Switching the reaction mode of 4-Methoxycarbonyl-4-chloro-5- spirocyclopropaneisoxazolidines by N -Aryl substitution

Article abstract of DOI:10.1055/s-0030-1258136

4-Methoxycarbonyl-4-chloro-5-spirocyclopropaneisoxazolidines, easily obtained by in situ cycloadditions of nitrones to methyl 2- chlorocyclopropylideneacetate and 2-chlorospiropentyl-ideneacetate, in contrast to their known thermal rearrangements leading

Full text of DOI:10.1055/s-0030-1258136

LETTER
1939
Switching the Reaction Mode of 4-Methoxycarbonyl-4-chloro-5-spirocyclo-
propaneisoxazolidines by N-Aryl Substitution
Switchingthe
t
Reactio
e
nMode of
f
Spirocy
a
c
lopropanei
n
soxazolidine
o
s
Cicchi,a Julia Revuelta,a Ina Objartel,a Armin de Meijere,b Alberto Brandi*a
a
Dipartimento di Chimica ‘Ugo Schiff’, Università degli Studi di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax +39(055)4573572; E-mail: alberto.brandi@unifi.it
b
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Göttingen, Tammannstr. 2, 37077 Göttingen,
Germany
Received 4 May 2010
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
trone counterpart in the reaction, affording different
products along the route, was also elucidated. However, in
no case was it possible to isolate the product derived from
the most common thermal rearrangement (Scheme 1, path
Abstract: 4-Methoxycarbonyl-4-chloro-5-spirocyclopropaneisox-
azolidines, easily obtained by in situ cycloadditions of nitrones to
methyl 2-chlorocyclopropylideneacetate and 2-chlorospiropentyl-
ideneacetate, in contrast to their known thermal rearrangements
leading to d-lactams, undergo rearrangement to their respective tet- A). This was ascribed to two reasons: a) the original ob-
rahydropyridones, when the nitrone nitrogen is substituted by an
aryl moiety.
servation that introducing a methoxycarbonyl group on C-
4 of the isoxazolidine ring retards the thermal rearrange-
Key words: 1,3-dipolar cycloadditions, chlorocyclopropylidene-
acetate, N-aryl nitrones, thermal rearrangement, tetrahydropyri-
dones
ment and lets it occur only at a much higher temperature;
b) the presence of a chloromethylenecyclopropane moiety
in the substrate offers the product a favorable alternative
reaction pathway, that is, the chloromethylcyclopropane
to chlorocyclobutane ring-enlargement process.
The thermal rearrangement of 5-spirocyclopropaneisox-
azolidines obtained by 1,3-dipolar cycloadditions of ni-
trones to alkylidenecyclopropanes has proved to be a
useful tool for the synthesis of different classes of N-
heterocycles1 and found application in the synthesis of
natural products2 as well as non-natural biologically ac-
tive compounds.3 A computational study of the mecha-
nism involved in this transformation4 has evidenced its
dependency on the nature of the substituents present both
on the alkylidenecyclopropane and the nitrone counter-
part. For example, switching from methylenecyclopro-
pane or cyclopropylideneacetate to 2-chlorocyclo-
propylideneacetate induced a remarkable change in the re-
action conditions and outcome of products as illustrated in
Scheme 1.
path A
path B
R1
+
R2
R
1 = CO2Me
R
1 = H, CO2Me
2 = H
R
2 = Cl
R
N+
O–
Cl
R1
N
N
CO2Me
O
O
2
3
n
3a n = 0, R1 = R2 = H
1a–c
4d–e
(
)
n
3b n = 1, R1 = R2 = H
(
)
n
3c n = 0, R1 = H, R2 = CO2Me
3d n = 0, R1 = Cl, R2 = CO2Me
3e n = 1, R1 = Cl, R2 = CO2Me
H
R1
CO2Me
6d–e
N
N
O
O
5a–c
Cl
(
)
n
(
)
n
Methylenecyclopropane (3a) reacts with nitrones to af-
ford the corresponding isoxazolidines which easily under-
go thermal rearrangement at 100–160 °C (Scheme 1, path
A). Cyclopropylideneacetate (3c) as well easily gives the
corresponding isoxazolidines, but the rearrangement step
requires higher temperatures and special techniques (flash
vacuum thermolysis, up to 600 °C).2d 2-Chlorocyclopro-
pylideneacetate (3d)5 furnishes the expected isoxazo-
lidines, but the rearrangement step afforded a totally
different product6 (Scheme 1, path B). The mechanism of
this transformation has been fully rationalized and the re-
action conditions (80–100 °C, reaction times from a few
hours to days) were optimized to afford enantiopure in-
dolizidine derivatives.7 The changing behavior of the ni-
CO2Me
R1
N
H
N
8d–e
Cl
O
(
)
n
(
)
n
7a–c
O
R1
O
CO2Me
N
N
O
9a–c
10d–e
(
)
n
(
)
n
Scheme 1
SYNLETT 2010, No. 13, pp 1939–1942
x
x
.x
x
.2
0
1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258136; Art ID: G15210ST
© Georg Thieme Verlag Stuttgart · New York

1940
S. Cicchi et al.
LETTER
If it was possible to lower the energy barrier of the thermal pane ring, but a singlet (d = 5.94 ppm) for the R1CHN pro-
rearrangement (path A), the latter would be favored over ton. The 13C NMR spectrum revealed the presence of a
the sequence involving a ring enlargement (Scheme 1, regular carbonyl (d = 197.7 ppm), which is not a lactam
path B). Such a possibility was conceivable, as according group. The mass spectrum confirmed the presence of a
to an earlier observation the use of N-aryl-substituted chlorine atom in the structure. Neither the corresponding
open chain nitrones with 3c allowed the rearrangement of cyclobutane derivative of type 6 nor the lactam of type 10
the corresponding isoxazolidines to occur at room temper- were detected in the crude reaction mixture. The relative
ature.8 This experimental observation was later rational- configuration of the formed diastereomer 13a could only
ized by a computational study showing a lower activation tentatively be assigned, lacking information of the struc-
energy (about 11 kcal/mol) for the initial formation of the ture of the isoxazolidine precursor, on the basis of previ-
1,5-diradical intermediate, when an aromatic substituent ous results of the cycloaddition of an N-Me,C-Ph-nitrone
is present on the nitrogen of the isoxazolidine ring.4 The to 3c.6b Therefore, the undefined designation of the con-
use of N-arylnitrones allows the synthesis of N-aryltet- figuration is preferred at this level of the study.
rahydropyridones in a multicomponent domino process
starting from nitrones and alkylidenecyclopropanes. In
this communication, we wish to report the results of a
The same reaction conditions were applied to the reac-
tions of 3c with other nitrones 11b–d only varying the re-
action time according to TLC monitoring. All the new
study concerning the cycloaddition reactions of 2-chloro-
compounds were isolated in comparable yields, and easily
cyclopropylideneacetate (3d) and (Z)-2-chlorospiropen-
identified by their characteristic NMR spectra as evi-
denced for compound 13a. In no case was it possible to
isolate from the crude reaction mixture any product evolv-
tylideneacetate (Z)-3e9 with N-arylnitrones that support
the hypothesis.
The cycloaddition of C,N-diphenyl nitrone (11a) to meth- ing by the ring-enlargement process of path B (Scheme 1)
yl 2-chlorocyclopropylideneacetate (3c) and subsequent leading to lactams. N-p-Methoxyphenyl-substituted ni-
rearrangement proceeded at room temperature and was trones gave only slightly better yields in shorter reaction
complete within five days to afford exclusively the tet- times, as would be expected for a lower activation energy
rahydropyridone derivative 13a in 40% yield as a single required with this substituent in the cleavage of the N–O
diastereomer (Table 1, entry 1).10
bond (about 3 kcal/mol less than the N-Ph derivatives).4
Table 1 Cycloaddition of N-Arylnitrones 11 to Methyl 2-Chlorocy-
clopropylideneacetate (3c) with Ensuing Rearrangement
MeO2C
Cl
Cl
CO2Me
R1
O
R1
O–
MeO2C
Cl
O
R2
O
CO2Me
R1
O–
3e
MeO2C
Cl
R1
N
Cl
O
N+
+
CO2Me
R2
3c
N+
R1
N
R2
R2
N
R2
R1
N
R2
13a–d
11a
11c
11d
14a 30%
14c 34%
14d 17%
15a 36%
15c 41%
11a–d
12
Entry Nitrone
Reaction
conditions (%)
Yield Product
R1
CO2Me
R2
N
1
2
11a R1 = R2 = Ph
11a R1 = R2 = Ph
r.t., 5 d
60 °C, 5 h
40
40
13a
13a
O
Cl–
3
4
5
11b R1 = Ph, R2 = 4-MeOC6H4 80 °C, 2 h
11c R1 = Fu, R2 = Ph
11d R1 = Fu, R2 = 4-MeOC6H4 80 °C, 5 h
45
13b
13c
13d
16
Scheme 2
80 °C, 12 h 38
40
The transformation was then extended to methyl (Z)-2-
chlorospiropentylideneacetate (Z)-3e. Its reactions with
nitrones 11a and 11c were carried out in 1,2-dichloro-
ethane at 80 °C for 3.5 hours, and in this case gave the tet-
rahydropyridones 14a and 14c, respectively, as mixtures
of diastereomers (designated as 14ax,ay and 14cx,cy),11
along with the d-lactams 15a and 15c in good overall
yields (Scheme 2).11 The structural assignment of com-
pounds 14a,c and 15a,c was made on the basis of diagnos-
As the nitrone 11a decomposes to a large extent, two
equivalents had to be employed, and in spite of that, the
product 13a was obtained only in a moderate yield. An in-
crease of the reaction temperature (60–80 °C, using
CHCl3 or 1,2-dichloroethane as solvent) reduced sensibly
the reaction time to several hours, but did not improve the
product yield. The intermediate isoxazolidine 12a could
be, tentatively, detected as a transient product in the reac-
tion mixture by NMR, but could not be isolated. The prod-
1
tic H NMR signals for each of them. For example,
compounds 14a showed an AB line pattern centered at
d = 3.65 and 3.20 ppm for diastereomers 14ax and 14ay,
respectively,11 for the methylene group near the nitrogen
1
uct 13a was easily identified on the basis of its H NMR
spectrum showing no high-field signals of the cyclopro-
Synlett 2010, No. 13, 1939–1942 © Thieme Stuttgart · New York

LETTER
Switching the Reaction Mode of Spirocyclopropaneisoxazolidines
1941
(5) (a) Liese, T.; Seyed-Mahdavi, F.; de Meijere, A. Org. Synth.
1990, 69, 148. (b) Limbach, M.; Dalai, S.; de Meijere, A.
Adv. Synth. Catal. 2004, 346, 760.
(6) (a) Zorn, C.; Goti, A.; Brandi, A.; Johnsen, K.; Kozhushkov,
S. I.; de Meijere, A. Chem. Commun. 1998, 903. (b) Zorn,
C.; Goti, A.; Brandi, A.; Johnsen, K.; Noltemeyer, M.;
Kozhushkov, S. I.; de Meijere, A. J. Org. Chem. 1999, 64,
755.
(7) Revuelta, J.; Cicchi, S.; Faggi, C.; Kozhushkov, S. I.;
de Meijere, A.; Brandi, A. J. Org. Chem. 2006, 71, 2417.
(8) Cordero, F. M.; Barile, I.; De Sarlo, F.; Brandi, A.
Tetrahedron Lett. 1999, 40, 6657.
atom, and showed a diagnostic isotopic pattern in the mass
spectrum due to the presence of the chlorine atom. In con-
trast, compound 15a showed the methylene signal at
much higher field (d = 1.2 ppm), and the mass spectrum
confirmed the absence of a chlorine atom. The lactams
15a,c must derive from the initial adducts of 11a,c to 3e
via chlorocyclobutane-annelated intermediates of type 6.
This reaction mode can compete with the one leading to
14a,c because the additional spirocyclopropane moiety
brought in with 3e may significantly stabilize (by up to
about 15 kcal/mol)12 the transient intimate ion pair inter-
mediate 16 (Scheme 2) in the chloromethylcyclopropane
to chlorocyclobutane ring-enlargement process.
(9) (a) Wessjohann, L.; Giller, K.; Zuck, B.; Skattebøl, L.;
de Meijere, A. J. Org. Chem. 1993, 58, 6442.
(b) de Meijere, A.; Kozhushkov, S. I.; Yufit, D. S.; Boese,
R.; Haumann, T.; Pole, D. L.; Sharma, P. K.; Warkentin, J.
Liebigs Ann. 1996, 601.
The 4-MeOC6H4-substituted nitrone 11d with 3e gave ex-
clusively the tetrahydropyridones 14d, albeit in poor
yield. Once more the result confirms the effect of elec-
tron-donating groups on the N-aryl substituent that reduc-
es the activation energy for the N–O cleavage.4
(10) A solution of 3d (37.0 mg, 0.252 mmol, 1 equiv) and 11a
(100 mg, 0.505 mmol, 2 equiv) in CHCl3 (1 mL) was left at
r.t. for 5 d. After concentration in vacuo, the crude material
was purified by flash column chromatography (silica gel,
eluent Et2O–PE = 1:5) to afford compound 13a (35 mg,
0.102 mmol, 40%) as a yellow oil (Rf = 0.13).
In conclusion, it was demonstrated that the reaction mode
of
3-methoxycarbonyl-3-chloro-5-spirocyclopropane-
Methyl 3-Chloro-1-phenyl-4-oxo-2-phenyl-piperidine-3-
carboxylate (13a)
isoxazolidines, the products of 1,3-dipolar cycloadditions
of nitrones to 2-chlorocyclopropylideneacetate, which un-
dergo an efficient ring enlargment to d-lactams, can be
driven to an alternative rearrangement leading to tetrahy-
dropyridones by switching the N-substituent of the nitro-
ne from an alkyl to an aryl group. In this case a two-
component domino process affords the tetrahydropyri-
dones in which the isoxazolidines are only nonisolable in-
termediates.
1H NMR (200 MHz, CDCl3): d = 2.81–3.00 (m, 1 H, CH2),
3.02–3.23 (m, 2 H, CH2), 3.31–3.43 (m, 1 H, CH2), 3.94 (s,
3 H, CO2CH3), 5.94 (s, 1 H, CH), 6.80–6.89 (m, 2 H, PhH),
6.92–7.05 (m, 4 H, PhH), 7.05–7.36 (m, 4 H, PhH). 13
C
NMR (50 MHz, CDCl3): d = 39.9 (t), 41.5 (t), 54.0 (q,
OCH3), 72.1 (d, CHN), 73.1 (s, CCl), 119.0 (d, 2 C, Ph),
121.8 (d, Ph), 127.8 (d, 2 C, Ph), 128.0 (d, Ph), 128.4 (d, 2
C, Ph), 128.9 (d, 2 C, Ph), 131.3 (s, Ph), 149.0 (s, NPh),
167.4 (s, CO2Me), 197.7 (s, C=O). Anal. Calcd for
C19H18ClNO3: N, 4.07; C, 66.38; H, 5.28. Found: N, 4.32; C,
66.20; H, 5.66.
(11) Representative Procedure
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
spectroscopic and analytical data of compounds 13b,c,d, 14cx,cy,
and 15c.
A solution of 3e (44.0 mg, 0.254 mmol, 1 equiv) and 11a
(100 mg, 0.507 mmol, 2 equiv) in DCE (1 mL) was heated
at 80 °C for 3.5 h. After concentration in vacuo, the crude
material was purified by flash column chromatography
(silica gel, eluent Et2O–PE = 1:5) to afford 14a (28 mg,
0.076 mmol, 30%) as a brown oil (Rf = 0.29) and 15a (30
mg, 0.090 mmol, 36%) brown oil (Rf = 0.18).
Acknowledgment
The authors thank the Ministry of University and Research (Rome)
for partial financial support. I.O. acknowledges a Sokrates student
exchange fellowship from the Georg-August-Universität Göttingen
(Germany).
Methyl 7-Chloro-6-phenyl-8-oxo-5-phenyl-5-
azaspiro[2.5]octane-7-carboxylate (14a): mixture of two
diastereomers.
Diastereomer 14ax: 1H NMR (400 MHz, CDCl3): d = 0.89–
0.95 (m, 1 H, c-PrH), 1.15–1.22 (m, 1 H, c-PrH), 1.70–1.73
(m, 2 H, c-PrH), 3.40 (d, 2J = 12.0 Hz, 1 H, CH2), 3.50 (s, 3
H, OCH3), 3.89 (d, 2J = 12.0 Hz, 1 H, CH2), 5.40 (s, 1 H,
CH), 6.76–7.43 (m, 10 H, Ph).
References and Notes
(1) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev.
2003, 103, 1213.
Diastereomer 14ay: 1H NMR (400 MHz, CDCl3): d = 0.89–
0.95 (m, 1 H, c-PrH), 1.15–1.22 (m, 1 H, c-PrH), 1.47–1.51
(m, 1 H, c-PrH), 1.90–1.95 (m, 1 H, c-PrH), 3.10 (dd,
2J = 12.0 Hz, 4J = 0.8 Hz, 1 H, CH2), 3.33 (dd, 2J = 12.0 Hz,
4J = 0.8 Hz, 1 H, CH2), 3.88 (s, 3 H, OCH3), 5.91 (d, J = 0.8
Hz, 1 H, CH), 7.60–7.43 (m, 10 H, PhH).
(2) (a) Cordero, F. M.; Brandi, A.; Querci, C.; Goti, A.;
De Sarlo, F.; Guarna, A. J. Org. Chem. 1990, 55, 1762.
(b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti,
A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806.
(c) Machetti, F.; Cordero, F. M.; De Sarlo, F.; Guarna, A.;
Brandi, A. Tetrahedron Lett. 1996, 37, 4205. (d) Cordero,
F. M.; Anichini, B.; Goti, A.; Brandi, A. Tetrahedron 1993,
49, 9867.
(3) (a) Goti, B.; Anichini, A.; Brandi, A.; de Meijere, A.; Citti,
L.; Nevischi, S. Tetrahedron Lett. 1995, 36, 5811. (b)Zorn,
C.; Anichini, B.; Goti, A.; Brandi, A.; Kozhushkov, S. I.;
de Meijere, A.; Citti, L. J. Org. Chem. 1999, 64, 7846.
(4) Ochoa, E.; Mann, M.; Sperling, D.; Fabian, J. Eur. J. Org.
Chem. 2001, 4223.
Diastereomers 14ax,ay: 13C NMR (100 MHz, CDCl3):
d = 16.8, 20.7, 22.1, 24.9, 26.9, 28.5, 49.9, 51.0, 52.9, 53.8,
71.5, 72.8, 115.1, 116.7, 119.4, 120.6, 122.4, 124.7, 127.7,
127.9, 128.1, 128.2, 128.3, 128.8, 128.9, 129.2, 132.5,
136.2, 148.7, 162.9, 167.2, 198.4. Anal. Calcd for
C21H20ClNO3: N, 3.79; C, 68.20; H, 5.45. Found: N, 4.20; C,
68.13; H, 5.77.
Synlett 2010, No. 13, 1939–1942 © Thieme Stuttgart · New York

1942
S. Cicchi et al.
LETTER
134.7 (s, Ph), 140.9 (s, NPh), 146.4 (s, CPh), 163.2 (s,
CO2Me), 175.7 (s, C=O). Anal. Calcd for C21H19NO3: N,
4.20; C, 75.66; H, 5.74. Found: N, 4.38; C, 75.26; H, 6.01.
(12) (a) de Meijere, A.; Weitemeyer, C.; Schallner, O.;
Spielmann, W. Chem. Ber. 1979, 112, 908. (b) de Meijere,
A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809; and
references cited therein.
Methyl 6-Phenyl-4-oxo-5-phenyl-5-azaspiro[2.5]oct-6-
ene-7-carboxylate (15a)
1H NMR (400 MHz, CDCl3): d = 0.42–0.59 (m, 2 H, CH2),
0.93–1.09 (m, 2 H, CH2), 1.21–1.30 (m, 2 H, CH2), 3.79 (s,
3 H, OCH3), 7.08–7.50 (m, 10 H, Ph). 13C NMR (100 MHz,
CDCl3): d = 17.1 (t), 20.8 (t, 2 C, c-Pr), 21.4 (s, c-Pr), 52.7
(q, OCH3), 76.9 (s, CCO2Me), 126.5 (d, Ph), 127.2 (d, Ph),
127.7 (d, Ph), 128.5 (d, Ph), 129.2 (d, Ph), 129.5 (d, Ph),
Synlett 2010, No. 13, 1939–1942 © Thieme Stuttgart · New York

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