A new three-component cascade reaction to yield 3-spirocyclopropanated β-lactams

Article abstract of DOI:10.1002/ejoc.200500838

A one-pot three-component reaction for the direct conversion of certain alkylhydroxylamine hydrochlorides 8 (alkyl = benzyl, p-methoxybenzyl, benzhydryl, tert-butyl), formaldehyde (9) or an alkyl glyoxylate (10) and bicyclopropylidene (2) to furnish 3-spi

Full text of DOI:10.1002/ejoc.200500838

FULL PAPER
DOI: 10.1002/ejoc.200500838
A New Three-Component Cascade Reaction to Yield 3-Spirocyclopropanated
β-Lactams[‡]
Alessandra Zanobini,[a] Alberto Brandi,[b] and Armin de Meijere*[a]
Keywords: Cascade reactions / Cycloadditions / β-Lactams / Microwaves / Small rings / Cyclopropanes
A one-pot three-component reaction for the direct conversion
of certain alkylhydroxylamine hydrochlorides 8 (alkyl = ben-
zyl, p-methoxybenzyl, benzhydryl, tert-butyl), formaldehyde
(9) or an alkyl glyoxylate (10) and bicyclopropylidene (2) to
furnish 3-spirocyclopropanated 2-azetidinones 7, 11 has
been developed. Microwave heating of mixtures of the three
components in the presence of sodium acetate in ethanol for
15–120 min furnished the products 7, 11 in 49–78% yield (7
examples). A new protocol for the oxidative deprotection of
the 3-spirocyclopropanated methyl 1-(p-methoxybenzyl)-2-
carboxylate 11b-Me provides the β-lactam building block 17-
Me in 90% yield, and the latter can be reprotected and acti-
vated with an N-tert-butoxycarbonyl (Boc) group in 82%
yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Not only are various β-lactams the most frequently em-
ployed kinds of antimicrobial agents,[1] but because of their
inherent ring strain, β-lactams can also favorably be em-
ployed as multifunctional building blocks. In fact, every sin-
gle bond in a β-lactam can undergo selective cleavage,[2] and
this favors the 2-azetidinone nucleus for various applica-
tions in organic synthesis.[3] As we have recently demon-
strated,[4] spirocyclopropanated β-lactams of type 7 can
conveniently be employed to prepare peptide mimics incor-
porating the 1-(aminomethyl)cyclopropanecarboxylic acid,
a β-alanine analog containing a cyclopropyl group.[5] 2-Az-
etidinones of type 7 are formed in high yields upon treat-
ment of cycloadducts 5 from nitrones 3 and bicyclopropyl-
idene (2) with trifluoroacetic acid.[6] This unprecedented
fragmentation of 5-spirocyclopropanated isoxazolidines of
types 4 and 5[7] constitutes a versatile access to β-lactams
of types 6 and 7, yet it suffers dramatically from the long
reaction times required for the formation of the unre-
arranged cycloadducts 4 and 5 (Scheme 1).[8]
Scheme 1. Fragmentations of the cycloadducts 4, 5 of nitrones 3 to
methylenecyclopropane (1) and bicyclopropylidene (2) under acidic
conditions.
In view of the multiple beneficial effects of microwave
heating on organic synthetic transformations reported in re-
cent years,[9] we tried out the possibility of shortening the
reaction times by using microwave heating during the 1,3-
dipolar cycloaddition of in situ generated unstable and/or
reactive nitrones[10] to bicyclopropylidene (2). Here we re-
port on our first results.
Results and Discussion
When a solution of a twofold excess of N-benzylhydrox-
ylamine hydrochloride (8a), a twofold excess of aqueous
formaldehyde (8 ), a twofold excess of sodium acetate and
[‡] Cyclopropyl Building Blocks in Organic Synthesis, 122. Part
121: T. Kurahashi, A. de Meijere, Angew. Chem. 2005, 114, bicyclopropylidene (2) in ethanol was heated in a screw-
capped glass vial in a microwave reactor[11] at 100 °C, the
8093–8096; Angew. Chem. Int. Ed. 2005, 44, 7881–7884. Part
120: T. Kurahashi, A. de Meijere, Synlett 2005, 2619–2622.
starting material 2 had been consumed within 60 min,[12]
[a] Institut für Organische und Biomolekulare Chemie, Georg-
August-Universität Göttingen,
and the 3-spirocyclopropanated 2-azetidinone 7a was iso-
lated in 68% yield. Apparently, the nitrone initially formed
from formaldehyde (9) and benzylhydroxylamine (8), had
undergone 1,3-dipolar cycloaddition to 2, and the resulting
isoxazolidine 5a, under the slightly acidic conditions of the
hydroxylamine hydrochloride/sodium acetate buffered sys-
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49-551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b] Dipartimento di Chimica Organica “Ugo Schiff”, Universitá
degli studi di Firenze, Polo Scientifico,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39-055-457-3572
Eur. J. Org. Chem. 2006, 1251–1255
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1251

A. Zanobini, A. Brandi, A. de Meijere
FULL PAPER
tem had fragmented via intermediates 12a, 13a[7b] to ethyl- uct,[8] the 3-spirocyclopropanated 4-oxopiperidine-2-car-
ene and the β-lactam 7a (Scheme 2).[13]
boxylate 15, was isolated (44%).
With N-methylhydroxylamine hydrochloride, formalde-
hyde (9) and 2, the yield of the corresponding N-methylaz-
etidinone was at best 10% and with the same hydroxyl-
amine derivative with ethyl glyoxylate (10-Et) and 2, none
of the corresponding azetidinone could be detected, even
not in the crude reaction mixture.
When methylenecyclopropane (1) was employed as di-
polarophile in this three-component reaction with 8a and
formaldehyde (9), the expected product 6a was isolated in
only 9% yield along with the spiro[cyclopropane-1,4Ј-isox-
azolidine] 16, which was formed along with the fragmented
5-spirocyclopropanated regioisomer, and cannot undergo
acid-catalyzed fragmentative rearrangement.
Scheme 2. One-pot three-component reaction under microwave
heating for the direct conversion of alkylhydroxylamine hydrochlo-
rides 8, aldehydes 9–10 and bicyclopropylidene (2) to 3-spirocy-
clopropanated 2-azetidinones 7 and 11. For details see Table 1.
The fragmentative rearrangement of 5-spirocyclopropan-
ated isoxazolidines 4 and 5 previously had been brought
about with reasonably strong acids such as trifluoroacetic,
p-toluenesulfonic or hydrochloric acid. To better under-
stand why this new one-pot three-component reaction
worked without any of these strong free acids present, con-
trol experiments were carried out with the isolated dispiro-
cyclopropanated 14a-Et. When the latter was heated with
added acetic acid in acetonitrile at 70 °C overnight, none of
the azetidinone 11a-Et was detected. But heating 14a-Et
under the same conditions with benzylhydroxylamine hy-
drochloride did furnish 11a-Et (59%). For the overall trans-
formation to occur, the added sodium acetate is essential as
well. An experiment with all the ingredients for the forma-
tion of 11a-Et, except for the added sodium acetate, carried
out in the microwave oven, gave no trace of product. In
fact, not even the condensation of the hydroxylamine and
the aldehyde to the nitrone took place.
Since this one-pot three-component sequential reac-
tion[14] has no precedent, it is difficult to estimate the role
of the microwave heating. In any case, it is remarkable that
the time required for the overall reaction is never longer
than 2 h, whereas with traditional heating at 45 °C the 1,3-
dipolar cycloaddition of the most reactive N-methyl-C-
(ethoxycarbonyl)nitrone onto bicyclopropylidene (2) re-
quires 16 d, and at higher temperatures only the corre-
sponding spirocyclopropanated piperidone derivative is
formed.[15]
Analogously, the 3-spirocyclopropanated 2-azetidinones
7b–d, 11a-Et, 11b-Me, 11d-Et were obtained from the corre-
sponding hydroxylamine hydrochlorides (or oxalate) and
formaldehyde 9 or ethyl 10-Et and methyl glyoxylate 10-Me,
respectively, in good to excellent yields (49–78%), as single
products after 30–120 min reaction times in a single opera-
tion (Scheme 2 and Table 1).
Table 1. One-pot three-component reaction under microwave heat-
ing for the direct conversion of alkylhydroxylamine hydrochlorides
8, aldehydes 9–10 and bicyclopropylidene (2) to 3-spirocyclopro-
panated 2-azetidinones 7 and 11 (see Scheme 2).
Starting
materials
R1
R2
Time
[min]
Temp. Product Yield
[°C]
(%)
8a + 9
8b + 9
8c + 9
8d + 9
8a + 10-Et Bn
8d + 10-Et tBu
8b + 10-Me PMB
Bn
H[a]
H[a]
H[a]
H[a]
60
45
30
30
100
80
100
80
80
80
7a
7b
7c
7d
68
53
49
73
PMB
BnH
tBu
CO2Et[b] 15
CO2Et[b] 105
CO2Me 120
11a-Et 72
11d-Et 53[c]
11b-Me 78
80
[a] Formaldehyde was used as an aqueous solution (8 ). [b] Ethyl
glyoxylate was used as a solution in toluene (50% w/w). [c] In ad-
dition, 47% of a mixture of 14d-Et and 15 (1.3:1) was isolated.
To demonstrate the accessibility of the unprotected 17-
Me, conditions for the removal of the p-methoxybenzyl
For hydroxylamine hydrochlorides 8a and 8c, the reac- group were developed, under which no trace of oxidized
tion was also performed with paraformaldehyde instead of byproduct was found, as had previously been observed.[4]
an aqueous solution of formaldehyde. The products 7a and
Treatment of 11b-Me with ceric ammonium nitrate
7c were obtained as well, but in slightly lower yields (56 (CAN) in aqueous acetonitrile (1:3) at room temperature
and 37%, respectively). From N-tert-butylhydroxylamine did indeed furnish 17-Me in 90% yield, and this in turn
hydrochloride (8d), ethyl glyoxylate (10-Et) and bicyclopro- could be protected with a t-Boc group to yield 18-Me
pylidene (2), a mixture of the unfragmented N-tert-butyl- (82%). The latter can serve as a building block for β-amino
isoxazolidine 14d-Et and the thermal rearrangement prod- acid peptides incorporating 1-(aminomethyl)cyclopro-
1252
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Eur. J. Org. Chem. 2006, 1251–1255

A New Three-Component Cascade Reaction
FULL PAPER
7.47 (m, 2 H). 13C NMR (62.9 MHz): δ = 56.0 (CH3), 56.4 (CH2),
115.7 (2 CH), 122.1 (C), 133.6 (2 CH), 162.1 (C), 165.5 (2 C).
C10H13NO6 (243.22): C 49.38, H 5.39, N 5.76; found C 49.13, H
5.61, N 5.90.
panecarboxylic acid, as it is activated towards ring opening
at the lactam bond (Scheme 3).[4]
One-Pot Three-Component Synthesis of β-Lactams 7a–d and
11a,b,d. General Procedure (GP) 1: A solution of the hydroxylamine
salt (2 equiv.), the aldehyde (2 equiv.), bicycloproppylidene (2)
(1 equiv.), and NaOAc (2 equiv.) in ethanol was sealed in a screw-
capped vial for the microwave apparatus and heated at the indi-
cated temperature for the indicated time. After cooling down to
room temperature, the solution was concentrated under reduced
pressure. An equal amount each of water and ethyl acetate was
added, and the two phases were separated. The water phase was
made basic with NaHCO3 (satd. solution) and extracted three
times with ethyl acetate. The combined organic layers were then
washed with brine and dried with Na2SO4.
Scheme 3. Modification of the β-lactam 11b-Me to yield the reac-
tive building block 18-Me.
5-Benzyl-5-azaspiro[2.3]hexan-4-one (7a): Column chromatography
(Rf = 0.10, 45 g of silica gel, 12×3 cm column, hexane/Et2O, 2:1)
of the residue obtained from the hydroxylamine 8a (0.638 g,
4.00 mmol), formaldehyde (9) solution (8.0 ) in water (0.250 mL,
2.00 mmol), bicyclopropylidene (2) (0.190 mL, 2.00 mmol), and
NaOAc (0.328 g, 4.00 mmol) in 1.75 mL of ethanol according to
GP1 (100 °C, 60 min) gave the product 7a (0.255 g, 68%) as a yel-
Experimental Section
NMR spectra were recorded with Bruker AM 250 (250 MHz for
1H and 62.9 MHz for 13C NMR), Varian Mercury 200 (200 MHz
1
for H and 50.3 MHz for 13C NMR), Varian Unity 300 (300 MHz
for 1H and 75.5 MHz for 13C NMR), Varian INOVA 600
(600 MHz for 1H and 150.8 MHz for 13C NMR) instruments in
CDCl3, if not otherwise specified. Multiplicities were determined
by DEPT (Distortionless Enhancement by Polarization Transfer)
or APT (Attached Proton Test) measurements. Chemical shifts re-
fer to δTMS = 0.00 according to the chemical shifts of residual
CHCl3 signals. IR: Bruker IFS 66 (FT-IR) spectrophotometer,
measured as KBr pellets, oils between KBr plates. MS (EI, 70 eV):
Finnigan MAT 95 spectrometer. M.p.: Büchi 510 capillary melting
point apparatus, uncorrected values. TLC: Macherey–Nagel pre-
coated sheets, 0.25 mm Sil G/UV254. Column chromatography:
Merck silica gel, grade 60, 230–400 mesh. Starting materials: meth-
ylenecyclopropane (1),[6] bicyclopropylidene (2),[6] N-benzhydrylhy-
droxylamine hydrochloride (8c),[16] and methylglyoxylate (10-
Me),[17] were prepared according to published procedures. All oper-
ations in anhydrous solvents were performed under an argon atmo-
sphere in flame-dried glassware. Diethyl ether was dried by distil-
lation from sodium benzophenone ketyl, CH2Cl2 and acetonitrile
from P2O5. Commercially available m-chloroperbenzoic acid
(mCPBA) was enriched according to a published procedure.[18] All
other chemicals were used as commercially available. Organic ex-
tracts were dried with MgSO4 or Na2SO4.
low oil. IR (film): ν = 3064 cm–1, 3004, 2890, 1751, 1496, 1455,
˜
1
1395, 1354. H NMR (250 MHz): δ = 0.92–0.97 (m, 2 H, cPr-H),
1.18–1.23 (m, 2 H, cPr-H), 3.33 (s, 2 H, CH2), 4.47 (s, 2 H, CH2),
7.17–7.39 (m, 5 H, Ar-H). 13C NMR (62.9 MHz): δ = 7.6 (2 CH2),
32.1 (C), 46.3 (CH2), 48.1 (CH2), 127.6 (CH), 128.1 (2 CH), 128.7
(2 CH), 136.0 (C), 172.6 (C). MS (EI): m/z (%) = 187 (44), 131 (10),
91 (100), 54 (21). C12H13NO (187.24): C 76.98, H 7.00, N 7.48;
found C 76.83, H 7.13, N 7.25.
5-(4-Methoxybenzyl)-5-azaspiro[2.3]hexan-4-one (7b): Column
chromatography (Rf = 0.28, 30 g of silica gel, 12×2.5 cm column,
hexane/Et2O, 3:1) of the residue obtained from the hydroxylamine
8b (0.780 g, 3.20 mmol), formaldehyde (9) solution (8.0 ) in water
(0.250 mL, 2.00 mmol), bicyclopropylidene (2) (0.190 mL,
2.00 mmol), and NaOAc (0.263 g, 3.20 mmol) in 2.50 mL of etha-
nol according to GP1 (80 °C, 45 min) gave the product 7b (0.232 g,
53%) as a yellow oil. IR (KBr): ν = 3080 cm–1, 3001, 2936, 2894,
˜
1
2839, 1732, 1512, 1401. H NMR (250 MHz): δ = 0.90–0.95 (m, 2
H, cPr-H), 1.16–1.21 (m, 2 H, cPr-H), 3.30 (s, 2 H), 3.80 (s, 3 H),
4.40 (s, 2 H), 6.85–6.91 (m, 2 H, Ar-H), 7.17–7.23 (m, 2 H, Ar-H).
13C NMR (62.9 MHz): δ = 7.33 (2 CH2), 31.8 (C), 45.6 (CH2), 47.7
(CH2), 55.1 (CH3), 113.9 (2 CH), 127.8 (C), 129.2 (2 CH), 158.9
(C), 172.3 (C). MS (EI): m/z (%) = 217 (100), 186 (8), 163 (10), 121
(85), 78 (10). C13H15NO2 (217.26): C 71.87, H 6.96, N 6.45; found
C 72.07, H 7.10, N 6.30.
Synthesis of N-(p-Methoxybenzyl)hydroxylamine Oxalate (8b): To a
solution
of
N-(p-methoxybenzyl)-C-cyanonitrone
(4.70 g,
25.0 mmol) in MeOH (125 mL) was added NH2OH·HCl (8.7 g,
125 mmol). After stirring for 2 h at 60 °C, the resulting mixture
was cooled to room temp., methanol was evaporated in vacuo, and
CHCl3 (100 mL) was added. The mixture containing some undis-
solved solids was filtered through a pad of Celite. The filtrate was
concentrated, and the residue was partitioned with CHCl3
(150 mL) and a satd. solution of NaHCO3 (150 mL). The acqueous
5-(Benzhydryl)-5-azaspiro[2.3]hexan-4-one
(7c):
Column
chromatography (Rf = 0.18, 36 g of silica gel, 15×2.5 cm column,
hexane/Et2O, 2:1) of the residue obtained from the hydroxylamine
8c (0.707 g, 3.00 mmol), formaldehyde (9) solution (8.0 ) in water
(0.375 mL, 3.00 mmol), bicyclopropylidene (2) (0.140 mL,
layer was extracted with CHCl3 (2×70 mL), and the combined ex- 1.50 mmol), and NaOAc (0.246 g, 3.00 mmol) in 2.00 mL of etha-
tracts were washed with satd. solution of NaCl (150 mL), dried
(MgSO4) and filtered. To the filtrate was added a solution of oxalic
acid (3.15 g, 250.0 mmol) in 25 mL of methanol, and the resulting
suspension was evaporated to dryness. The solid obtained was trit-
urated with ether/pentane, and collected by suction. After drying
in vacuo, analytically pure 8b (4.84 g, 80%) was obtained as a yel-
nol according to GP1 (100 °C, 30 min) gave the product 7c
(193 mg, 49%) as a colorless solid, m.p. 95–96 °C. IR (KBr): ν =
˜
3080 cm–1, 3060, 2962, 2892, 1888, 1745, 1597, 1581, 1494, 1446,
1
1384, 1364. H NMR (250 MHz): δ = 0.93–0.98 (m, 2 H, cPr-H),
1.20–1.25 (m, 2 H, cPr-H), 3.39 (s, 2 H, CH2), 6.25 (s, 1 H, CH),
7.02–7.28 (m, 5 H, Ar-H), 7.30–7.40 (m, 5 H, Ar-H). 13C NMR
(62.9 MHz): δ = 7.8 (2 CH2), 31.4 (C), 47.4 (CH2), 59.3 (CH), 127.6
(2 CH), 128.1 (4 CH), 128.6 (4 CH), 139.2 (2 C), 172.5 (C). MS
(EI): m/z (%) = 263 (45), 186 (20), 167 (100), 165 (25), 152 (18), 91
lowish solid, m.p. 145 °C. IR (KBr): ν = 3424 cm–1, 2932, 2837,
˜
1721, 1612, 1515, 1454, 1306, 1253, 826, 710. 1H NMR (250 MHz,
CD3OD): δ = 3.85 (s, 3 H), 4.35 (s, 2 H), 7.01–7.05 (m, 2 H), 743–
Eur. J. Org. Chem. 2006, 1251–1255
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A. Zanobini, A. Brandi, A. de Meijere
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(18). C18H17NO (263.33): C 82.10, H 6.51, N 5.32; found C 82.12,
H 6.25, N 5.16.
65.7 (C), 67.9 (CH), 171.7 (C). MS (EI): m/z (%) = 253 (15), 210
(5), 180 (40), 124 (100), 96 (45), 57 (100), 41 (75). C14H23NO3
(253.34): calcd. C 66.37, H 9.15, N 5.53; found C 66.15, H 9.09, N
5-tert-Butyl-5-azaspiro[2.3]hexan-4-one (7d): Column chromatog-
raphy (Rf = 0.19, 25 g of silica gel, 12×2 cm column, hexane/Et2O,
2:1) of the residue obtained from the hydroxylamine 8d (0.251 g,
2.00 mmol), formaldehyde (9) solution (8.0 ) in water (0.250 mL,
2.00 mmol), bicyclopropylidene (2) (0.09 mL, 1.00 mmol), and
NaOAc (0.164 g, 2.00 mmol) in 0.5 mL of ethanol according to
GP1 (80 °C, 30 min) gave the product 7d (0.111 g, 73%) as a color-
5.47. 11d-Et (R = 0.7, hexane/Et O, 3:1): IR (film): ν = 2937 cm–1,
˜
f
2
1
1766, 1749, 1368, 1186. H NMR (250 MHz): δ = 0.68–0.74 (m, 1
H, cPr-H), 1.05–1.24 (m, 3 H, cPr-H), 1.28 (t, J = 7.5 Hz, 3 H),
1.37 (s, 9 H), 4.18 (s, 1 H), 4.21 (dq, J = 7.5, 2.5 Hz, 2 H). 13C
NMR (62.9 MHz): δ = 6.4 (CH2), 8.0 (CH2), 14.3 (CH3), 27.9 (3
CH3), 35.6 (C), 54.3 (C), 57.8 (CH), 61.3 (CH2), 170.5 (C), 171.0
(C). MS (EI): m/z (%) = 225 (15), 210 (80), 182 (100), 152 (35), 136
(20), 96 (40), 41 (35). C12H19NO3 (225.29): C 63.98, H 8.50, N 6.22;
found C 64.07, H 8.73, N 6.01.
less oil. IR (film): ν = 2970 cm–1, 2935, 2885, 2839, 1753, 1379,
˜
1
1336. H NMR (250 MHz): δ = 0.87–0.91 (m, 2 H, cPr-H), 1.09–
1.14 (m, 2 H, cPr-H), 1.35 (s, 9 H), 3.35 (s, 2 H). 13C NMR
(62.9 MHz): δ = 7.3 (2 CH2), 27.9 (3 CH3), 30.2 (C), 45.5 (CH2),
Methyl 5-(4-Methoxybenzyl)-6-oxo-5-azaspiro[2.3]hexane-4-carbox-
64.3 (C), 171.3 (C). MS (EI): m/z (%) = 153 (10), 138 (100), 84 (5), ylate (11b-Me): Column chromatography (Rf = 0.12, 70 g of flash
70 (100), 57 (40). HRMS (EI) calcd. for C9H15NO 153.1154 [M+],
found 153.1154.
silica gel, 20×3 cm column, hexane/Et2O, 3:2) of the residue ob-
tained from the hydroxylamine 8b (0.486 g, 2.00 mmol), methyl
glyoxylate 10-Me (0.176 g, 2.00 mmol), bicyclopropylidene (2)
(0.090 mL, 1.00 mmol), and NaOAc (0.164 g, 2.00 mmol) in
1.10 mL of ethanol according to GP1 (80 °C, 120 min) gave the
Ethyl 5-Benzyl-6-oxo-5-azaspiro[2.3]hexane-4-carboxylate (11a-Et):
Column chromatography (Rf = 0.29, 35 g of silica gel, 12×2.5 cm
column, hexane/Et2O, 3:1) of the residue obtained from the hydrox-
ylamine 8a (0.479 g, 3.00 mmol), ethyl glyoxylate (10-Et) as a solu-
tion in toluene (50% weight) (0.60 mL, 3.00 mmol), bicyclopropyl-
idene (2) (0.140 mL, 1.50 mmol), and NaOAc (0.246 g, 3.00 mmol)
in 0.70 mL of ethanol according to GP1 (80 °C, 15 min) gave the
product 11b-Me (0.215 g, 78%) as a light-yellow oil. IR (film): ν
˜
1
= 2954 cm–1, 2837, 1775, 1735, 1612, 1514, 1392, 1248. H NMR
(250 MHz): δ = 0.84–0.91 (m, 1 H, cPr-H), 1.04–1.30 (m, 3 H, cPr-
H), 3.71 (s, 3 H), 3.80 (s, 3 H), 3.99 (s, 1 H), 4.14–4.20 (d, J =
15 Hz, 1 H), 4.82–4.88 (d, J = 15 Hz, 1 H), 6.84–6.90 (m, 2 H, Ar-
H), 7.15–7.21 (m, 2 H, Ar-H). 13C NMR (62.9 MHz): δ = 6.6
(CH2), 8.0 (CH2), 37.1 (C), 45.1 (CH2), 52.2 (CH), 55.3 (CH3), 57.3
(CH3), 114.1 (2 CH), 127.2 (C), 129.8 (2 CH), 159.2 (C), 170.2 (C),
170.9 (C). MS (EI): m/z (%) = 275 (4), 243 (5), 215 (5), 188 (25),
148 (10), 121 (100), 78 (15). C15H17NO4 (275.30): C 65.44, H 6.22,
N 5.09; found C 65.17, H 6.20, N 4.91.
product 11a-Et (0.279 g, 72%) as a yellow oil. IR (film): ν =
˜
2981 cm–1, 1775, 1744, 1496, 1456, 1388, 1199. 1H NMR
(300 MHz): δ = 0.84–0.90 (ddd, J = 9.4, 7.8, 4.2 Hz, 1 H), 1.04–
1.28 (m, 3 H), 1.20–1.25 (t, J = 9.0 Hz, 3 H), 3.98 (s, 1 H), 4.10–
4.21 (m, 2 H), 4.21–4.25 (d, J = 12.0 Hz, 1 H), 4.86–4.91 (d, J =
12.0 Hz, 1 H), 7.22–7.36 (m, 5 H). 13C NMR (75.5 MHz): δ = 6.4
(CH2), 8.0 (CH2), 14.2 (CH3), 37.2 (C), 45.6 (CH2), 57.5 (CH), 61.3
(CH2), 127.8 (CH), 128.4 (2 CH), 128.8 (2 CH), 135.3 (C), 169.6 Deprotection of β-Lactam 11b-Me: To a stirred solution of β-lactam
(C), 171.1 (C). MS (EI): m/z (%) = 259 (4), 231 (18), 186 (5), 158
(39), 91 (100), 65 (15). C15H17NO3 (259.30): C 69.48, H 6.61, N
5.40; found C 68.76, H 6.72, N 5.52.
11b-Me (0.114 g, 0.41 mmol), in acetonitrile (3.0 mL) was added a
solution of ceric ammonium nitrate (CAN) (0.50 g, 0.90 mmol) in
water/acetonitrile (2.0:3.0 mL). After 1 h of stirring at room tem-
perature additional CAN (0.110 g, 0.20 mmol) was added. After
30 min, Na2S2O3·5 H2O (0.273 g, 1.1 mmol) was added, and the
color of the suspension turned to a lighter yellow. NaHCO3 was
also added until the pH turned from 1 to 7. The suspension was
evaporated to dryness, methanol (15 mL) was added, and the sus-
pension obtained was filtered through a pad of silica gel (soaked
with diethyl ether) to eliminate salts. The column was washed with
methanol (Ϸ 200 mL), and the 68 mg of crude product, obtained
after evaporation of the solvent, was purified by column
chromatography. The β-lactam 17-Me [Rf = 0.47, 70 g of flash silica
gel, 20×3 cm column, CH2Cl2/MeOH (1 vol.-% NH4OH concd.)
One-Pot Protocol Applied to Hydroxylamine 8d and Ethyl Glyoxyl-
ate 10-Et: A solution of tert-butylhydroxylamine hydrochloride (8d)
(250 mg, 2.00 mmol), ethyl glyoxylate (10-Et) as a toluene solution
(50% w/w) (0.408 g, 0.40 mL, 2.0 mmol), bicyclopropylidene (2)
(80 mg, 0.090 mL, 1.00 mmol) and NaOAc (164 mg, 2.0 mmol) in
ethanol (0.50 mL), was sealed in a screw capped vial for the micro-
wave oven and heated at 80 °C for 105 min. After cooling to room
temperature, the solution was concentrated under reduced pressure.
An equal amount each of water and ethyl acetate (30 mL) was
added, and the two phases were separated. The water phase was
made basic with NaHCO3 (satd. solution) and extracted with ethyl
acetate (3×30 mL). The combined organic layers were then washed
with brine and dried with Na2SO4. The crude product was purified
by column chromatography (50 g of flash silica gel, 3×15 cm col-
umn, hexane/Et2O, 3:1) to give ethyl 8-tert-butyl-7-oxa-8-azadi-
spiro[2.0.2.3]nonane-9-carboxylate (14d-Et) and ethyl 5-tert-butyl-
8-oxo-5-azaspiro[2.5]octane-4-carboxylate (15) (0.111 g, 44%) in a
ratio 14d-Et/15 of 1.3:1 and ethyl 5-tert-butyl-6-oxo-5-azaspiro-
[2.3]hexane-4-carboxylate (11d-Et) (0.119 g, 53%) as a yellow solid,
50:1] was obtained as a light-yellow oil (58 mg, 90%). IR (film): ν
˜
1
= 3006 cm–1, 2955, 1792, 1733, 1438, 1289. H NMR (250 MHz):
δ = 0.87–0.97 (m, 1 H, cPr-H), 1.08–1.31 (m, 3 H, cPr-H), 3.73 (s,
3 H), 4.24 (s, 1 H). 13C NMR (62.9 MHz): δ = 7.2 (CH2), 8.5 (CH2),
38.3 (C), 52.3 (CH), 54.9 (CH3), 170.7 (C), 172.8 (C). MS (EI):
m/z (%) = 155 (1), 135 (15), 112 (22), 96 (30), 85 (62), 83 (100), 82
(8), 69 (8), 48 (50), 46 (22). C7H9NO3 (155.15): C 54.19, H 5.85, N
9.03; found C 53.94, H 5.74, N 8.78.
m.p. 58–60 °C. (14d-Et): IR (film): ν = 3076 cm–1, 2977, 2936, 1757,
Protection of β-Lactam 17-Me: Di-tert-butyl pyrocarbonate
(Boc2O, 0.113 g, 0.52 mmol) and DMAP (3 mg, 0.03 mmol) were
˜
1465, 1363, 1275. 1H NMR (600 MHz): δ = 0.09–0.13 (ddd, J =
10.5, 7.2, 6.3 Hz, 1 H), 0.15–0.18 (m, 1 H), 0.50–0.54 (ddd, J = added in one portion to β-lactam 17-Me (40.0 mg, 0.26 mmol) in
10.5, 7.1, 5.6 Hz, 1 H), 0.65–0.70 (m, 3 H), 0.82–0.86 (dt, J = 11.2,
6.7 Hz, 1 H), 0.90–0.94 (ddd, J = 11.2, 7.2, 5.6 Hz, 1 H), 1.13 (s, 9
anhydrous acetonitrile (3.90 mL) at 0 °C. After 1 h, the starting
material was no longer detectable by TLC. The reaction mixture
H), 1.24–1.26 (t, J = 7.2 Hz, 3 H), 3.69 (s, 1 H), 4.14–4.19 (dq, J was stirred at ambient temperature for an additional 13 h, diluted
= 10.5, 7.1 Hz, 1 H), 4.23–4.28 (dq, J = 10.5, 7.1 Hz, 1 H). 13C
NMR (62.9 MHz): δ = 4.7 (CH2), 5.1 (CH2), 11.4 (CH2), 12.2
with dichloromethane (20 mL), washed successively with 5% aq.
NaHSO3 solution (3×20 mL), aq. satd. NaHCO3 solution
(CH2), 14.3 (CH3), 25.4 (3 CH3), 31.3 (C), 58.8 (C), 60.9 (CH2), (1×20 mL), dried and concentrated under reduced pressure. Col-
1254 Eur. J. Org. Chem. 2006, 1251–1255
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A New Three-Component Cascade Reaction
FULL PAPER
[5] a) S. Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1–15; b) Y.
Yamamoto, N. Assao, N. Tsukada, in: Advances in Asymmetric
Synthesis Vol. 3. (Ed.: A. Hassner), JAI Press Inc., Stamford,
1988; c) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 25,
117–128; d) Enantioselective Synthesis of β-Amino Acids (Ed.:
E. Juaristi), Wiley-VCH, New York, 1997; e) E. Juaristi, D.
Quintana, J. Escalante, Aldrichimica Acta 1994, 27, 3–11.
[6] The preparation and chemical transformations of methylenecy-
clopropane (1) and its close relative bicyclopropylidene (2) have
been reviewed extensively; a) P. Binger, H. M. Büch, Top. Curr.
Chem. 1987, 135, 77–151; b) P. Binger, T. Schmidt, in: Methods
of Organic Chemistry, (Houben-Weyl), vol. E 17c (Ed.: A.
de Meijere), Thieme, Stuttgart, 1997, pp. 2217–2294; c) A.
Brandi, A. Goti, Chem. Rev. 1998, 98, 589–635; d) A. de Mei-
jere, S. I. Kozhushkov, A. F. Khlebnikov, Zh. Org. Khim. 1996,
32, 1607–1626; Russ. J. Org. Chem. (Engl. Transl.) 1996, 32,
1555–1575; e) A. de Meijere, S. I. Kozhushkov, A. F. Khlebni-
kov, Top. Curr. Chem. 2000, 207, 89–147; f) A. de Meijere, S. I.
Kozhushkov, T. Späth, M. von Seebach, S. Löhr, H. Nüske, T.
Pohlmann, M. Es-Sayed, S. Bräse, Pure Appl. Chem. 2000, 72,
1745–1756.
[7] a) F. M. Cordero, M. Salvati, F. Pisaneschi, A. Brandi, Eur. J.
Org. Chem. 2004, 2205–2213; b) F. M. Cordero, F. Pisaneschi,
M. Salvati, V. Paschetta, J. Ollivier, J. Salaün, A. Brandi, J.
Org. Chem. 2003, 68, 3271–3280.
[8] For a recent review see: A. Brandi, S. Cicchi, F. M. Cordero,
A. Goti, Chem. Rev. 2003, 103, 1213–1269.
[9] C. O. Kappe, Angew. Chem. 2004, 116, 6408–6443; Angew.
Chem. Int. Ed. 2004, 43, 6250–6284, and references therein.
[10] In situ generation of nitrones, especially the unstable one from
formaldehyde, for 1,3-dipolar cycloadditions to alkenes, has
been used before, see: I. S. Young, J. L. Williams, M. A. Kerr,
Org. Lett. 2005, 7, 953–955.
umn chromatography (Rf = 0.17, 12 g of silica gel, 2×8 cm column,
hexane/Et2O, 2:1) furnished 18-Me (54 mg, 82%) as a colorless so-
lid, m.p. 69–70 °C. IR (film): ν = 2978 cm–1, 2950, 1814, 1743, 1723,
˜
1382, 1319, 1151. 1H NMR (250 MHz): δ = 0.95–1.01 (m, 1 H),
1.24–1.44 (m, 3 H), 1.51 (s, 9 H), 3.78 (s, 3 H), 4.48 (s, 1 H). 13C
NMR (50.3 MHz): δ = 8.7 (CH2), 10.5 (CH2), 27.9 (3 CH3), 36.1
(C), 51.5 (CH3), 57.2 (CH), 83.6 (C), 168.4 (C), 168.7 (2 C). MS
(EI): m/z (%) = 200 (1), 140 (19), 96 (10), 57 (100). MS (DCI):
m/z (%) = 273 (100) [M + NH4+]. C12H17NO5 (255.3): C 56.46, H
6.71, N 5.49; found C 56.50, H 6.89, N 5.54.
One-Pot Protocol Applied to the Hydroxylamine 8a and Formalde-
hyde (9) with Methylenecyclopropane (1) as Dipolarophile: A solu-
tion of benzylhydroxylamine hydrochloride (8a) (0.479 g,
3.00 mmol), formaldehyde (9) solution (8 ) in water (0.375 mL,
3.00 mmol), methylenecyclopropane (1) (81 mg, 0.1 mL, 1.5 mmol)
and NaOAc (0.246 g, 3.0 mmol) in ethanol (1.0 mL), was sealed in
a screw-capped vial for the microwave oven, and heated at 80 °C
for 70 min. After cooling to room temperature, the solution was
concentrated under reduced pressure. An equal amount each of
water and ethyl acetate (30 mL) was added, and the two phases
were separated. The water phase was made basic with NaHCO3
(satd. solution) and extracted with ethyl acetate (3×30 mL). The
combined organic layers were then washed with brine (2×30 mL)
and dried with Na2SO4. After filtration and evaporation of the sol-
vent a crude mixture was obtained, containing 1-benzylazetidin-2-
one (6a, R1 = Bn; R2 = H) and 6-benzyl-5-oxa-6-azaspiro[2.4]hep-
tane (16). Column chromatography (35 g of silica gel, 15×2.5 cm
column, hexane/Et2O, 3:1) of the residue gave 16 (0.234 g, 82%):
R = 0.28. IR (film): ν = 3087 cm–1, 3068, 2997, 2867, 1496, 1454,
˜
f
1
1030, 1018. H NMR (300 MHz, C2D2Cl4, 100 °C): δ = 0.73–0.81
[11] The reactions under microwave heating were carried out in a
Smith Creator, part of Coherent SynthesisTM from Personal
Chemistry. The used system operated with an emission fre-
quency of 2.45 GHz and a reactor with on-line temperature,
pressure and microwave power control. In this apparatus, reac-
tions can be performed at any temperature in the range of 60 to
250 °C at pressures of up to 2 MPa (20 bar). The temperature
increase can be varied in the range 2–5 °C/s, depending on the
solvent. The reactions are performed under magnetic stirring,
in vials with caps supplied by Personal Chemistry. The instru-
ment processes reaction volumes between 0.5 and 5 mL.
[12] Initially, the reactions were monitored by NMR spectroscopy
on aliquots of the crude reaction mixtures, taken from the vials
with a syringe.
[13] Although not applicable to the synthesis of spirocyclopropan-
ated azetidiones as reported here, another one-pot approach to
β-lactams applying nitrones has recently been reported, see: R.
Shintani, G. C. Fu, Angew. Chem. 2003, 115, 4216–4219; An-
gew. Chem. Int. Ed. 2003, 42, 4082–4085.
[14] One of the referees of this article criticized our calling this a
“three-component reaction”, but we really cannot see the dif-
ference between our reaction and the well-known Ugi multi-
component reactions in which, according to Ugi’s own state-
ment “the starting materials do not react simultaneously in one
step, but rather in a sequence of elementary steps, according to
a program.” See: A. Dömling, I. Ugi, Angew. Chem. 2000, 112,
3300–3344; Angew. Chem. Int. Ed. 2000, 39, 3168–3210.
[15] A. Goti, B. Anichini, A. Brandi, S. I. Kozhushkov, C. Gratkow-
ski, A. de Meijere, J. Org. Chem. 1996, 61, 1665–1672.
[16] H. Tokuyama, T. Kuboyama, A. Amano, T. Yamashita, T. Fu-
kuyama, Synthesis 2000, 1299–1304.
(m, 4 H, cPr-H), 2.97 (s, 2 H), 3.88 (s, 2 H), 4.09 (s, 2 H), 7.28–
7.43 (m, 5 H, Ar-H). 13C NMR (75.5 MHz, C2D2Cl4, 100 °C): δ =
10.2 (2 CH2), 24.8 (C), 61.8 (CH2), 62.2 (CH2), 72.9 (CH2), 126.9
(C), 128.0 (2 CH), 128.8 (2 CH), 137.4 (C). MS (EI): m/z (%) =
190 (2) [M + H+], 189 (12), 161 (2), 106 (4), 91 (100), 77 (5).
C12H15NO (189.25): C 76.16, H 7.99, N 7.40; found C 76.18, H
7.72, N 7.22. A second column chromatography (12 g of silica gel,
8×2 cm, column, hexane/Et2O, 2:1) was necessary to separate 6a
(R1 = Bn; R2 = H) (21 mg, 9%, Rf = 0.12) from benzylhydroxyl-
amine.
Acknowledgments
This work was supported by the State of Niedersachsen, the Fonds
der Chemischen Industrie as well as the companies BASF AG and
Bayer CropScience AG. The authors are grateful to Dr. Burkhard
Knieriem, Göttingen, for his careful proofreading of the final ma-
nuscript.
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[2] B. Alcaide, P. Almendros, Synlett 2002, 381–393.
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Received: October 26, 2005
Published Online: December 27, 2005
Eur. J. Org. Chem. 2006, 1251–1255
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1255