounds gave satisfactory analytical and spectral
data.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-
dimethylcyclopropane-1,1-dicarboxylate (4a).
White crystals. Rf (neutral Al2O3, hexane–Et2O 2:1) = 0.32.
Mp 87.3–87.7 °C. 1H NMR (270 MHz, CDCl3): d = 1.14 (s,
3 H), 1.56 (s, 3 H), 3.47 (s, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H),
7.22–7.59 (m, 10 H). 13C NMR (67.5 MHz, CDCl3):
d = 18.5, 20.5, 34.4, 46.2, 52.2, 52.5, 55.8, 128.0, 128.35,
128.41, 128.44, 128.8, 130.0, 136.2, 139.3, 166.9, 168.5,
169.2. IR (KBr): n = 1745, 1731, 1618 cm–1. MS (ES, pos.
mode): m/z (%) = 366 (100) [M + H+]. Anal. Calcd for
C22H23NO4: C, 72.31; N, 3.83. Found: C, 72.04; N, 3.70.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-
diethylcyclopropane-1,1-dicarboxylate (4b).
(36) (a) Caramella, P.; Huisgen, R.; Schmolke, B. J. Am. Chem.
Soc. 1974, 96, 2997. (b) Caramella, P.; Huisgen, R.;
Schmolke, B. J. Am. Chem. Soc. 1974, 96, 2999.
(37) Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. Synlett 2002,
113.
(38) General Experimental Procedure.
To a mixture of cyclopropane 4 (0.5 mmol) and MeOH (3
mL) was added NaCNBH3 (1.25 mmol) and HOAc (0.6
mmol). The reaction mixture was stirred at r.t. (12a: 17 h;
12b: 42 h; 12c: 4 h; 12d and 11d: 48 h). The reaction mixture
was poured into aq NaOH (0.5 N, 10 mL) and extracted with
CH2Cl2 (3 × 5 mL). After drying of the organic layer
(MgSO4), filtration and evaporation, the pure pyrrolidin-2-
ones 12a–c, or the mixture of 12d and 11d was obtained.
Analytically pure samples could be obtained upon
recrystallisation (Et2O–hexane) for 12a; flash column
chromatography (silica gel, petroleum ether–EtOAc, 4:1) for
12b,c; flash column chromatography (silica gel, hexane–
Et2O, 4:1) for 12d and 11d.
Viscous oil. Rf (silica gel, hexane–Et2O, 9:1) = 0.03. 1H
NMR (300 MHz, CDCl3): d = 0.80 (t, J = 7.4 Hz, 3 H), 1.01
(t, J = 7.4 Hz, 3 H), 1.28–1.57 (m, 2 H), 1.95–2.19 (m, 2 H),
3.51 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.25–7.64 (m, 10
H). 13C NMR (75 MHz, CDCl3): d = 9.8, 10.6, 20.3, 21.7,
44.2, 47.2, 52.1, 52.5, 55.9, 128.0, 128.3, 128.4, 128.5,
128.8, 129.9, 136.2, 139.5, 166.9, 167.0, 168.7. IR (NaCl):
n = 1732, 1622 cm–1. MS (ES, pos. mode): m/z (%) = 394
(100) [M + H+]. Anal. Calcd for C24H27NO4: C, 73.26; N,
3.56. Found: C, 73.02; N, 3.47.
Dimethyl 2-[(Diphenylmethylidene)amino]spi-
ro[2.5]octane-1,1-dicarboxylate (4c).
(39) All compounds gave satisfactory analytical and spectral
data.
White crystals. Rf (silica gel, hexane–Et2O, 2:1) = 0.29. Mp
92.8–94.2 °C. 1H NMR (270 MHz, CDCl3): d = 1.41–2.11
(m, 10 H), 3.50 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.26–
7.57 (m, 10 H). 13C NMR (67.5 MHz, CDCl3): d = 25.3,
25.5, 26.1, 28.7, 30.1, 41.2, 47.1, 52.2, 52.5, 54.9, 128.0,
128.3, 128.4, 128.5, 128.8, 129.9, 136.2, 139.5, 166.9,
168.3, 168.7. IR (KBr): n = 1749, 1728, 1623 cm–1. MS (ES,
pos. mode): m/z (%) = 406 (100) [M + H+]. Anal. Calcd for
C25H27NO4: C, 74.05; N, 3.45. Found: C, 73.91; N, 3.41.
Diethyl 3-[(Diphenylmethylidene)amino]-2,2-
Methyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-
carboxylate (12a).
White crystals. Mp 83.3–83.7 °C. 1H NMR (270 MHz,
CDCl3): d = 1.04 (s, 3 H), 1.11 (s, 3 H), 2.82 (d, J = 9.6 Hz,
1 H), 3.15 (s, 1 H), 3.23 (d, J = 9.6 Hz, 1 H), 3.72 (s, 3 H),
6.65 (s, 1 H), 7.21–7.35 (m, 10 H). 13C NMR (67.5 MHz,
CDCl3): d = 22.6, 28.6, 36.8, 52.0, 56.1, 58.8, 60.8, 127.4,
127.6, 128.3, 128.4, 128.5, 128.8, 138.0, 138.5, 169.4,
170.3. IR (KBr): n = 1749, 1694 cm–1. MS (ES, pos. mode):
m/z (%) = 338 (100) [M + H+], 167 (9). Anal. Calcd for
C21H23NO3: C, 74.75; N, 4.15. Found: C, 74.36; N, 4.14.
Methyl 1-Benzhydryl-4,4-diethyl-2-oxopyrrolidine-3-
carboxylate (12b).
dimethylcyclopropane-1,1-dicarboxylate (4d).
White crystals. Rf (silica gel, hexane–Et2O, 9:1) = 0.08. Mp
56.2–58.6 °C. 1H NMR (300 MHz, CDCl3): d = 1.14 (s, 3
H), 1.16 (t, J = 7.15 Hz, 3 H), 1.23 (t, J = 7.15 Hz, 3 H), 1.59
(s, 3 H), 3.46 (s, 1 H), 4.06–4.23 (m, 4 H), 7.21–7.61 (m, 10
H). 13C NMR (75 MHz, CDCl3): d = 14.1, 14.2, 18.5, 20.5,
34.2, 46.4, 55.6, 60.8, 61.3, 127.9, 128.4, 128.8, 129.9,
136.3, 139.4, 166.4, 168.1, 169.1. IR (KBr): n = 1738, 1716,
1619 cm–1. MS (ES, pos. mode): m/z (%) = 394 (100) [M +
H+]. Anal. Calcd for C24H27NO4: C, 73.26; N, 3.56. Found:
C, 73.04; N, 3.44.
Viscous oil. Rf (silica gel, petroleum ether–EtOAc,
4:1) = 0.18. 1H NMR (300 MHz CDCl3): d = 0.68 (t, J = 7.4
Hz, 3 H), 0.76 (t, J = 7.4 Hz, 3 H), 1.26–1.56 (m, 4 H), 2.87
(d, J = 10 Hz, 1 H), 3.23 (d, J = 10 Hz, 1 H), 3.25 (s, 1 H),
3.73 (s, 3 H), 6.64 (s, 1 H), 7.22–7.49 (m, 10 H). 13C NMR
(75 MHz, CDCl3): d = 7.6, 8.1, 24.8, 28.3, 43.4, 52.0, 53.0,
58.9, 59.1, 127.4, 127.8, 128.2, 128.4, 128.6, 129.1, 138.0,
138.6, 169.7, 170.6. IR (NaCl): n = 1734, 1694 cm–1. MS
(ES, pos. mode): m/z (%) = 366 (100) [M +H+], 167 (52).
Anal. Calcd for C23H27NO3: C, 75.59; N, 3.83. Found: C,
75.34; N, 3.78.
(35) These new compounds 7 and 8 gave satisfactory analytical
and spectral data. Selected characterisation data.
Dimethyl {2-Methoxy-1,1-dimethyl-2-
[(diphenylmethylidene)amino]ethyl}malonate (7).
Viscous oil. Rf (petroleum ether–EtOAc, 4:1) = 0.24. 1H
NMR (270 MHz, CDCl3): d = 1.01 (s, 3 H), 1.31 (s, 3 H),
3.16 (s, 3 H), 3.50 (s, 3 H), 3.67 (s, 3 H), 3.81 (s, 1 H), 4.46
(s, 1 H), 7.16–7.19 (m, 2 H), 7.31–7.47 (m, 6 H), 7.66–7.70
(m, 2 H). 13C NMR (67.5 MHz, CDCl3): d = 20.3, 20.9, 42.7,
51.7, 51.8, 56.0, 56.6, 94.9, 128.0, 128.1, 128.2, 128.4,
129.0, 130.6, 136.4, 139.2, 168.7, 168.8, 170.8. IR (NaCl):
n = 1756, 1732, 1620 cm–1. MS (70 eV): m/z (%) = no M+,
365 (60), 223 (83), 216 (72), 192 (81), 181 (44), 180 (100),
Methyl 2-Benzhydryl-3-oxo-2-azaspiro[4.5]decane-4-
carboxylate (12c).
Viscous oil. Rf (silica gel, petroleum ether–EtOAc,
4:1) = 0.17. 1H NMR (300 MHz, CDCl3): d = 1.11–1.57 (m,
10 H), 2.98 (d, J = 10 Hz, 1 H), 3.21 (d, J = 10 Hz, 1 H),
3.24 (s, 1 H), 3.72 (s, 3 H), 6.65 (s, 1 H), 7.15–7.44 (m, 10
H). 13C NMR (75 MHz, CDCl3): d = 22.0, 22.5, 25.4, 32.1,
36.3, 40.7, 52.0, 53.1, 58.8, 60.2, 127.4, 127.7, 128.4, 128.5,
128.8, 138.1, 138.7, 169.4, 170.5. IR (NaCl): n = 1736, 1694
Synlett 2005, No. 10, 1521–1526 © Thieme Stuttgart · New York

1526
S. Mangelinckx, N. De Kimpe
LETTER
cm–1. MS (ES, pos. mode): m/z (%) = 378 (100) [M + H+],
167 (35). Anal. Calcd for C24H27NO3: C, 76.36; N, 3.71.
Found: C, 76.05; N, 3.61.
Ethyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-
carboxylate (12d).
Calcd for C22H25NO3: C, 75.19; N, 3.99. Found: C, 74.98; N,
3.93.
Diethyl [2-(Benzhydrylamino)-1,1-dimethylethyl]malon-
ate (11d).
Viscous oil. Rf (silica gel, hexane–Et2O, 1:1) = 0.23. 1H
NMR (300 MHz, CDCl3): d = 1.11 (s, 6 H), 1.22 (t, J = 7.15
Hz, 6 H), 1.63 (br s, 1 H), 2.53 (s, 2 H), 3.69 (s, 1 H), 4.14
White crystals. Rf (silica gel, hexane–Et2O, 4:1) = 0.27. Mp
94.9–96.1 °C. 1H NMR (300 MHz, CDCl3): d = 1.06 (s, 3
H), 1.12 (s, 3 H), 1.26 (t, J = 7.15 Hz, 3 H), 2.81 (d, J = 9.63
Hz, 1 H), 3.12 (s, 1 H), 3.24 (d, J = 9.63 Hz, 1 H), 4.20 (q,
(q, J = 7.15 Hz, 4 H), 4.72 (s, 1 H), 7.17–7.37 (m, 10 H). 13
NMR (75 MHz, CDCl3): d = 14.1, 24.0, 37.5, 57.4, 57.6,
60.9, 67.8, 126.9, 127.4, 128.4, 144.2, 168.7. IR (NaCl):
C
J = 7.15 Hz, 2 H), 6.65 (s, 1 H), 7.21–7.38 (m, 10 H). 13
C
NMR (75 MHz, CDCl3): d = 14.2, 22.6, 28.8, 36.9, 56.2,
58.9, 61.0, 61.2, 127.5, 127.8, 128.4, 128.6, 128.8, 138.1,
138.7, 169.0, 170.5. IR (KBr): n = 1737, 1683 cm–1.
MS (ES, pos. mode): m/z (%) = 352 (100) [M + H+]. Anal.
n = 3351, 1755, 1732 cm–1. MS (ES, pos. mode): m/z (%) =
398 (100) [M + H+]. Anal. Calcd for C24H31NO4: C, 72.52;
N, 3.52. Found: C, 72.28; N, 3.43.
(40) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
Synlett 2005, No. 10, 1521–1526 © Thieme Stuttgart · New York