Michael-induced ring closure to 2-azidocyclopropane-1,1-dicarboxylates and their staudinger reduction to 5-alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones

Article abstract of DOI:10.1055/s-2006-926259

An easy and short synthesis of new β-azidocyclopropanedicarboxylates, a rather unexplored class of conformationally constrained N-protected β-aminocyclopropanecarboxylic acid derivatives, is described. Michael-induced ring closure (MIRC) of sodium azide t

Full text of DOI:10.1055/s-2006-926259

LETTER
369
Michael-Induced Ring Closure to 2-Azidocyclopropane-1,1-dicarboxylates
and their Staudinger Reduction to 5-Alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-
ones
M
ichael-Induc
v
ed Ring-Clo
e
sure to 2-A
n
zidocyclopropane-
M
1,1-dicarboxylates angelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 8 November 2005
2-(diphenylmethylidenamino)cyclopropane-1,1-dicar-
Abstract: An easy and short synthesis of new b-azidocyclo-
boxylates 6 via Michael-induced ring closure (MIRC) of
propanedicarboxylates, a rather unexplored class of conformation-
diphenylmethylideneamine to 2-bromoalkylidenema-
lonates, making 2-aminocyclopropane-1,1-dicarboxylates
ally constrained N-protected b-aminocyclopropanecarboxylic acid
derivatives, is described. Michael-induced ring closure (MIRC) of
sodium azide to 2-bromoalkylidenemalonates in alcoholic solvents available for the first time with an easily deprotectable
group at nitrogen.9 The 2-(diphenylmethylidenamino)cy-
leads to 3,3-dialkyl-2-azidocyclopropane-1,1-dicarboxylates,
whereas other polar solvents give increasing amounts of competi-
tive 2-azidoalkylidenemalonates. The reactivity of the azidocyclo-
sensitive to hydrolysis, with the corresponding ring-open-
propanes was investigated under reducing conditions, giving an
clopropane-1,1-dicarboxylates 6 proved, however, quite
ing to g-oxocarboxylates like 7, and azavinylcyclopro-
easy access to diastereomeric mixtures of 5-alkoxy-3-(alkoxy-
pane–azacyclopentene rearrangement. Therefore, it was
reasoned that protection of the amino function as an azido
group would give more stable, easily deprotectable 2-ami-
nocyclopropane-1,1-dicarboxylates. Furthermore, until
recently, only one report has been made on the synthesis
of 2-azidocyclopropane-1-carboxylates, namely the de-
composition of methyl diazoacetate catalysed by (trimeth-
ylphosphito)copper(I) chloride in the presence of (1-
azidovinyl)benzene which resulted in a separable diaste-
reomeric mixture of b-ACC derivatives, although in only
low yield.10 However, simultaneous with our work and
published very recently, the synthesis of one 2-azidocy-
clopropane-1,1-dicarboxylate and one 2-azido-1-cyano-
cyclopropane-1-carboxylate via the MIRC reaction has
been described.11 Accordingly, we are forced to disclose
in the present article our similar but more extensive and
elaborated results on the synthesis of new 2-azidocyclo-
propane-1,1-dicarboxylates and their reactivity under re-
ducing conditions. These reductive reactions give rise to
ring expansions to five-membered azaheterocycles.
carbonyl)pyrrolidin-2-ones.
Key words: Michael-induced ring closure, cyclopropanes, b-azido
acids, Staudinger reduction, ring expansion
2-Aminocyclopropanecarboxylic acids (b-ACCs) 1 are
one of the most conformationally constrained classes of b-
amino acids, which have already proven to be very useful
in the field of b-peptide chemistry and synthetic organic
chemistry.1 However, an appropriate N-protecting group
has to be introduced during the synthesis of b-ACCs to in-
hibit their ring-opening to g-oxocarboxylates 2, due to the
1,2-push–pull substitution on the cyclopropane ring
(Scheme 1).2 The presence of additional functional groups
besides the 1-carboxyl group and protected 2-amino func-
tion in the b-ACC structures would allow their use for side
chain functionalization of pseudopeptides in which the b-
ACC structure is incorporated or for the further synthesis
of highly functionalised heterocyclic compounds. Signif-
icant research has been performed on the introduction of
an additional carboxylic group in the 2-position of the b-
ACC structure, giving cyclopropane aspartic acid deriva-
tives 3,3 and an additional carboxylic group in the 3-posi-
tion, i.e. 3-aminocyclopropane-1,2-dicarboxylates 4.4
However, only few reports have been made on the syn-
thesis of N-protected 2-aminocyclopropane-1,1-dicarbox-
ylates 5, namely b-purinyl-,5 b-imidazolyl-,6 b-nitro-,7
NH2
O
R
H2O
H2N
COOH
H
COOH
H
COOH
R
R
1
2
Scheme 1
In analogy with diphenylmethylideneamine,9 sodium
azide proved to be a suitable nucleophile for the Michael-
induced ring closure of 2-bromoalkylidenemalonates 8
(Scheme 2). Treatment of 2-bromoalkylidenemalonates
8a–c with sodium azide in methanol or ethanol under re-
flux conditions overnight, resulted in the formation of 3,3-
dialkyl-2-azidocyclopropane-1,1-dicarboxylates 9a–c in
moderate to good isolated yield. The use of a boiling polar
protic solvent like methanol or ethanol was necessary to
drive the cyclisation of compounds 8 to completion and to
and
b-N,N-(bistrimethylsilyloxy)aminocyclopropane-
dicarboxylates (Figure 1).8 Moreover, the aforementioned
2-aminocyclopropane-1,1-dicarboxylates have the dis-
advantage of lacking an easily deprotectable group at
nitrogen to be regarded as direct building blocks for fur-
ther elaboration. Recently, we described the synthesis of
SYNLETT 2006, No. 3, pp 0369–0374
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926259; Art ID: G36205ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
2.
2
0
0
6

370
S. Mangelinckx, N. De Kimpe
LETTER
Ph
NHP
NHP
Ph
R1
N
PNH COOR
O
COOMe
COOMe
COOR3
COOR
H
COOR
ROOC
COOR
R2 COOR3
COOR
4
5
3
6
7
P = protecting group
R = H or alkyl
Figure 1
N3
R1
R2 N3
COOR3
R1
R2 Br
COOR3
1.2 equiv NaN3
R3OH, ∆, 14–16 h
COOMe
COOMe
R1
COOR3
+
+
R2 COOR3
COOR3
10a (3%)
COOR3
8a (R1 = R2 = R3 = Me)
9a (85%)
9b (68%)
9c (29%)
8b (R1 = R2 = Me, R3 = Et)
8c (R1, R2 = (CH2)5, R3 = Me)
10b (9%)
10c (–)
11 (27% from 8c)
Scheme 2
suppress the competitive substitution reaction with forma- (Scheme 3).15 However, it is not clear if this compound 13
tion of g-azido-a,b-unsaturated diesters 10 to less then results from substitution and subsequent migration of the
10%.12 The latter side reaction has not been described in double bond or from ring-opening of the corresponding
the reported synthesis of diethyl 3,3-dimethyl-2-azido- azidocyclopropanecarboxylate. Repeating the reaction at
cyclopropane-1,1-dicarboxylate (9b) under similar condi- room temperature only gave starting compound 12. It is
tions.11
known that the substitution reaction of phenol with methyl
bromocrotonate 12 leads to the corresponding (Z)-b,g-un-
saturated ester via isomerisation of the a,b-unsaturated
ester.16 However, several examples of similar ring-open-
ing of vicinally donor–acceptor substituted cyclopropanes
to b,g-unsaturated esters both under thermolytic
conditions17 or catalysed by transition metals or trimethyl-
silyl iodide18 have been described.
As can be seen from Table 1 for the reaction of 8a, the use
of acetonitrile, acetone or dimethylsulfoxide resulted in
increased amounts of unreacted starting material and side
product 10a. In the MIRC reaction of alkylidenemalonate
8c a large amount of dehydrobromination product 1113
was formed which made the purification of cyclopropane
9c more difficult and decreased the isolated yield.
When performing the MIRC reaction with methyl 4-bro-
mocrotonate 12 neither the cyclopropanation compound
nor the expectable g-azido-a,b-unsaturated ester14 were
obtained, but instead g-azido-b,g-unsaturated ester 13 was
obtained in high yield with a Z/E ratio of 88:12
1.2 equiv NaN3
COOMe
Br
COOMe
MeOH, ∆, 14 h
N3
13 (82%, Z/E 88:12)
12
Scheme 3
Table 1 Overview on the Michael-Induced Ring Closure through
Reaction of Dimethyl 2-Bromo-2-methylpropylidenemalonate (8a)
with Sodium Azide
In the next part, the reduction with in situ protection of the
formed amino function of azidocyclopropanecarboxylate
9a was investigated in an attempt to obtain other N-pro-
tected b-aminocyclopropanedicarboxylates. A simple
method would involve palladium-catalysed hydrogena-
tion in the presence of a protecting reagent like di-tert-bu-
tyl dicarbonate.19 However, this reaction resulted only in
the isolation of the N-Boc protected g-amino diester 14,
together with low amounts of g-oxoester 7 (Scheme 4).
Also the catalytic hydrogenation of 9a in the presence of
acetic anhydride failed to deliver the desired N-acetyl b-
aminocyclopropanedicarboxylate. Clearly reduction of
the azide function occurred as could be seen from the IR
spectrum of the reaction mixture, but it proved impossible
to identify the reaction products, besides a low amount of
g-oxoester 7. These failures support the fact that cyclo-
propane compounds in general, and more specific vicinal
donor–acceptor cyclopropanes, are sensitive to trans-
formations under catalytic hydrogenation conditions.20
Reaction conditions
Result (%)a
8a
100
27
31
12
12
–
9a
10a
–
1 Equiv NaN3, MeCN, D, 2 h
1 Equiv NaN3, MeCN, D, 20 h
3 Equiv NaN3, MeCN, D, 24 h
3 Equiv NaN3, acetone, D, 24 h
5 Equiv NaN3, acetone, D, 50 h
1 Equiv NaN3, DMSO, D, 7 h
1 Equiv NaN3, MeOH, D, 4 h
1.2 Equiv NaN3, MeOH, D, 14 h
–
32
41
37
22
26
56
6
32
66
62
44
22
72
1–2
92–94
4–7
a Ratio of reaction products based on integrations of 1H NMR spectra
of the reaction mixtures.
Synlett 2006, No. 3, 369–374 © Thieme Stuttgart · New York

LETTER
Michael-Induced Ring-Closure to 2-Azidocyclopropane-1,1-dicarboxylates
371
N3
H2, Pd-C
1.1 equiv Boc2O
COOMe
COOMe
O
COOMe
COOMe
COOMe
COOMe
+
BocHN
H
MeOH, r.t., 24 h
9a
14 (33%)
7 (not isolated)
Scheme 4
N3
1) 1.05 equiv Me3P
toluene, r.t., 1 h
1 equiv Boc2O
0.05 equiv DMAP
H
N
Boc
N
MeO
MeO
O
O
COOMe
COOMe
2) 2 equiv Boc-ON
toluene, r.t., 8 d
CH3CN, r.t., 2 h
COOMe
COOMe
9a
15a
16a
77% (from 15a) dr 14:1
27% (from 9a) dr 5:1
(45% dr 4:1)
1) 1.05 equiv Me3P
toluene, r.t., 1 h
2) 1.05 equiv Boc-ON
toluene, ∆, 14 h
Scheme 5
Another chemoselective reductive acetylation method of column chromatography. Also in the reaction of cyclopro-
azides through reaction with thioacetic acid21 gave no re- pane 9a with triphenylphosphine followed by treatment
action with azidocyclopropane 9a and also the combina- with benzaldehyde, benzyl chloroformate or acetyl chlo-
tion chlorotrimethylsilane–acetic anhydride failed.22
ride, the formation of pyrrolidinone 15a (44–77%) was
the major reaction besides the formation of g-oxoester 7
(23–56%, Scheme 6). This ring transformation reaction
was generalised for the three azidocyclopropanecarbox-
ylates 9a–c by treatment with triphenylphosphine in tet-
rahydrofuran at room temperature to give diastereomeric
mixtures of pyrrolidinones 15a–c in moderate to good
isolated yield after column chromatography to remove
triphenylphosphine oxide (Scheme 7).26 In case of pyr-
rolidinone 15a, this purification proved to be difficult and
a better yield of pyrrolidinone 15a (dr 2:1) could be ob-
tained upon performing the Staudinger reduction with
trimethylphosphine in toluene. This has the advantage that
the trimethylphosphine oxide formed at workup is re-
moved by extraction with water.23b
These unsuccessful reduction results are also in corre-
spondence with the reported unsuccessful attempts of
reduction of b-azidocyclopropanedicarboxylates.11 How-
ever, as an alternative, the one-pot reaction involving
Staudinger reaction of 9a with triphenylphosphine or tri-
methylphosphine followed by reaction of the presumably
formed iminophosphorane with protecting reagents
(Boc2O, Boc-ON,23 Cbz-Cl24) or aza-Wittig reaction with
aldehydes was studied.25 Treatment of azidocyclopropan-
ecarboxylate 9a with trimethylphosphine in toluene at
room temperature resulted in a rapid evolution of nitrogen
gas, and further treatment after one hour with 2-(tert-bu-
toxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON)
at room temperature for several days resulted in the isola-
tion of an inseparable diastereomeric mixture of the pyr-
rolidinones 15a in a ratio of 4:1 after aqueous workup
(Scheme 5). Repeating the reaction with Boc-ON under
reflux conditions gave a 5:1 diastereomeric mixture of the
N-Boc protected pyrrolidinones 16a in low isolated yield.
Subsequent introduction of the tert-butoxycarbonyl sub-
stituent as N-protective group on the pyrrolidinones 15a
by treatment with di-tert-butyl dicarbonate in the presence
of a catalytic amount of 4-(dimethylamino)pyridine also
furnished the pyrrolidinones 16a in 77% yield, strongly
enriched, however, with the major diastereoisomer after
N3
H
N
MeO
O
COOMe
COOMe
+
7
a or b or c
COOMe
9a
15a
ratio 15a:7 4:6–8:2
Scheme 6 Reagents and conditions: a) 1.2 equiv Ph3P, 1 equiv
PhCHO, THF, r.t., 24 h; b) i) 1.01 equiv Ph3P, THF, –78 °C to r.t., 2
h; ii) 1.2 equiv ClCOOBn, –78 °C to r.t., 30 min; c) 1.05 equiv Me3P,
1.05 equiv AcCl, toluene, r.t., 18 h.
N3
H
H
N
N
1.05 equiv Ph3P
THF, 2.5–3 h, r.t.
MeO
R3O
R1
1.05 equiv Me3P
toluene, 2 h, r.t.
O
O
R1
COOR3
R2 COOR3
COOMe
COOR3
R2
9a–c
15a (55%, dr 2:1)
15a (39%, dr 4:1)
15b (75%, dr 4:1)
15c (81%, dr 2:1)
Scheme 7
Synlett 2006, No. 3, 369–374 © Thieme Stuttgart · New York

372
S. Mangelinckx, N. De Kimpe
LETTER
From a mechanistic point of view, the formation of these A signal at d = –4.7 ppm for PPh3,28 a large signal at d =
pyrrolidinones 15 can be explained through a process in 34.0 ppm for phosphonium salt 20a (R1 = R2 = R3 = Me),
which the nucleophilic aza-ylide 18, formed from the a minor signal at d = 13.4 ppm for aza-ylide 18, a minor
phosphazide 17, first reacts in an intramolecular fashion signal at d = 24.5 ppm for triphenylphosphine oxide and a
to the strained bicyclic phosphonium salt 19.27 Relief of minor signal at d = 18.0 ppm which cannot be assigned
strain occurs by ring expansion initiated by the attack of unambiguously at this moment to some intermediate like
alkoxide. Further hydrolysis of the phosphonium salt 20 phosphazide 17 or phosphonium salt 19. The 31P chemical
during workup gives pyrrolidinones 15 (Scheme 8). shifts of aza-ylide 18 and phosphonium salt 20a are con-
Strong support for the proposed mechanism was obtained sistent with 31P chemical shifts reported for other aza-
by performing the Staudinger reduction of cyclopropane ylides,29 and other related aminophosphonium salts.30 The
9a with triphenylphosphine in THF in an NMR tube and signal for aza-ylide 17 disappeared after 60 minutes, by
monitoring the course of the reaction with 31P NMR spec- which also the peak of triphenylphosphine diminished to
troscopy (Figure 2 and Table 2). In the initial 31P NMR the 5% excess present. The minor amount of triphen-
spectrum, taken after 10 minutes of reaction, five signals ylphosphine oxide observed in the reaction mixture
appeared.
probably arises from some hydrolysis due to the presence
of traces of water. No pentacoordinated intermediates
could be detected that have shifts that are almost always
strongly negative and far upfield of those of the tetracoor-
dinated aminophosphonium ions.28,29a
PPh3
N
N
N3
N
Ph3P
R1
COOR3
R1
COOR3
Table 2 Normalized Integrated 31P NMR Signals for the Staudinger
Reaction of Cyclopropane 15a with Triphenylphosphine
R2 COOR3
R2 COOR3
9a–c
17
Time (min)
Compounds
Ph3P
N2
18
Unknowna Ph3P=O
20a
R3O
R1
PPh3
N
PPh3
10
20
45
60
15.5
10.1
5.4
5.8
2.1
0.6
0.4
4.2
3.9
3.5
3.2
6.7
6.5
6.7
6.5
67.7
77.4
83.9
85.3
N
R3O
R1
COOR3
O
R2 COOR3
R2 COOR3
18
19
4.5
a dP = 18.0 ppm in THF.
PPh3
H
N
N
O
H2O
R3O
R3O
R1
O
After 90 minutes of reaction, a white precipitate was
formed in the NMR tube, and was isolated via decantation
of the solvent and identified as the single isomeric phos-
phonium salt 20a on the basis of NMR spectroscopy
(CDCl3), IR analysis and mass spectroscopy.31 The 31P
NMR spectrum showed a signal at dP = 34.8 ppm. The 1H
NMR spectrum displayed an upfield singlet at dH = 2.65
ppm for the 5-methoxy protons which are shielded due to
the anisotropic effect of the neighbouring phenyl groups,
and a singlet at dH = 3.87 ppm for the 5-methine proton.
The 13C NMR spectrum gave doublets at dC = 97.0 ppm
(2JP,C = 3.5 Hz) for the 5-methine carbon, at dC = 79.9
ppm (3JP,C = 8.1 Hz) for the carbon atom of the double
bond substituted with the ester group and a singlet at
dC = 165.5 ppm for the carbon atom of the double bond
substituted with the nitrogen and oxygen atom. The IR
spectrum showed a weak absorption band at 1667 cm–1 in-
dicating the carbonyl group of the ester and a strong ab-
sorption band at 1615 cm–1 characteristic for the carbon–
carbon double bond. The latter absorption is consistent
with reported IR absorption bands for closely related ami-
nophosphonium salts.32 The mass spectrum gave a peak at
462, corresponding to the [M + H+] ion.
Ph3P=O
R1
COOR3
20a–c
COOR3
R2
R2
15a–c
Scheme 8
Figure 2 Stack plot of the 31P NMR spectra (121 MHz, THF)
obtained from the reaction of azidocyclopropane 9a with triphenyl-
phosphine (a–d) and triphenylphosphine (e).
Synlett 2006, No. 3, 369–374 © Thieme Stuttgart · New York

LETTER
Michael-Induced Ring-Closure to 2-Azidocyclopropane-1,1-dicarboxylates
373
420559, 1991; Chem. Abstr. 1991, 115, 28993. (d)Hayashi,
T.; Yasuoka, J.; Nishikawa, J. Jpn. Kokai Tokkyo Koho JP
2000327593, 2000; Chem. Abstr. 2000, 133, 362933.
(e) Hayashi, T.; Yasuoka, J.; Nishiura, A. Eur. Pat. Appl. EP
916674, 1999; Chem. Abstr. 1999, 131, 5268. (f) Kim, H.
S.; Barak, D.; Harden, T. K.; Boyer, J. L.; Jacobson, K. A. J.
Med. Chem. 2001, 44, 3092.
Upon storing this phosphonium salt 20a in CDCl3, it slow-
ly hydrolysed to the diastereomeric mixture of pyrroli-
dinones 15a (dr 5:1) due to traces of water present in the
chloroform.
Only few reports have been made on the synthesis of
similar highly functionalised 5-alkoxy-3-(alkoxycarbon-
yl)pyrrolidin-2-ones. One synthesis is based on the reac-
tion of g-oxodicarboxylates similar to 7 with ammonium
carbonate in ethanol,33 while another report involves a
[3+2] cycloaddition reaction of a 2,2-dimethoxycyclopro-
panecarboxylate with phenylisocyanate.34 Interesting to
mention is the fact that g-oxodicarboxylates like 7 form
the corresponding g-alkoxy-a-alkoxycarbonyl-g-butyro-
lactones upon prolonged standing35 or treatment with
sodium methoxide.36
(6) Su, Q.; Wood, J. L. Synth. Commun. 2000, 30, 3383.
(7) (a) Trukhin, E. V.; Makarenko, S. V.; Berestovitskaya, V.
M. Russ. J. Org. Chem. 1998, 34, 59; Chem. Abstr. 1998,
130, 3661. (b) Villemin, D.; Thibault-Starzyk, F.; Hachemi,
M. Synth. Commun. 1994, 24, 1425. (c) Le Menn, J. C.;
Tallec, A.; Sarrazin, J. Can. J. Chem. 1991, 69, 761.
(d) Sopova, A. S.; Bakova, O. V.; Metelkina, E. L.;
Perekalin, V. V. Zh. Org. Khim. 1975, 11, 68; Chem. Abstr.
1975, 83, 9406. (e) Sopova, A. S.; Yurchenko, O. I.;
Perekalin, V. V. Zh. Obshch. Khim. 1965, 1, 1707; Chem.
Abstr. 1966, 64, 3726. (f) Kohler, E. P.; Darling, S. F. J. Am.
Chem. Soc. 1930, 52, 424.
(8) (a) Smirnov, V. O.; Tishkov, A. A.; Lyapkalo, I. M.; Ioffe,
S. L.; Kachala, V. V.; Strelenko, Y. A.; Tartakovsky, V. A.
Russ. Chem. Bull. 2001, 50, 2433; Chem. Abstr. 2002, 137,
279247. (b) Danilenko, V. M.; Tishkov, A. A.; Ioffe, S. L.;
Lyapkalo, I. M.; Strelenko, Y. A.; Tartakovsky, V. A.
Synthesis 2002, 635. (c) Tishkov, A. A.; Kozintsev, A. V.;
Lyapkalo, I. M.; Ioffe, S. L.; Kachala, V. V.; Strelenko, Y.
A.; Tartakovsky, V. A. Tetrahedron Lett. 1999, 40, 5075.
(9) Mangelinckx, S.; De Kimpe, N. Synlett 2005, 1521.
(10) Harnisch, J.; Szeimies, G. Chem. Ber. 1979, 112, 3914.
(11) Su, J.; Qiu, G.; Liang, S.; Hu, X. Synth. Commun. 2005, 35,
1427.
In conclusion, the Michael-induced ring-closure of 2-bro-
moalkylidenemalonates with sodium azide lead to g,g-di-
alkyl-b-azidocyclopropanedicarboxylates. This reaction
also afforded g-azido-a,b-unsaturated diesters as minor
side products resulting from substitution reaction. Starting
from methyl 4-bromocrotonate, only an isomeric mixture
of the corresponding g-azido-b,g-unsaturated ester was
formed. Hydrogenation of g,g-dialkyl-b-azidocyclopro-
panedicarboxylates resulted in ring-opening reactions,
while Staudinger reduction offered a new route to highly
functionalised g-lactams.
(12) General Procedure for the Synthesis of 3-Azido-2,2-
dialkyl-1,1-dicarboxylates 9.
Acknowledgment
To a solution of 2-bromoalkylidenemalonate 813 (5 mmol) in
MeOH (5 mL) (or EtOH for 9b) was added NaN3 (6 mmol).
The reaction mixture was stirred at reflux for 14–16 h. The
reaction mixture was then evaporated, diluted with dry Et2O,
filtered and concentrated. The pure cyclopropanes 9a–c, g-
azido-a,b-unsaturated diesters 10a,b and olefin 1113 were
obtained by column chromatography (silica gel, PE–EtOAc,
4:1) for 9a and 10a; (silica gel, PE–Et2O, 9:1) for 9b and
10b; (silica gel, hexane–Et2O, 95:5) for 9c and 11.
Cyclopropanes 9a,b and g-azido-a,b-unsaturated diesters
10a,b are reported as representative examples.
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.
References and Notes
(1) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603.
(2) (a) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(b) Reissig, H. U. Top. Curr. Chem. 1988, 144, 73. (c) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
Dimethyl 3-Azido-2,2-dimethylcyclopropane-1,1-
dicarboxylate (9a): colourless oil. Rf = 0.47 (PE–EtOAc,
4:1). 1H NMR (270 MHz, CDCl3): d = 1.24 (s, 3 H), 1.26 (s,
3 H), 3.70 (s, 1 H), 3.75 (s, 3 H), 3.79 (s, 3 H). 13C NMR (68
MHz, CDCl3): d = 17.9, 19.6, 31.1, 42.3, 51.9, 52.5, 52.9,
165.8, 167.7. IR (NaCl): n = 2113, 1732 cm–1. MS (ES, pos.
mode): m/z (%) = 200(19) [M – N2 + H+], 173 (100) [M –
CHN3 + H+]. Anal. Calcd for C9H13N3O4: C, 47.57; H, 5.77;
N, 18.49. Found: C, 47.32; H, 5.69; N, 18.65.
Dimethyl (2-Azido-2-methylpropylidene)malonate
(10a): colourless oil. Rf = 0.32 (PE–EtOAc, 4:1). 1H NMR
(270 MHz, CDCl3): d = 1.49 (s, 6 H), 3.80 (s, 3 H), 3.87 (s,
3 H), 6.80 (s, 1 H). 13C NMR (68 MHz, CDCl3): d = 26.5,
52.6, 52.8, 60.7, 127.2, 148.0, 164.0, 166.2. IR (NaCl):
n = 2110, 1737, 1654 cm–1. MS (EI, 70 eV): m/z (%) = no
[M+], 196 (2), 185 (59), 184 (10), 168 (3), 154 (5), 153 (53),
125 (10), 124 (11), 88 (11), 86 (73), 84 (100), 59 (10). Anal.
Calcd for C9H13N3O4: N, 18.49. Found: N, 18.21.
(3) (a) Horikawa, H.; Nishitani, T.; Iwasaki, T.; Inoue, I.
Tetrahedron Lett. 1983, 24, 2193. (b) El Abdioui, K.;
Martinez, J.; Viallefont, P.; Vidal, Y. Bull. Soc. Chim. Belg.
1997, 106, 425. (c) Papageorgiou, C. D.; Cubillo de Dios,
M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004,
43, 4641. (d) Adams, L. A.; Charmant, J. P. H.; Cox, R. J.;
Walter, M.; Whittingham, W. G. Org. Biomol. Chem. 2004,
2, 542. (e) Adams, L. A.; Cox, R. J.; Gibson, J. S.; Mayo-
Martín, M. B.; Walter, M.; Whittingham, W. Chem.
Commun. 2002, 2004. (f) Jiménez, J. M.; Rifé, J.; Ortuño, R.
M. Tetrahedron: Asymmetry 1995, 6, 1849. (g) Jiménez, J.
M.; Rifé, J.; Ortuño, R. M. Tetrahedron: Asymmetry 1996,
7, 537. (h) Yamazaki, S.; Inoue, T.; Hamada, T.; Takada, T.;
Yamamoto, K. J. Org. Chem. 1999, 64, 282. (i) Wick, L.;
Tamm, C.; Boller, T. Helv. Chim. Acta 1995, 78, 403.
(4) (a) Bubert, C.; Voigt, J.; Biasetton, S.; Reiser, O. Synlett
1994, 675. (b) Bubert, C.; Cabrele, C.; Reiser, O. Synlett
1997, 827. (c) Maas, G.; Müller, A. J. Prakt. Chem. 1998,
340, 315.
Diethyl 3-Azido-2,2-dimethylcyclopropane-1,1-
dicarboxylate (9b): colourless oil. Rf = 0.39 (PE–Et2O,
4:1). The 1H NMR and 13C NMR data are in good agreement
with reported data, with the exception that in the 1H NMR
the signals at d = 1.23 and 1.27 ppm are two times a singlet
(5) (a) Geen, G. R.; Kincey, P. M.; Choudary, B. M.
Tetrahedron Lett. 1992, 33, 4609. (b) Geen, G. R.; Harnden,
M. R.; Parratt, M. J. Bioorg. Med. Chem. Lett. 1991, 1, 347.
(c) Geen, G. R.; Grinter, T. J.; Moore, S. Eur. Pat. Appl. EP
Synlett 2006, No. 3, 369–374 © Thieme Stuttgart · New York

374
S. Mangelinckx, N. De Kimpe
LETTER
and not doublet of doublet, and in the 13C NMR, the signals
for CHN3 (d = 51.6 ppm) and CMe2 (d = 30.7 ppm) were
mistakenly attributed.11 1H NMR (300 MHz, CDCl3):
d = 1.23 (s, 3 H), 1.27 (s, 3 H), 1.27 (t, J = 7.15 Hz, 3 H),
1.31 (t, J = 7.15 Hz, 3 H), 3.68 (s, 1 H), 4.11–4.31 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 17.9, 19.6, 30.7, 42.8,
51.6, 61.4, 61.9, 165.2, 167.4. IR (NaCl): n = 2112, 1729
cm–1. MS (ES, pos. mode): m/z (%) = 228 (17) [M – N2 +
H+], 201 (100) [M – CHN3 + H+]. Anal. Calcd for
C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found C, 51.46; H,
6.65; N, 16.33.
Diethyl (2-Azido-2-methylpropylidene)malonate (10b):
colourless oil. Rf = 0.20 (PE–Et2O, 4:1). 1H NMR (300
MHz, CDCl3): d = 1.30 (t, J = 7.15 Hz, 3 H), 1.36 (t, J = 7.15
Hz, 3 H), 1.49 (s, 6 H), 4.25 (q, J = 7.15 Hz, 2 H), 4.34 (q,
J = 7.15 Hz, 2 H), 6.76 (s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 13.97, 14.05, 26.6, 60.7, 61.7, 61.9, 128.0, 147.2, 163.6,
165.7. IR (NaCl): n = 2111, 1735, 1655 cm–1. MS (ES, pos.
mode): m/z (%) = 228 (52) [M – N2 + H+], 213 (100). Anal.
Calcd for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found:
C, 51.53; H, 6.63; N, 16.38.
(26) General Procedure for the Synthesis of Alkyl 5-Alkoxy-
4,4-dialkyl-2-oxopyrrolidine-3-carboxylates (15).
To a solution of azidocyclopropane 9 (1 mmol) in dry THF
(4 mL) under nitrogen atmosphere was added Ph3P (0.275 g,
1.05 mmol). The reaction mixture was stirred for 3 h at r.t.
The reaction mixture was poured into H2O (10 mL) and
extracted with CH2Cl2. After drying of the organic layer
(MgSO4), filtration and evaporation, the pure pyrrolidin-2-
ones 15 were obtained as diastereomeric mixtures after
column chromatography (silica gel, PE–EtOAc).
Pyrrolidinone 15a is reported as a representative example.
Methyl 5-Methoxy-4,4-dimethyl-2-oxopyrrolidine-3-
carboxylate (15a): amorphous white solid. Rf = 0.29 and
0.22 (PE–EtOAc, 1:3). Mp 73.8–74.7 °C. Spectral data
obtained from the mixture of two isomers (ratio 4:1). 1H
NMR (300 MHz, CDCl3): d = 1.09 (s, 3 H), 1.25 (s, 3 H),
2.98 (s, 1/5 H), 3.34 (s, 12/5 H), 3.36 (s, 3/5 H), 3.37 (s, 4/5
H), 3.73 (s, 3/5 H), 3.76 (s, 12/5 H), 4.31 (d, J = 1.24 Hz, 4/
5 H), 4.33 (d, J = 1.10 Hz, 1/5 H), 8.62 (br s, 4/5 H), 8.67 (br
s, 1/5 H). 13C NMR (75 MHz, CDCl3): d (for the major
isomer) = 22.1, 23.5, 44.2, 52.1, 55.9, 56.7, 93.2, 168.8,
174.4; d (for the minor isomer) = 19.1, 29.5, 43.3, 52.2, 56.1,
59.0, 94.0, 169.1, 174.7. IR (KBr): n = 3218, 3116, 1733,
1698 cm–1. LCMS (ES, pos. mode): m/z (for the major
isomer, %) = 425 (7) [2 M + Na+], 202 (100) [M + H+]; m/z
(for the minor isomer, %) = 425 (7) [2 M + Na+], 170 (100)
[M – MeOH + H+]. Anal. Calcd for C9H15NO4: C, 53.72; H,
7.51; N, 6.96. Found: C, 53.47; H, 7.58; N, 6.88.
(13) Verhé, R.; De Kimpe, N.; De Buyck, L.; Courtheyn, D.;
Schamp, N. Bull. Soc. Chim. Belg. 1978, 87, 215.
(14) (a) Murahashi, S. I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y.
J. Org. Chem. 1989, 54, 3292. (b) Hoffman, R. V.; Severns,
B. S. J. Org. Chem. 1996, 61, 5567.
(15) Methyl 4-Azidobut-3-enoate (13): colourless oil. Rf = 0.37
(PE–EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): d
(Z-isomer) = 3.14 (dd, J = 7.15 Hz, J = 1.65 Hz, 2 H), 3.70
(s, 3 H), 5.06 (dt, J = 7.43 Hz, J = 7.15 Hz, 1 H), 6.32 (dt,
J = 7.43 Hz, J = 1.65 Hz, 1 H); d (E-isomer) = 3.07 (dd,
J = 7.43 Hz, J = 1.38 Hz, 2 H), 3.70 (s, 3 H), 5.45 (dt,
J = 13.76 Hz, J = 7.43 Hz, 1 H), 6.03 (dt, J = 13.76 Hz,
J = 1.38 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d
(Z-isomer) = 31.0, 52.0, 111.4, 128.3, 171.6; d (E-isomer) =
34.5, 52.1, 111.8, 129.9, 171.6. IR (NaCl): n = 2111, 1739,
1648 cm–1. MS (ES, pos. mode): m/z (%) = 283 (100)
[2 M + H+]. Anal. Calcd for C5H7N3O2: C, 42.55; H, 5.00; N,
29.77. Found: C, 42.35; H, 5.15; N, 29.63.
(16) Sunitha, K.; Balasubramanian, K. K. Tetrahedron 1987, 43,
3269.
(17) Graziano, M. L.; Scarpati, R. J. Chem. Soc., Perkin Trans. 1
1985, 289.
(18) (a) Doyle, M. P.; van Leusen, D. J. Org. Chem. 1982, 47,
5326. (b) Reissig, H. U. Tetrahedron Lett. 1985, 26, 3943.
(19) (a) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T.
Tetrahedron Lett. 1989, 30, 837. (b) Woltering, T. J.;
Weitz-Schmidt, G.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 9033.
(20) von Angerer, S. Carbocyclic Three-Membered Ring
Compounds, In Houben-Weyl, Vol. E 17c; de Meijere, A.,
Ed.; Thieme: Stuttgart, 1997, 2121–2123.
(27) For a recent review on the intramolecular reaction of
iminophosphoranes with esters see: Fresneda, P. M.;
Molina, P. Synlett 2004, 1.
(28) Quin, L. D. A. A Guide to Organophosphorus Chemistry;
Wiley: New York, 2000.
(29) (a) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.;
Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686.
(b) Shalev, D. E.; Chiacchiera, S. M.; Radkowsky, A. E.;
Kosower, E. M. J. Org. Chem. 1996, 61, 1689.
(30) (a) Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc.,
Perkin Trans. 1 1990, 2193. (b) Palacios, F.; Ochoa de
Retana, A. M.; Pagalday, J. Eur. J. Org. Chem. 2003, 913.
(31) 5-Methoxy-3-(methoxycarbonyl)-4,4-dimethyl-1-
(triphenylphosphonio)-4,5-dihydro-1H-pyrrol-2-olate
(20a): hygroscopic white crystals; mp 76.5–78.0 °C. 1H
NMR (300 MHz, CDCl3): d = 1.32 (s, 3 H), 1.46 (s, 3 H),
2.65 (s, 3 H), 3.63 (s, 3 H), 3.87 (s, 1 H), 7.50–7.80 (m, 15
H). 13C NMR (75 MHz, CDCl3): d = 20.4, 28.5, 46.5 (d,
3JP,C = 9.2 Hz), 49.4, 56.5, 79.9 (d, 3JP,C = 8.1 Hz), 97.0 (d,
2JP,C = 3.5 Hz), 122.3 (d, 1JP,C = 105.0 Hz), 129.4 (d, 3JP,C
=
13.9 Hz), 133.9 (d, 4JP,C = 2.3 Hz), 134.1 (d, 2JP,C = 11.5 Hz),
165.5, 167.6. 31P NMR (121 MHz, CDCl3): d = 34.8. IR
(KBr): n = 1667, 1615 cm–1. MS (ES, pos. mode): m/z (%) =
462 (100) [M + H+].
(21) Rosen, T.; Lico, J. M.; Chu, D. T. W. J. Org. Chem. 1988,
53, 1580.
(22) Barua, A.; Bez, G.; Barua, N. C. Synlett 1999, 553.
(23) (a) Afonso, C. A. M. Tetrahedron Lett. 1995, 36, 8857.
(b) Ariza, X.; Urpi, F.; Viladomat, C.; Vilarrasa, J.
Tetrahedron Lett. 1998, 39, 9101.
(24) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J.
Am. Chem. Soc. 2002, 124, 10773.
(25) Hemming, K.; Bevan, M. J.; Loukou, C.; Patel, S. D.;
Renaudeau, D. Synlett 2000, 1565.
(32) (a) Leguern, D.; Le Moing, M. A.; Morel, G.; Foucaud, A.
Tetrahedron 1977, 33, 27. (b) Leguern, D.; Morel, G.;
Foucaud, A. Tetrahedron Lett. 1974, 15, 955.
(33) Neidlein, R.; Shatzmiller, S.; Sinnreich, D. Liebigs Ann.
Chem. 1983, 8.
(34) Graziano, M. L.; Iesce, M. R. J. Chem. Res., Synop. 1987,
362.
(35) Kolsaker, P.; Jensen, A. K. Acta Chem. Scand., Ser. B 1988,
42, 345.
(36) Takeda, A.; Tsuboi, S.; Oota, Y. J. Org. Chem. 1973, 38,
4148.
Synlett 2006, No. 3, 369–374 © Thieme Stuttgart · New York