3-Spirocyclopropanedihydro- and -tetrahydropyridin-4-ones from nitrone cycloadducts of bicyclopropylidene via 1-(1′-aminomethylcyclopropyl)- cyclopropanol under PdII catalysis

Article abstract of DOI:10.1002/ejoc.200700912

A series of 3-spirocyclopropanedihydro- and -tetrahydropyrid-4-ones have been synthesized by nitrone cycloaddition to 1,1′-bicyclopropylidene (BCP), chemoselective reduction of the N-O bond of the isoxazolidine ring, and Pd^II-catalyzed cascade rearrangement of the β-aminocyclopropanol derivatives into the final products. The new tetrahydropyridone derivatives were also prepared by thermal rearrangement of the isoxazolidines. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700912

FULL PAPER
DOI: 10.1002/ejoc.200700912
3-Spirocyclopropanedihydro- and -tetrahydropyridin-4-ones from Nitrone
Cycloadducts of Bicyclopropylidene via 1-(1Ј-Aminomethylcyclopropyl)-
cyclopropanol under PdII Catalysis[‡]
Julia Revuelta,[a][‡‡] Stefano Cicchi,[a] Armin de Meijere,[b] and Alberto Brandi*[a]
Keywords: Cycloaddition / Cascade reactions / Heterocycles / Palladium / Catalysis / Rearrangement
A series of 3-spirocyclopropanedihydro- and -tetrahydropy- tives into the final products. The new tetrahydropyridone de-
rid-4-ones have been synthesized by nitrone cycloaddition to
1,1Ј-bicyclopropylidene (BCP), chemoselective reduction of
the N–O bond of the isoxazolidine ring, and PdII-catalyzed
cascade rearrangement of the β-aminocyclopropanol deriva-
rivatives were also prepared by thermal rearrangement of
the isoxazolidines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
can be prepared by the facile assembly of functionalized
The release of strain energy associated with the opening isoxazolidines through a 1,3-dipolar cycloaddition reaction
of a cyclopropane ring in an organic molecule may lead to of nitrones to alkylidenecyclopropanes[4] and feature a
multiple transformations, the selectivity of which depends highly strained cyclopropane ring that is highly reactive,[1]
on the nature and pattern of substituents on the cyclopro- resulting in a variety of new reactions. The synthesis and
pane ring and on the adjacent positions.[1] The presence of reactivity of 2 are tuned by the substituents present on the
electron-donor substituents on the cyclopropane ring en- parent alkylidenecyclopropane and on the nitrone counter-
hances its reactivity and may lead to a high degree of con- parts as well as by the reaction conditions applied. The re-
trol in the regioselectivity of the ring-opening reaction.[2]
arrangement of 2,[5] which has been extensively studied,[3,4,6]
In this context, the transformations of isoxazolidine-5- is an example of a useful thermal domino transformation
spirocyclopropanes 2 have recently established themselves of cyclopropanes, leading to mono- and oligocyclic tetra-
as versatile tools in organic synthesis.[3] These compounds hydropyridones 1 which have found widespread application
Scheme 1.
in the synthesis of natural and nonnatural compounds. On
the other hand, as was found very recently,[7] β-aminocy-
[‡] Cyclopropyl Building Blocks in Organic Synthesis, 146. Part
145: I. Emme, C. Bruneau, P. H. Dixneuf, A. de Meijere, Syn-
clopropanols 3, easily obtained by reduction of 2,[8] un-
thesis, in press. Part 144: I. Nakamura, R. Nagata, T. Nemoto,
Y. Yamamoto, A. de Meijere, Eur. J. Org. Chem. 2007, 4479– dergo a PdII-catalyzed rearrangement eventually leading to
4482.
dihydropyridones 4. (Scheme 1).
[a] University of Florence, Department of Organic Chemistry
The choice of 1,1Ј-bicyclopropylidene (BCP, 6)[9] as di-
“Ugo Schiff” and HeteroBioLab,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
E-mail: alberto.brandi@unifi.it
polarophile in these processes appeared particularly inter-
esting to expand the synthetic utility of this methodology.
In fact, certain spirocyclopropanated heterocyclic ketones
originating from BCP through thermal rearrangement of
isoxazolidines 7 have demonstrated an ability to cleave su-
percoiled DNA in analogy to natural products like illudines
and ptaquiloside.[10] In this paper, we report the synthesis
of several new spirocyclopropane-annelated azaheterocycles
[b] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: Armin.deMeijere@chemie.uni-gottingen.de
[‡‡] Current address: Departamento de Química Bioorgánica, In-
stituto Química Orgánica, CSIC,
Juan de la Cierva, 3, 28006, Madrid, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1085–1091
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J. Revuelta, S. Cicchi, A. de Meijere, A. Brandi
FULL PAPER
by a two-step metal-mediated transformation and by ther- out at a relatively low temperature (60 °C) with extended
mal rearrangement of isoxazolidine-4,5-dispirocyclopro- reaction times to avoid thermal isomerization of the ad-
panes 7.
ducts.
In fact, the reaction shown in entry 5 (Table 1), for exam-
ple, when carried out at 110 °C was complete within 5 d,
but 32 and 4% yields, respectively, of the rearrangement
products 23 and 24 were obtained in addition to a 45%
yield of the cycloadduct 17 (Scheme 3). The unexpected
amine 24 must have been formed in a common side-reaction
of the thermal process,[3,4] that is, by a hydrogen shift of the
1,6-diradical intermediate, which here must have occurred
through a 1,7 mechanism from the N-methyl substituent
and the resulting formaldehyde imine subsequently must
have undergone hydrolysis during purification.
Results and Discussion
All isoxazolidine-4,5-dispirocyclopropanes 7 used as
starting materials in this work were obtained by 1,3-dipolar
cycloaddition of the appropriate nitrone
(Scheme 2). Whereas compounds 13 and 14 have previously
been described,[10b] the analogues 15, 16, and 17 were newly
prepared in excellent yields (Table 1) from 6 and the nitro-
nes 10,[11] 11,[12] and 12[13]. The cycloadditions were carried
5 to BCP
The structural assignments for the new cycloadducts 15–
1
17 were made on the basis of their H and 13C NMR spec-
tra which show characteristic peaks for the cyclopropane
protons (δ = 0–1 ppm) and carbons (δ = 1–12 ppm).
Reductive opening of the N–O bonds in simple isoxazol-
idines can be performed with a variety of reagents.[14] How-
Scheme 2.
Table 1. Cycloaddition of nitrones 8–12 to bicyclopropylidene 6 and reduction of cycloadducts with SmI2.
Scheme 3.
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PdII-Catalyzed Rearrangements of β-Aminocyclopropanols
ever, with the spirocyclopropane rings present in 18–22 it is Table 2. PdII-mediated rearrangement of γ-(aminoalkyl)cyclopro-
panols.
advantageous to use a reasonably chemoselective reducing
agent such as SmI2.[7b,8] Treatment of isoxazolidines 13–17
with an excess of a commercial 0.1  solution of SmI2 in
THF led to a smooth and efficient conversion into the cor-
responding γ-(aminoalkyl)cyclopropanols 18–22 in good
yields (Table 1). In these cases, the SmIII alkoxides[15]
formed are rather stable and so it was necessary to work-
up the reaction mixture at pH 12 by adding a 1  solution
of NH3 in MeOH and thus avoid the extraction of such
complexes into the organic phase. The integrity of the cy-
clopropane moiety in the amino alcohols was corroborated
1
by their H and 13C NMR spectra with signals at δ = 0.3–
0.8 and 5–14 ppm, respectively.
The amino alcohols 18–22 were then subjected to the
best reaction conditions previously elaborated for their pal-
ladium-catalyzed conversion into tetrahydropyridones,[7b]
that is, by treatment with Pd(OAc)2 (10 mol-%), pyridine
(2 equiv.), and oxygen at 5 atm pressure in toluene at 80 °C.
Only the amino alcohol 22 provided the expected dihy-
dropyridone 29 in excellent yield (90%) (Table 2, entry 5).
All the other substrates gave almost 1:1 mixtures of dihy-
dropyridones 25–28 and tetrahydropyridones 30–33[10b]
which could be separated by flash chromatography in good
overall yields (Table 2, entries 1–4).
The structural assignments for the new products were
1
made on the basis of their H and 13C NMR spectra. The
enaminone moiety in compounds 25–29 each display char-
acteristic arrays of signals due to the vinylic protons and
carbons. The =CH protons α to the nitrogen resonate
[a] Ratio determined spectroscopically (1H NMR) on the crude re-
action mixture. [b] Yield obtained upon thermal rearrangement by
heating at 125 °C for 12 h.
downfield (δ = 7.20–7.00 ppm), as do the corresponding
carbon nuclei (δ = 152–149 ppm). Conversely, the =CH pro-
tons β to the nitrogen resonate at δ = 5.10–5.00 ppm and
the corresponding carbon nuclei at δ = 96–100 ppm. On the
other hand, compounds 30–33 were assigned by compari-
The formation of mixtures of tetrahydro- and dihydro-
son of their NMR spectra with those of the known com- pyridones in the PdII-catalyzed rearrangement of γ-(ami-
pounds 30 and 31 and on the basis of characteristic signals, noalkyl)cyclopropanols 18–21 contrasts the results ob-
for example, for the piperidone carbonyl group (13C NMR: tained in earlier work[7] and raises questions about the
δ = 207.4 and 208.6 ppm for 32 and 33, respectively) and mechanism of the catalytic process proposed previously.[7b]
the cyclopropane moiety. In order to confirm their struc- The formation of dihydropyridones was postulated to origi-
tures, compounds 32, 33, and 23 were also prepared in 65, nate from a palladium–enolate intermediate 37 which
95, and 65% yields by thermal rearrangement upon heating would be formed by a PdII-catalyzed intramolecular
1  solutions of isoxazolidines 15, 16, and 17, respectively, Michael-type addition of the amino group to the enone
in xylenes at 125 °C for 12 h.
moiety in the intermediate α,β-unsaturated ketone 35, in
Scheme 4.
Eur. J. Org. Chem. 2008, 1085–1091
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J. Revuelta, S. Cicchi, A. de Meijere, A. Brandi
FULL PAPER
turn derived from the PdII-catalyzed rearrangement of the
cyclopropanol moiety in 34.[16–18] The palladium enolate 37,
after enol/ketone tautomerization to 38, would then un-
dergo β-dehydropalladation to yield the final product 39
(Scheme 4). The formation of tetrahydropyridones 36 in the
cases above, however, does not rule out this mechanism and
can be explained by an uncatalyzed intramolecular Michael
addition in 35. The uncatalyzed intramolecular Michael ad-
dition might be favored by the 1,1-disubstituted cyclopro-
pane ring in which the enone moiety is proximal to the ni-
trogen.[19] The exclusive formation of the dihydropyridone
29 must then be due to a difference in the preferred orienta-
tion of the two substituents on the cyclopropane ring in the
intermediate 35, when the amino group is not part of a
heterocycle as in 18–21, so that cyclization of 35 requires
palladium(II) catalysis.
(3ЈaR,4ЈS)-4Ј-tert-Butoxydispiro[cyclopropane-1,2Ј-(hexahydro-
pyrrolo[1,2-b]isoxazole)-3Ј,1ЈЈ-cyclopropane] (14): See ref.[10]
(3ЈaS,4ЈS,5ЈR)-4Ј,5Ј-O-Isopropylidenedispiro[cyclopropane-1,2Ј-
(hexahydropyrrolo[1,2-b]isoxazole)-3Ј,1ЈЈ-cyclopropane] (15): The
toluene solution was heated at 60 °C for 2 d. Yellow solid, yield
201 mg, 85%. Rf = 0.36 (AcOEt/light petroleum, 1:4). [α]2D0 = +12.0
1
(c = 0.5, CH2Cl2), m.p. 65–67 °C. H NMR (200 MHz, CDCl3): δ
= 0.23–0.53 (m, 4 H, cPr-H), 0.68–0.83 (m, 4 H, cPr-H), 1.28 (s, 3
H, Me), 1.45 (s, 3 H, Me), 3.32 (dd, J = 4.4, 1.8 Hz, 1 H, 6-H),
3.40 (dd, J = 4.4, 1.8 Hz, 1 H, 7-H), 3.54–3.65 (m, 1 H, 3a-H), 4.58
(dt, J = 2.2, 6.6 Hz, 1 H, 5-H), 4.85–4.94 (m, 1 H, 4-H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 5.7 (t, cPr-C), 6.1 (t, cPr-C), 8.9 (t,
cPr-C), 10.0 (t, cPr-C), 25.2 (q, Me), 27.2 (q, Me), 30.0 (s, cPr-C),
62.3 (t, C-6), 66.4 (s, cPr-C), 77.6 (d, C-3a), 80.4 (d, C-5), 84.0 (d,
C-4), 112.6 (s, acetonide group) ppm. IR (CDCl ): ν = 2987, 1469,
˜
3
1383, 1216, 1163, 1095 cm–1. MS: m/z (%) = 237 (33), 194 (13), 123
(77), 122 (72), 67 (90), 55 (100). C13H19NO3 (237.30): calcd. C
65.80, H 8.07, N 5.90; found C 65.78, H 8.43, N 6.04.
(3ЈaS,4ЈS,5ЈS,6ЈS)-4Ј,5Ј-Bis(benzyloxy)-6Ј-(benzyloxymethyl)di-
spiro[cyclopropane-1,2Ј-(hexahydropyrrolo[1,2-b]isoxazole)-3Ј,1ЈЈ-cy-
clopropane] (16): The toluene solution was heated at 60 °C for 2 d.
Pale orange oil, yield 447 mg, 90%. Rf = 0.28 (AcOEt/light petro-
Conclusions
The PdII-catalyzed rearrangement of γ-(aminoalkyl)cy-
clopropanols to dihydropyrid-4-one derivatives has been ex-
tended to more complex substrates bearing an additional
1,1-disubstituted cyclopropane moiety in the chain. In the
presence of a second cyclopropane ring, the rearrangement,
except in one case, leads to a mixture of dihydro- and tetra-
hydropyrid-4-one derivatives, most likely because of compe-
tition between a catalyzed and noncatalyzed Michael-type
leum, 1:4). [α]2D0 = –15.3 (c = 0.95, CH2Cl2). H NMR (200 MHz,
1
CDCl3): δ = 0.03–0.15 (m, 2 H, cPr-H), 0.56–1.00 (m, 6 H, cPr-H),
3.61 (d, J = 5.0 Hz, 1 H, 6-H), 3.74 (d, J = 1.8 Hz, 1 H, 3a-H),
4.09–4.20 (m, 2 H, 4-H, 5-H), 4.51–4.75 (m, 6 H, CH2Ph), 7.20–
7.45 (m, 15 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 1.2
(t, cPr-C), 3.8 (t, cPr-C), 11.9 (t, 2 C, cPr-C), 30.7 (s, cPr-C), 65.3
(s, cPr-C), 68.5 (d, C-6), 68.9 (t, CH2Ph), 72.1 (t, CH2Ph), 72.9 (d,
C-3a), 73.4 (t, CH2Ph), 83.0 (d, C-5), 86.0 (d, C-4), 127.3 (d, Ar-
cyclization of the intermediate β-amino-substituted α,β-un- C), 127.5 (d, Ar-C), 127.6 (d, Ar-C), 127.7 (d, 3 C, Ar-C), 127.8
(d, 3 C, Ar-C), 128.1 (d, 4 C, Ar-C), 128.2 (d, 2 C, Ar-C), 137.7 (s,
saturated ketone. The overall process, which is carried out
at a lower temperature, represents a valuable alternative to
the thermal rearrangement, in particular for those com-
pounds sensitive to elevated temperatures. Work is in pro-
gress in our laboratory to confirm the mechanism proposed
and the role of the palladium species.
Ar-C), 137.9 (s, Ar-C), 138.1 (s, Ar-C) ppm. IR (CDCl ): ν = 3032,
˜
3
2864, 1454, 1363, 1265, 1208, 1097, 1028 cm–1. MS: m/z (%) = 497
(2) [M]+, 407 (19), 406 (67), 377 (38), 376 (73), 150 (42), 92 (37), 91
(100). C32H35NO4 (497.63): calcd. C 77.24, H 7.09, N 2.81; found C
77.23, H 7.13, N 2.83.
9-(2-Bromophenyl)-8-methyl-7-oxa-8-azadispiro[2.0.2.3]nonane (17):
The toluene solution was heated at 60 °C for 20 d. Colorless solid,
yield 264 mg, 90%. Rf = 0.75 (AcOEt/light petroleum, 1:30), m.p.
45–46 °C. 1H NMR (200 MHz, CDCl3): δ = 0.83–0.94 (m, 4 H,
cPr-H), 0.96–1.01 (m, 4 H, cPr-H), 2.86 (s, 3 H, Me), 4.59 (s, 1 H,
9-H), 7.14 (td, J = 7.7, 1.8 Hz, 1 H, Ar-H), 7.36 (t, J = 7.7 Hz, 1
H, Ar-H), 7.51 (d, J = 7.7 Hz, 1 H, Ar-H), 7.78 (dd, J = 7.7, 1.8 Hz,
1 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 6.4 (t, cPr-C),
6.5 (t, cPr-C), 9.6 (t, 2 C, cPr-C), 33.6 (s, cPr-C), 45.2 (q, Me), 68.8
(s, cPr-C), 76.4 (d, 9-C), 124.1 (s, Ar-C), 127.6 (d, Ar-C), 128.9 (d,
Ar-C), 130.9 (d, Ar-C), 132.9 (d, Ar-C), 138.6 (s, Ar-C) ppm. IR
Experimental Section
General Remarks: All reactions were carried out under nitrogen or
in sealed tubes filled with nitrogen. Rf values refer to TLC on
0.25 mm silica gel plates (Merck F254) obtained by using the same
eluent as in the corresponding column chromatography. Melting
points were determined with a 510 Büchi apparatus. NMR spectra
were recorded with a Varian Gemini (1H, 200 MHz; 13C, 50 MHz),
with CDCl3 as solvent; the NMR spectroscopic data are reported
in δ (ppm) relative to TMS. The multiplicities of the 13C signals,
derived from APT spectra, are reported to support assignments. IR
spectra were recorded in CDCl3 solution. Mass spectra were re-
corded at 70 eV. Compounds 6 and 8–14 were prepared according
to published procedures.[9–13]
(CDCl ): ν = 3074, 3003, 2876, 1589, 1437, 1029 cm–1. MS: m/z
˜
3
(%) = 295 (2) [M + 2]+, 293 (2) [M]+, 197 (6), 195 (7), 186 (36),
184 (32), 130 (36), 128 (100). C14H16BrNO (294.19): calcd. C 57.16,
H 5.48, N 4.76; found C 57.08, H 5.46, N 4.69.
1-{1-[Amino(2-bromophenyl)methyl]cyclopropyl}propan-1-one (24):
This product was obtained as a yellow oil as a byproduct in the
cycloaddition of nitrone 12 to 6 in toluene at 110 °C for 5 d, yield
11 mg, 4 %. Rf = 0.31 (AcOEt/light petroleum, 1:30). 1H NMR
(200 MHz, CDCl3): δ = 0.38–0.48 (m, 1 H, cPr-H), 0.79–0.90 (m,
1 H cPr-H), 1.06 (t, J = 7.3 Hz, 3 H, Me), 1.14–1.27 (m, 2 H, cPr-
H), 2.40 (q, J = 7.3 Hz, 2 H, CH2), 5.24 (s, 1 H, 1-H), 7.12 (t, J =
8.2 Hz, 1 H, Ar-H), 7.29 (t, J = 8.2 Hz, 1 H, Ar-H), 7.45 (d, J =
8.0 Hz, 1 H, Ar-H), 7.54 (d, J = 8.0 Hz, 1 H, Ar-H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 7.9 (t, cPr-C), 8.4 (t, cPr-C), 9.7 (q,
Cycloaddition of Nitrones to BCP. General Procedure: A solution of
the respective nitrone (1 mmol) and BCP (1.3 mmol) in toluene
(1 mL) was heated in a screw-capped Sovirel tube. After cooling to
room temperature, the solvent was removed in vacuo, and the crude
material was purified by flash column chromatography on silica
gel.
8Ј,9Ј-Dimethoxydispiro[cyclopropane-1,1Ј-(1,5,6,10b-tetrahydro-2H-
isoxazolo[3,2-a]isoquinoline)-2Ј,1ЈЈ-cyclopropane] (13): See ref.[10]
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PdII-Catalyzed Rearrangements of β-Aminocyclopropanols
Me), 14.7 (s, cPr-C), 29.8 (t, CH2), 52.9 (d, C-1), 124.9 (s, Ar-C),
60.2 (d, C-4), 68.3 (s, cPr-C), 70.5 (d, C-3a), 82.2 (d, C-6a), 110.0
127.4 (d, Ar-C), 127.9 (d, Ar-C), 128.6 (d, Ar-C), 132.6 (d, Ar-C), (s, C-2) ppm. IR (CDCl ): ν = 3691, 3154, 2902, 1455, 1382, 1262,
˜
3
150.0 (s, Ar-C), 212.8 (s, C=O) ppm. IR (CDCl ): ν = 3400, 3067,
1095 cm–1. MS: m/z (%) = 239 (4) [M]+, 180 (100), 142 (31) 100
(25). C13H21NO3 (239.15): calcd. C 65.25, H 8.84, N 5.85; found C
˜
3
2990, 2879, 1684, 1590, 1466, 1438, 1377, 1024 cm–1. MS: m/z (%)
= 283 (14) [M + 2]+, 281 (14) [M]+, 268 (52), 242 (60), 204 (36), 65.47, H 8.67, N 5.79.
162 (100). C13H16BrNO (282.17): calcd. C 55.33, H 5.72, N 4.96;
found C 55.39, H 5.80, N 4.98.
1Ј-{(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]pyrrol-
idin-2-yl}-1,1Ј-bicyclopropyl-1-ol (21): Pale yellow oil, yield 187 mg,
75%. Rf = 0.35 (CH2Cl2/MeOH, 3:1). [α]2D0 = 7.3 (c = 0.5, CH2Cl2).
1H NMR (200 MHz, CDCl3): δ = 0.45–0.71 (m, 4 H, cPr-H), 0.74–
1.09 (m, 4 H, cPr-H), 2.95 (d, J = 7.3 Hz, 1 H, 2-H), 3.50–3.59 (m,
1 H, 5-H), 3.92 (t, J = 4.3 Hz, 1 H, 4-H), 4.40 (dd, J = 7.3, 4.3 Hz,
1 H, 3-H), 4.50 (AB system, 2 H, CH2Ph), 4.57 (AB system, 2 H,
CH2Ph), 4.52–4.59 (m, 2 H, 1-H), 4.61 (AB system, 2 H, CH2Ph),
7.15–7.47 (m, 15 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ =
7.3 (t, cPr-C), 8.6 (t, cPr-C), 9.5 (t, cPr-C), 13.2 (t, cPr-C), 29.8 (s,
cPr-C), 58.3 (d, C-2), 59.8 (d, C-5), 61.0 (s, cPr-C), 71.7 (t, C-1),
71.9 (t, CH2Ph), 72.8 (t, CH2Ph), 73.2 (t, CH2Ph), 84.1 (d, C-4),
84.8 (d, C-3), 127.3 (d, Ar-C), 127.5 (d, Ar-C), 128.0 (d, Ar-C),
128.1 (d, Ar-C), 137.4 (s, 2 C, Ar-C), 137.6 (s, Ar-C) ppm. IR
General Procedure for the Reduction of Isoxazolidines: A commer-
cial 0.1  THF solution (17.5 mL) of SmI2 (3.5 equiv.) was added
to a 100 mL Schlenk flask charged with the respective isoxazolidine
(0.5 mmol) under nitrogen at room temperature. The resulting blue
solution was stirred for 2 h. A 1  solution of NH3 in MeOH
(8.5 mL) was added and the mixture left to stir for 20 min. Finally,
water (17 mL) was added and the resulting mixture was brought to
pH 8 by addition of a 1  solution of aqueous NaOH. The mixture
was then saturated with Na2SO3 and extracted with diethyl ether
(3ϫ15 mL). The organic phase was dried (Na2SO4), filtered, and
concentrated to afford the crude product. The crudes were suffi-
ciently pure to be used directly in the next step. Filtration of an
aliquot of the crude through a short pad of silica gel afforded the
pure products for elemental analysis.
(CDCl ): ν = 3691, 3154, 2902, 1455, 1382, 1262, 1095 cm–1. MS:
˜
3
m/z (%) = 499 (2) [M]+, 408 (5), 378 (12), 91 (100). C32H37NO4
(499.60): calcd. C 76.92, H 7.46, N 2.80; found C 76.53, H 7.64, N
2.65.
1Ј-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-1,1Ј-bicyclo-
propyl-1-ol (18): Colorless solid, yield 127 mg, 88%. Rf = 0.33
(CH2Cl2/MeOH, 14:1), m.p. 148–150 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.02–0.06 (m, 1 H, cPr-H), 0.27–0.16 (m, 2 H, cPr-H),
0.87–0.40 (m, 6 H, cPr-H + 4-H), 2.52–2.65 (m, 1 H, 4-H), 2.80–
3.12 (m, 2 H, 3-H, OH), 3.32–3.47 (m, 1 H, 3-H), 3.80 (s, 3 H,
Me), 3.85 (s, 3 H, Me), 4.62 (s, 1 H, 1-H), 6.59 (s, 1 H, Ar-H), 6.81
(s, 1 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 8.3 (t, cPr-
C), 9.2 (t, cPr-C), 10.3 (t, cPr-C), 14.6 (t, cPr-C), 32.3 (s, cPr-C),
42.4 (t, C-4), 43.8 (t, C-3), 55.9 (q, Me), 56.1 (q, Me), 61.6 (s, cPr-
C), 64.1 (d, C-1), 110.4 (d, Ar-C), 111.5 (d, Ar-C), 126.2 (s, Ar-C),
127.6 (s, Ar-C), 146.8 (s, Ar-C), 147.9 (s, Ar-C) ppm. IR (CDCl3):
1Ј-[(2-Bromophenyl)(methylamino)methyl]-1,1Ј-bicyclopropyl-1-ol
(22): Colorless solid, yield 133 mg, 90%. Rf = 0.25 (CH2Cl2/MeOH,
10:1), m.p. 119–121 °C. 1H NMR (200 MHz, CDCl3): δ = 0.18–
0.33 (m, 2 H, cPr-H), 0.37–0.64 (m, 2 H, cPr-H), 0.67–0.83 (m, 4
H, cPr-H), 2.35 (s, 3 H, Me), 3.63 (s, 2 H, NH2), 4.58 (s, 1 H, C-
1), 7.08–7.19 (m, 2 H, Ar-H), 7.21–7.38 (m, 1 H, Ar-H), 7.56 (m,
1 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 5.1 (t, cPr-C),
9.6 (t, cPr-C), 12.1 (t, cPr-C), 12.3 (t, cPr-C), 26.8 (s, cPr-C), 34.1
(q, Me), 61.3 (s, cPr-C), 68.2 (d, C-1), 126.2 (s, Ar-C), 127.0 (d, Ar-
C), 127.3 (d, Ar-C), 128.7 (d, Ar-C), 133.0 (d, Ar-C), 136.9 (s, Ar-
ν = 3691, 3154, 2960, 2937, 2903, 2835, 1514, 1465, 1382, 1267,
˜
C) ppm. IR (CDCl ): ν = 3690, 3150, 3087, 2961, 1468, 1439, 1383,
˜
3
1246, 1218, 1115, 1096 cm–1. MS: m/z (%) = 289 (6) [M]+, 288 (11),
192 (100), 91 (8). C17H23NO3 (289.37): calcd. C 70.56, H 8.01, N
4.84; found C 70.75, H 7.84, N 4.68.
1261, 1237, 1097, 1025 cm–1. MS: m/z (%) = 297 (5) [M + 2]+, 295
(5) [M]+, 200 (59), 198 (61), 192 (21), 185 (67), 167 (15), 160 (56),
129 (100). C14H18BrNO (296.21): calcd. C 56.77, H 6.13, N 4.73;
found C 56.54, H 6.10, N 4.52.
1Ј-[(2R,3S)-3-tert-Butoxypyrrolidin-2-yl]-1,1Ј-bicyclopropyl-1-ol
(19): Yellow oil, yield 83 mg, 69%. Rf = 0.15 (CH2Cl2/MeOH, 3:1).
[α]2D0 = 7.5 (c = 0.48, MeOH). 1H NMR (200 MHz, CDCl3): δ =
0.04–0.16 (m, 2 H, cPr-H), 0.27–0.42 (m, 1 H, cPr-H), 0.43–0.50
(m, 2 H, cPr-H), 0.50–0.64 (m, 1 H, cPr-H), 0.67–0.7 (m, 1 H, cPr-
H), 0.78–0.91 (m, 1 H, cPr-H), 1.18 (s, 9 H, tert-butyl), 1.72 (ddt,
J = 9.5, 6.6, 2.9 Hz, 1 H, 4-H), 2.02–2.22 (m, 1 H, 4-H), 2.65 (d, J
= 4.3 Hz, 1 H, 2-H), 2.95–3.10 (ABX system, 2 H, 5-H), 4.41 (ddd,
J = 6.6, 4.3, 2.9 Hz, 1 H, 3-H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 7.4 (t, cPr-C), 8.0 (t, cPr-C), 11.3 (t, cPr-C), 14.0 (t, cPr-C),
28.9 (q, tert-butyl), 29.9 (s, cPr-C), 35.5 (t, C-4), 44.3 (t, C-5), 56.6
(s, cPr-C), 58.9 (d, C-2), 72.8 (s, tert-butyl), 74.9 (d, C-3) ppm. IR
General Procedure for the Preparation of Dihydropyridones: A sus-
pension of the respective β-aminocyclopropanol (0.5 mmol),
Pd(OAc)2 (0.05 mmol), and pyridine (1 mmol) in toluene (5 mL)
was stirred at 80 °C for 3 h in a steel reactor under a pressure of
O2 (5 atm). The suspension was then filtered and concentrated, and
the residue was purified by flash column chromatography.
9Ј,10Ј-Dimethoxyspiro[cyclopropane-1,1Ј-(1,6,7,11b-tetrahydro-2H-
pyrido[2,1-a]isoquinolin)]-2Ј-one (25): Yellow oil, yield 57 mg, 40%.
1
Rf = 0.33 (AcOEt/MeOH, 2:1). H NMR (200 MHz, CDCl3): δ =
0.16–0.52 (m, 1 H, cPr-H), 0.65–1.01 (m, 2 H, cPr-H), 1.32–1.48
(m, 1 H, cPr-H), 2.74 (dt, J = 15.3, 2.9 Hz, 1 H, 7-H), 3.02 (ddd,
J = 15.3, 10.6, 5.1 Hz, 1 H, 7-H), 3.48 (td, J = 9.5, 3.6 Hz, 1 H, 6-
H), 3.64 (ddd, J = 9.5, 5.1, 2.9 Hz, 1 H, 6-H), 3.86 (s, 6 H, 2Me),
4.74 (s, 1 H, 11b-H), 5.12 (d, J = 7.3 Hz, 1 H, 3-H), 6.63 (s, 1 H,
Ar-H), 6.68 (s, 1 H, Ar-H), 7.18 (d, J = 7.3 Hz, 1 H, 4-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 9.4 (t, cPr-C), 9.8 (t, cPr-C), 28.5
(CDCl ): ν = 3685, 3153, 2900, 1455, 1382, 1262, 1095 cm–1. MS:
˜
3
m/z (%) = 237 (4), 182 (100), 110 (28). C14H25NO2 (239.35): calcd.
C 70.25, H 10.53, N 5.85; found C 70.46, H 10.41, N 6.05.
1Ј-[(3aS,4S,6aR)-2,2-Dimethyltetrahydro-2H,3aH-[1,3]dioxolo[4,5-
c]pyrrol-4-yl]-1,1Ј-bicyclopropyl-1-ol (20): Yellow oil, yield 93 mg,
70%. Rf = 0.18 (CH2Cl2/MeOH, 15:1). [α]2D0 = – 10.4 (c = 0.70
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 0.14–0.28 (m, 1 H, cPr- (s, cPr-C), 30.0 (t, C-7), 49.7 (t, C-6), 55.6 (q, Me), 55.8 (q, Me),
H), 0.28–0.44 (m, 4 H, cPr-H), 0.49–0.62 (m, 1 H, cPr-H), 0.64–
0.77 (m, 2 H, cPr-H), 1.29 (s, 3 H, Me), 1.46 (s, 3 H, Me), 2.96–
60.3 (d, C-11b), 98.4 (d, C-3), 110.8 (d, Ar-C), 111.1 (d, Ar-C),
123.4 (s, Ar-C), 127.8 (s, Ar-C), 146.8 (s, Ar-C), 147.8 (s, Ar-C),
3.22 (m, 2 H, 6-H), 3.58 (s, 1 H, 4-H), 4.17 (d, J = 5.8 Hz, 1 H, 151.8 (d, C-4), 193.1 (s, C=O) ppm. IR (CDCl ): ν = 3050, 2980,
˜
3
3a-H), 4.66 (t, J = 5.8 Hz, 1 H, 6a-H) ppm. 13C NMR (50 MHz,
2850, 1695, 1620, 1590, 1580, 1430, 1210 cm–1. HRMS: calcd. for
CDCl3): δ = 6.7 (t, cPr-C), 8.8 (t, cPr-C), 10.6 (t, cPr-C), 12.3 (t, C17H20NO3+: 286.1443; found 286.1442. The reaction mixture af-
cPr-C), 22.0 (s, cPr-C), 24.0 (q, Me), 26.4 (q, Me), 52.1 (t, C-6),
forded also compound 30: yield 68 mg, 47%.[10b]
Eur. J. Org. Chem. 2008, 1085–1091
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1089

J. Revuelta, S. Cicchi, A. de Meijere, A. Brandi
FULL PAPER
(1ЈS,8aЈR)-1Ј-tert-Butoxyspiro[cyclopropane-1,8Ј-(2,3,8,8a-tetra- (CDCl ): ν = 3020, 3000, 1694, 1595, 1430 cm–1. HRMS: calcd. for
˜
3
hydroindolizin)]-7Ј(1ЈH)-one (26): Yellow oil, yield 41 mg, 35%. Rf C14H15BrNO+: 292.0332; found: 292.0332.
1
= 0.20 (AcOEt). H NMR (200 MHz, CDCl3): δ = 0.54–1.01 (m,
General Procedure for the Preparation of Tetrahydropyridones. Ther-
mal Rearrangement of Adducts 2, 4, and 5: A solution of the respec-
tive nitrone cycloadduct 2, 4, or 5 (0.5 mmol) in xylenes (0.5 mL)
was heated in a screw-cap sealed Sovirel tube at 120 °C for 12 h.
After the solution had been cooled to room temperature the solvent
was removed in vacuo and the crude material was purified by flash
chromatography on silica gel.
4 H, cPr-H), 1.19 (s, 9 H, tert-butyl), 1.32–1.68 (m, 1 H, 2-H), 1.72
–1.95 (m, 1 H, 2-H), 2.01–2.48 (m, 2 H, 2-H, 3-H), 3.61 (m, 1 H,
3-H), 3.86 (s, 1 H, 8a-H), 5.03 (d, J = 7.3 Hz, 1 H, 6-H), 7.06 (d,
J = 7.3 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 11.4
(t, cPr-C), 16.3 (t, cPr-C), 28.7 (q, 3 C, tert-butyl), 31.5 (s, cPr-C),
33.4 (t, C-2), 52.9 (t, C-3), 69.3 (d, C-8a), 73.5 (d, C-1), 74.0 (s,
tert-butyl), 98.3 (d, C-6), 151.8 (d, C-5), 193.0 (s, C=O) ppm. IR
(CDCl ): ν = 3010, 2978, 2812, 1684, 1336 cm–1. MS: m/z (%) =
˜
3
235 (2) [M]+, 178 (100). C14H21NO2 (235.39): calcd. C 71.46, H
8.99, N 5.95; found C 71.58, H 8.67, N 5.73. The reaction mixture
afforded also compound 31: yield 47 mg, 40%.[10b]
4-(2-Bromophenyl)-5-methyl-5-azaspiro[2.5]octan-8-one (23): Yellow
oil, yield 96 mg, 65%. Rf = 0.31 (AcOEt/light petroleum, 1:30). 1H
NMR (200 MHz, CDCl3): δ = 0.36–0.43 (m, 1 H, cPr-H) 0.82–0.90
(m, 1 H, cPr-H), 1.25 (m, 2 H, cPr-H), 2.35 (s, 3 H, Me), 2.67 (t,
J = 5.8 Hz, 2 H, 7-H), 2.84–2.97 (m, 1 H, 6-H), 3.15–3.21 (m, 1 H,
6-H), 4.11 (s, 1 H, 4-H), 7.09–7.16 (ddd, J = 8.0, 6.6, 2.6 Hz, 1 H,
Ar-H), 7.26–7.35 (m, 2 H, Ar-H), 7.54 (d, J = 1.4 Hz, 1 H, Ar-
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.3 (t, cPr-C), 18.7 (t,
cPr-C), 31.3 (s, cPr-C), 38.2 (q, Me), 43.6 (C-7), 50.3 (t, C-6), 70.1
(d, C-4), 125.4 (s, Ar-C), 127.2 (d, Ar-C), 128.9 (d, Ar-C), 130.9
(d, Ar-C), 132.9 (d, Ar-C), 138.6 (s, Ar-C), 208.5 (s, C=O) ppm.
(3aЈR,9aЈS,9bЈS)-2Ј,2Ј-Dimethylspiro[cyclopropane-1,9Ј-(3a,9,9a,9b-
tetrahydro[1,3]dioxolo[4,5-a]indolizin)-8(4H)-one (27): Yellow oil,
yield 54 mg, 45%. Rf = 0.45 (CH2Cl2/MeOH, 15:1). [α]2D0 = –57.2
(c = 0.85, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 0.65–0.90 (m,
2 H, cPr-H), 0.92–1.06 (m, 1 H, cPr-H), 1.09–1.27 (m, 1 H, cPr-
H), 1.32 (s, 3 H), 1.51 (s, 3 H), 3.57 (dd, J = 11.7, 2.9 Hz, 1 H, 4-
H), 3.85 (dd, J = 11.7, 5.8 Hz, 1 H, 4-H), 3.97 (d, J = 6.6 Hz, 1 H,
9a-H), 4.21 (t, J = 6.6 Hz, 1 H, 9b-H), 4.79 (ddd, J = 6.6, 5.8,
2.9 Hz, 1 H, 3a-H), 5.07 (d, J = 7.3 Hz, 1 H, 7-H), 7.01 (d, J =
7.3 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 8.9 (t,
cPr-C), 13.0 (t, cPr-C), 25.5 (q, Me), 25.7 (s, cPr-C), 27.6 (q, Me),
54.7 (t, C-4), 66.1 (d, C-9a), 78.3 (d, C-3a), 79.7 (d, C-9b), 100.2
(d, C-7), 114.0 (s, acetonide group), 149.3 (d, C-6), 192.8 (s,
IR (CDCl ): ν = 3000, 2956, 1692, 1467, 1439, 1365, 1277, 1102,
˜
3
1025 cm–1. MS: m/z (%) = 295 (7) [M + 2]+, 293 (7) [M]+, 223 (23),
138 (100), 127 (43). C14H16BrNO (294.19): calcd. C 57.16, H 5.48,
N 4.76; found C 57.01, H 5.49, N 4.70.
(3aЈR,9aS,9bS)-2Ј,2Ј-Dimethylspiro[cyclopropane-1,9Ј-(hexahydro-
[1,3]dioxolo[4,5-a]indolizin)]-8(4H)-one (32): Pale orange oil, yield
82 mg, 69%. Rf = 0.15 (AcOEt/light petroleum, 3:7). [α]2D0 = –103.0
(c = 0.75, CH2Cl2). 1H NMR (200 MHz, CDCl3): δ = 0.72–0.93
(m, 2 H, cPr-H), 1.18–1.27 (m, 2 H, cPr-H), 1.28 (s, 3 H, Me), 1.48
(s, 3 H, Me), 2.44–2.61 (m, 3 H, 7-H, 6-H), 2.65–2.84 (m, 1 H, 6-
H), 2.90 (d, J = 6.5 Hz, 1 H, 9a-H), 3.22 (dd, J = 10.2, 5.1 Hz, 1
H, 4-H), 3.50 (dd, J = 10.2, 6.5 Hz, 1 H, 4-H), 4.09 (t, J = 6.5 Hz,
1 H, 3a-H), 4.74 (dd, J = 6.5, 5.1 Hz, 1 H, 9a-H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 10.4 (t, cPr-C), 16.2 (t, cPr-C), 24.9 (q, Me),
26.9 (q, Me), 30.0 (s, cPr-C), 38.1 (t, C-7), 49.2 (t, C-6), 59.6 (t, C-
4), 69.3 (d, C-9a), 77.9 (d, C-3a), 80.4 (d, C-9b), 113.8 (s, acetonide
C=O) ppm. IR (CDCl ): ν = 3018, 2987, 1693, 1629, 1584, 1460,
˜
3
1384 cm–1. HRMS: calcd. for C13H18NO3+: 236.1281; found
236.1282. The reaction mixture afforded also compound 32: yield
56 mg, 47%.
(1ЈR,2ЈR,3ЈR,8aЈR)-1Ј,2Ј-Bis(benzyloxy)-3Ј-[(benzyloxy)methyl]-
spiro[cyclopropane-1,8Ј-(2,3,8,8a-tetrahydroindolizin)]-7Ј(1ЈH)-one
(28): Pale yellow oil, yield 109 mg, 44%. [α]2D0 = –16.7 (c = 0.36,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 0.56–0.66 (m, 1 H, cPr-
H), 0.72–0.95 (m, 2 H, cPr-H), 1.54 (ddd, J = 10.2, 6.7, 3.7 Hz, 1
H, cPr-H), 3.53 (d, J = 6.0 Hz, 1 H, 8a-H), 3.67 (dd, J = 6.5,
3.2 Hz, 1 H, 3-H), 3.87 (dd, J = 6.3, 3.0 Hz, 1 H, 1-H), 3 ppm. 95
(t, J = 3.0 Hz, 1 H, 2-H), 4.21 (d, J = 6.7 Hz, 1 H, CH2Ph), 4.35–
4.65 (m, 7 H, CH2Ph), 5.05 (d, J = 7.4 Hz, 1 H, 6-H), 7.1–7.5 (m,
16 H, Ar-H, 5-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 8.6 (t,
cPr-C), 13.9 (t, cPr-C), 25.7 (s, cPr-C), 63.8 (d, C-3), 65.2 (d, C-
8a), 69.0 (t, C-1), 71.5 (t, CH2Ph), 71.8 (t, CH2Ph), 73.2 (t, CH2Ph),
83.0 (d, C-1), 84.2 (d, C-2), 98.5 (d, C-6), 127.4 (d, Ar-C), 127.5
(d, Ar-C), 127.6 (d, Ar-C), 127.7 (d, Ar-C), 127.8 (d, Ar-C), 128.2
(d, Ar-C), 136.6 (s, Ar-C), 136.8 (s, Ar-C), 137.0 (s, Ar-C), 148.9
group), 207.4 (s, C=O) ppm. IR (CDCl ): ν = 2981, 2939, 2870,
˜
3
1697, 1458, 1382, 1210, 1060 cm–1. MS: m/z (%) = 238 (7)
[M + 1]+, 237 (48) [M]+, 236 (97), 178 (88), 137 (100). C13H19NO3
(237.30): calcd. C 65.80, H 8.07, N 5.90; found C 65.99, H 8.45, N
5.58.
(1ЈR,2ЈR,3ЈR,8aЈR)-1Ј,2Ј-Bis(benzyloxy)-3Ј-[(benzyloxy)methyl]-
spiro[cyclopropane-1,8Ј-(hexahydroindolizin)]-7Ј(1ЈH)-one (33): Yel-
low oil, yield 236 mg, 95%. Rf = 0.50 (AcOEt/petroleum ether, 3:7).
(d, C-5), 192.3 (s, C=O) ppm. IR (CDCl ): ν = 3018, 2987, 1692,
˜
3
1
[α]2D0 = –25.0 (c = 1.04, CHCl3). H NMR (200 MHz, CDCl3): δ =
1625, 1586, 1460, 1384 cm–1. HRMS: calcd. for C32H34NO4
:
+
0.66–0.83 (m, 1 H, cPr-H), 0.98–1.21 (m, 1 H, cPr-H), 1.25–1.42
(m, 2 H, cPr-H), 2.37–2.53 (m, 2 H, 6-H), 2.56–2.76 (m, 2 H, 5-
H), 3.20–3.33 (m, 2 H, 3-H, 8a-H), 3.35–3.47 (m, 3 H, 2-H,
CH2Ph), 3.52–3.68 (m, 3 H, 2-H, 1-H), 4.44 (s, 2 H, CH2Ph), 4.48
(AB system, part B, 1 H, CH2Ph), 4.54 (s, 2 H, CH2Ph), 4.57 (AB
496.2482; found 496.2483. The reaction mixture afforded also com-
pound 33: yield 127 mg, 51%.
4-(2-Bromophenyl)-5-methyl-5-azaspiro[2.5]oct-6-en-8-one (29): Yel-
low oil, yield 132 mg, 90%. Rf = 0.42 (AcOEt/light petroleum,
1:30). 1H NMR (200 MHz, CDCl3): δ = 0.59–0.71 (m, 1 H, cPr-
H), 0.80–0.98 (m, 1 H, cPr-H), 1.10–1.28 (m, 1 H, cPr-H), 1.43–
system, part A, 1 H, CH2Ph), 7.18–7.45 (m, 15 H, Ar-H) ppm. 13
NMR (50 MHz, CDCl3): δ = 14.1 (t, cPr-C), 14.5 (t, cPr-C), 29.5
C
1.53 (m, 1 H, cPr-H), 2.91 (s, 3 H, Me), 4.54 (s, 1 H, 4-H), 5.02 (d, (s, cPr-C), 37.4 (t, C-6), 45.2 (t, C-5), 65.5 (d, C-3), 65.9 (d, C-8a),
J = 7.3 Hz, 1 H, 7-H), 7.03 (d, J = 7.3 Hz, 1 H, 6-H), 7.14 (dt, J 69.3 (t, C-1), 71.6 (t, CH2Ph), 72.2 (t, CH2Ph), 73.1 (t, CH2Ph),
= 8.0, 1.5 Hz, 1 H, Ar-H), 7.22–7.33 (m, 1 H, Ar-H), 7.51 (dd, J 85.1 (d, C-2), 85.6 (d, C-1), 127.3 (d, Ar-C), 127.5 (d, 2 C, Ar-C),
= 8.0, 1.5 Hz, 1 H, Ar-H), 7.84 (dd, J = 8.0, 1.5 Hz, 1 H, Ar- 127.6 (d, Ar-C), 127.7 (d, Ar-C), 127.8 (d, Ar-C), 127.9 (d, Ar-C),
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 9.7 (t, cPr-C), 22.9 (t, 128.2 (d, Ar-C), 128.3 (d, Ar-C), 137.2 (s, Ar-C), 137.4 (s, Ar-C),
cPr-C), 28.9 (s, cPr-C), 41.5 (q, Me), 67.2 (d, C-4), 96.2 (d, C-7), 137.7 (s, Ar-C), 208.6 (s, C=O) ppm. IR (CDCl ): ν = 3010, 2865,
˜
3
122.9 (s, Ar-C), 128.4 (d, 2 C, Ar-C), 129.5 (d, Ar-C), 132.4 (d, Ar- 1696, 1584, 1454, 1363 cm–1. HRMS: calcd. for C32H36NO4
:
+
C), 139.1 (s, Ar-C), 153.3 (d, C-6), 190.2 (s, C=O) ppm. IR 498.2639; found 498. 2638.
1090
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1085–1091

PdII-Catalyzed Rearrangements of β-Aminocyclopropanols
Chemistry Series, 22, 2nd ed., Pergamon Press, Oxford, 2002,
p. 42.
[6] J. E. Baldwin, Chem. Rev. 2003, 103, 1197–1212.
[7] a) S. Cicchi, J. Revuelta, A. Zanobini, M. Betti, A. Brandi,
Synlett 2003, 2305–2308; b) J. Revuelta, S. Cicchi, A. Brandi,
J. Org. Chem. 2005, 70, 5636–5642.
Supporting Information (see also the footnote on the first page of
this article): 13C NMR spectra of compounds 25, 27, 28, 29, and
33.
Acknowledgments
[8] J. Revuelta, S. Cicchi, A. Brandi, Tetrahedron Lett. 2004, 45,
8375–8377.
Britta Valentin, Sokrates exchange student from the University of
Göttingen (Germany), is acknowledged for her experimental con-
tribution to this work. Brunella Innocenti and Maurizio Passaponti
are acknowledged for their technical assistance.
[9] For reviews on the synthesis of alkylidenecyclopropanes, see
ref.[1a] and: A. Brandi, A. Goti, Chem. Rev. 1998, 98, 589–635.
[10] a) A. Goti, B. Anichini, A. Brandi, A. de Meijere, L. Citti, S.
Nevischi, Tetrahedron Lett. 1995, 36, 5811–5814; b) C. Zorn,
B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Mei-
jere, L. Citti, J. Org. Chem. 1999, 64, 7846–7855.
[11] S. Cicchi, M. Corsi, A. Brandi, A. Goti, J. Org. Chem. 2002,
67, 1678–1681.
[1] a) A. de Meijere (Ed.), Houben-Weyl, Methods of Organic
Chemistry, Carbocyclic Three Membered Ring Compounds,
Thieme, Stuttgart, 1997, vol. E17; b) O. G. Kulinkovich, Chem.
Rev. 2003, 103, 2597–2632; c) H. N. C. Wong, M.-Y. Hon, C.-
W. Tse, Y.-C. Yip, J. Tanko, T. Hudlicky, Chem. Rev. 1989, 89,
165–198; d) D. H. Gibson, C. H. Deluy, Chem. Rev. 1974, 74,
605–623.
[2] a) V. Ming, B. L. Pagenkopf, Tetrahedron 2005, 61, 321–347; b)
H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151–1196;
c) H.-U. Reissig, Top. Curr. Chem. 1998, 194–198, 73–135.
[3] a) A. Brandi, S. Cicchi, F. M. Cordero, A. Goti, Chem. Rev.
2003, 103, 1213–1269; b) A. Goti, F. M. Cordero, A. Brandi,
Top. Curr. Chem. 1996, 178, 1–97.
[12] F. Cardona, E. Faggi, F. Liguori, M. Cacciarini, A. Goti, Tetra-
hedron Lett. 2003, 44, 2315–2318.
[13] R. D. Hinton, E. G. Janzen, J. Org. Chem. 1992, 57, 2646–2651.
[14] S. Cicchi, A. Bonanni, F. Cardona, J. Revuelta, A. Goti, Org.
Lett. 2003, 5, 1773–1776, and references cited therein.
[15] G. A. Molander, Org. React. 1994, 46, 211–367.
[16] B. A. Steinhoff, I. A. Guzei, S. S. Stahl, J. Am. Chem. Soc.
2004, 126, 11268–11278.
[17] H. Okumoto, T. Jinnai, H. Shimizu, Y. Harada, H. Mishima,
A. Suzuki, Synlett 2000, 629–630.
[18] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.
[19] For a similar effect of a 1,1-disubstituted cyclopropane ring,
see: A. Goti, B. Anichini, A. Brandi, S. Kozhushkov, C. Grat-
kowski, A. de Meijere, J. Org. Chem. 1996, 61, 1665–1672.
Received: September 26, 2007
[4] a) F. M. Cordero, F. De Sarlo, A. Brandi, Monatsh. Chem.
2004, 135, 649–669; b) A. Brandi, F. M. Cordero, F. De Sarlo,
A. Goti, A. Guarna, Synlett 1993, 1–8.
[5] a) E. Ochoa, M. Mann, D. Sperling, J. Fabian, Eur. J. Org.
Chem. 2001, 4223–4231; b) A. Hassner, C. Stumer, Organic
Synthesis Based on Name Reactions, Tetrahedron Organic
Published Online: December 18, 2007
Eur. J. Org. Chem. 2008, 1085–1091
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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