Two-step metal-mediated transformation of isoxazolidine-5- spirocyclopropanes into pyridone derivatives

Article abstract of DOI:10.1021/jo050640q

The two-step metal-catalyzed overall transformation of isoxazolidine-5- spirocyclopropanes into the corresponding dihydro- and tetrahydropyridones is described. The first step is the chemoselective reduction of the N-O bond of the isoxazolidine ring prese

Full text of DOI:10.1021/jo050640q

Two-Step Metal-Mediated Transformation of
Isoxazolidine-5-spirocyclopropanes into Pyridone Derivatives†
Julia Revuelta, Stefano Cicchi, and Alberto Brandi*
Dipartimento di Chimica Organica “Ugo Schiff”, Universita` di Firenze and ICCOM (Istituto per la
Chimica dei Composti Organometallici), CNR, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
alberto.brandi@unifi.it
Received April 1, 2005
The two-step metal-catalyzed overall transformation of isoxazolidine-5-spirocyclopropanes into the
corresponding dihydro- and tetrahydropyridones is described. The first step is the chemoselective
reduction of the N-O bond of the isoxazolidine ring preserving the fragile cyclopropanol moiety
while the second transformation is the Pd(II) or Pd(0) conversion of the â-aminocyclopropanol
derivatives into the final compounds. The scope and limitations of this strategy are described.
SCHEME 1
Introduction
The reactivity of the cyclopropane ring, due to its high
level of strain, has found many applications in synthetic
organic chemistry, and it is so peculiar of this three-
membered ring that it can be better considered as a real
functional group rather than a simple structural unit.1
Most of its chemistry concerns with ring-opening reac-
tions mediated by a variety of reagents.1 The presence
of electron-donor substituents on the cyclopropane ring
enhances its reactivity and allows a high control on the
regioselectivity of the ring opening reaction.2 Recently,
several works dealing with the palladium-catalyzed ring
cleavage of hydroxy substituted small cycles were pub-
lished. Pd(OAc)2 was reported to catalyze the ring cleav-
age of cyclopropanols 1,3 or cyclobutanols 3, into R,â- and
â,γ-unsaturated ketones 2 and 4, respectively (Scheme
1).
This transformation can find interesting application
onto substrates bearing other functionalities which are
reactive toward the palladium intermediates formed in
the reaction4 or toward the double bond: for example,
an intramolecular Michael reaction would afford cyclic
compounds. Recently, we have started a research project
aimed to the transformation of isoxazolidine-5-spiro-
cyclopropanes mediated by transition metals, trying to
conjugate the wide structural variability and easiness of
assembly of isoxazolidines with the reactivity of the
cyclopropane ring. These compounds have been studied
thoroughly by our group, mainly for their thermal rear-
rangement into tetrahydropyridone derivatives 6 (Scheme
2, eq 1),5 and this transformation has found wide ap-
† Dedicated to Professor Armin de Meijere on the occasion of his
65th birthday.
(1) (a) Houben-Weyl, Methods of Organic Chemistry, Carbocyclic
Three Membered Ring Compounds; de Meijere, A., Ed.; Thieme:
Stuttgart, 1997; Vol. E1. (b) Kulinkovich, O. G. Chem. Rev. 2003, 103,
2597-2632. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165-198. (d) Gibson, D.
H.; DePuy, C. H. Chem. Rev. 1974, 74, 605-623.
(2) (a) Ming, Y.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321-347.
(b) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151˜-1196. (c)
Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73-135.
(3) (a) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147-149. (b)
Okumoto, H.; Jinnai, T.; Shimizu, H.; Harada, Y.; Mishima, H.; Suzuki,
A. Synlett 2000, 629-630.
(4) (a) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999,
121, 2645-2646. (b) Nishimura, T.; Ohe, K.; Uemura, S. J. Org. Chem.
2001, 66, 1455-1465.
(5) Brandi, A.; Cordero, F. M.; De Sarlo, F.; Goti, A.; Guarna, A.
Synlett 1993, 1-8.
10.1021/jo050640q CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/16/2005
5636
J. Org. Chem. 2005, 70, 5636-5642

Metal-Mediated Synthesis of Dihydropyridones
SCHEME 2
SCHEME 4
SCHEME 5 a
SCHEME 3
plication in the syntheses of several natural compounds
and interesting heterocyclic structures.6
The remark that the simple reduction of the N-O bond
of 5 affords the corresponding â-aminocyclopropanol 8 led
us to explore the reactivity of this rather unknown class
of cyclopropanols with the scope of building up a domino
process affording pyridone derivatives 10 (Scheme 2, eq
2). The preliminary results obtained demonstrated that
this domino process is possible and affords pyridone
derivatives as expected, but with the added bonus of
bringing about a new oxidative process leading, selec-
tively, to dihydropyridones.7 In fact, the complex
Pd(OAc)2/Py in combination with atmospheric oxygen as
stoichiometric oxidant, as originally reported by Uemura4
and Cha,3 catalyzed the transformation of amino alcohols
11 and 12 to the corresponding dihydropyridone 13 and
14, respectively (Scheme 3), and not to the expected
saturated isomers.
Several issues remained to be addressed to make the
overall process efficient and to give insight into the
mechanistic aspects of this transformation. The reduction
of the N-O bond of isoxazolidine-5-spirocyclopropanes
was not a trivial task because of the known reactivity of
the cyclopropane moiety under reducing conditions. It
was then necessary to develop a new reliable procedure
for this reduction. Finally, it was necessary to optimize
the reaction conditions for the final transformation
mediated by Pd(OAc)2 and to demonstrate its generality
and mechanistic implications.
a Key: (a) Pd(OH)2/C, H2; (b) SmI2, 0.1 M THF solution.
oxide (15) to methylenecyclopropane together with its
4-spirocyclopropane regioisomer 17 (Scheme 4).
The reduction of the N-O bond of simple isoxazolidines
can be performed using a variety of different reagents;8
however,the presence of a spirocyclopropane group R to
the oxygen atom makes this reaction troublesome.
Mo(CO)6, for example, which was able to reduce 5-
spirocyclopropane isoxazolines to cyclopropyl ketones,9
failed to afford the analogous transformation for the
corresponding isoxazolidine derivatives, although isox-
azolidines are generally reduced by this reagent.10 Sev-
eral other reducing agents were tested, but always
afforded complex mixtures of compounds. In two cases,
for isoxazolidines 16 and 1811 (Scheme 5), Pd(OH)2/C in
the presence of H2 atmosphere proved useful for the
desired transformation. Due to the difficult separation
of the two regioisomers, compound 18 was reduced in
mixture with its 4-spirocyclopropane isomer 19 and the
mixture of the two amino alcohols, 12 and 20, respec-
tively, was easily separated. Unfortunately, the extension
of this procedure to other substrates was not possible.
Results and Discussion
All isoxazolidine-5-spirocyclopropanes used as starting
material in this work are obtained through 1,3-dipolar
cycloaddition reactions of the proper nitrone to methyl-
enecyclopropane and most of these reactions have been
previously described. The isoxazolidine 16 is new and was
obtained by cycloaddition of 3,4-dihydroisoquinoline 2-
(8) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J. Goti, A. Org.
Lett. 2003, 5, 1773-1776 and references therein.
(9) Guarna, A.; Guidi, A.; Goti, A.; Brandi, A.; De Sarlo, F. Synthesis
1989, 178.
(10) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351-3354.
(11) Brandi, A.; Garro, S.; Guarna, A.; Goti, A.; Cordero, F. M.; De
Sarlo, F. J. Org. Chem. 1988, 53, 2434.
(6) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003,
103, 1213-1269.
(7) Cicchi, S.; Revuelta, J.; Zanobini, A.; Betti, M.; Brandi, A. Synlett
2003, 2305-2308.
J. Org. Chem, Vol. 70, No. 14, 2005 5637

Revuelta et al.
SCHEME 6 a
The known ability of SmI2 to reductively cleave the
N-O bond in several substrates12 suggested the use of
SmI2 as reducing agent for these compounds. Treatment
of isoxazolidines 16, 18, 2113 and 2314 with an excess of
a commercial 0.1 M solution of SmI2 allowed a smooth
and efficient conversion to the corresponding amino-
cyclopropanols (Scheme 5).15
The compared yields for the Pd(OH)2/C and the SmI2
reduction of isoxazolidines 16 and 18 are reported in
Scheme 5. In the case of isoxazolidines 21 and 23 the
catalytic Pd hydrogenation was unsuccessful. The workup
procedure needed for the reduction with SmI2 caused
partial hydrolysis of the ester group15 and this made the
procedure not useful for the reduction of isoxazolidine
25. The amino alcohol 26, however, was efficiently
obtained by hydrogenolysis, although the complete depro-
tection of the amino group was achieved. The reduction
with SmI2, therefore, nicely complements the catalytic
hydrogenolysis and even if the latter is an experimentally
easier procedure, the use of SmI2 allowed the transfor-
mation of more reactive isoxazolidine-5-spirocyclopro-
panes.
Subjecting amino alcohols 22, 24, and 26 to the
conditions previously used provided dihydropyridones 27
and 28 in moderate yields (eqs 3 and 4, reaction condi-
tions a, Scheme 6), confirming the same trend observed
before. In contrast the primary amine 26 (eq 5, Scheme
6) did not cyclize under these conditions. Therefore, under
Pd(OAc)2/Py catalyzed conditions, secondary-amine-γ-
cyclopropanols undergo a new process consisting of a
rearrangement of the cyclopropanol followed by oxidative
ring closure.
An elevated pressure of molecular oxygen to 0.5 MPa
(Scheme 6, reaction conditions b), improved yields re-
markably and even the primary amine 26 could be
cyclized to compound 29, albeit in low yields. Interest-
ingly, in a singular case where a mixture of dihydro- and
tetrahydropyridone was observed (eq 1, Scheme 6) the
new conditions also increased the selectivity from (1:1.5)
to (5: 1). The use of a pressure apparatus and a more
complex experimental procedure of this variation there-
fore is justified by the higher efficiency of the transfor-
mations.
a Reaction conditions: (a) Pd(OAc)2 10 mol %, Py, air, toluene,
80 °C; (b) Pd (OAc)2 10 mol %, Py, O2 (5 atm); (c) Pd (OAc)2 10
mol %, LiOAc, Cu(OAc)2; (d) Pd2(dba)3 10 mol %.
SCHEME 7
The structures of all compounds were easily assigned
from their 1H and 13C spectra. The characteristic signals
of the enaminone moiety also proved that the double bond
is on the unsubstituted side of the piperidone ring.7
Other Pd(II) salts used in the process were less
effective. PdCl2 generally gave lower yields,7 but interest-
ingly transformed 11 cleanly to 13 (Scheme 6, eq 1)
without concomitant formation of 13a. In contrast PdI2
was completely inactive7 for both 11 and 12. Pyridine as
a base was superior to a hindered aliphatic amine, i.e.,
DIPEA.
As previously reported,14 the thermal rearrangement
of 23 peculiarly did not cyclize to 28a, but afforded 30 as
the main component of a complex mixture via cyclopropyl
ring cleavage and elimination of methylamine (Scheme
7). In contrast, the process herein reported, afforded 28
in moderate to good yields, thus substantiating the first
successful transformation of 23 into a hitherto unknown
4a,5,6,10b-tetrahydro-1H-benzo[h][1,6]naphthyridin-4-
one tricyclic fused system (Scheme 6, eq 4).
(12) Nitro compounds: Kende, S.; Mendoza, J. S. Tetrahedron Lett.
1991, 32, 1699-1702. Hydroxylamines and hydroxamic acids: Keck,
G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995, 36, 7419-
7422. 1,2-Oxazine: Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett.
2002, 4, 2353-2355. Keck, G. E.; McHardy, S. F.; Wager, T. T.
Tetrahedron Lett. 1995, 36, 7419-7422. Isoxazoles and isoxazolines:
Natale, N. R. Tetrahedron Lett. 1982, 23, 5009-5012. Fan, X.; Zhang,
Y. Tetrahedron Lett. 2002, 43, 7001-7003. Bode, J. W.; Carreira, E.
M. Org. Lett. 2001, 3, 1587-1590. Jung, S. H.; Lee, J. E.; Koh, H. Y.
Bull. Korean Chem. Soc. 1998, 19, 33-35.
(13) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743-
4748.
(14) Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Salun, J.;
Brandi, A. J. Am. Chem. Soc. 2000, 122, 8075-8076.
(15) Revuelta, J.; Cicchi, S.; Brandi, A. Tetrahedron Lett. 2004, 45,
8375-8377.
Dihydropyridones with an unprotected nitrogen func-
tionality could be obtained by thermal rearrangement of
spirocyclopropane isoxazolines.16 We now succeeded in
(16) Brandi, A.; Cordero, F. M.; de Sarlo, F.; Goti, A.; Guarna, A.
Synlett 1993, 1-8.
5638 J. Org. Chem., Vol. 70, No. 14, 2005

Metal-Mediated Synthesis of Dihydropyridones
SCHEME 8
SCHEME 9
the direct synthesis of N-unprotected dihydropyridone 29
by cyclization of aminocyclopropanol 26, albeit yields
were low (eq 5, Scheme 6). Attempts to improve the
yields, even by using stoichiometric amounts of Pd(OAc)2
remained unsuccessful. To study the cyclization process,
26 was converted into the corresponding CBz derivatives
31 (Scheme 8).
Due to the lowered nucleophilicity of the nitrogen, the
intermediate ketone 32 could be trapped almost quanti-
tatively under the usual conditions. Subsequent cycliza-
tion would explain generation of a saturated tetra-
hydripyridone, as singularly observed in Scheme 6, eq
1, but not the formation of dihydropyridones being
predominantly observed in all other reactions. Oxidation
of a tetrahydropyridone to the corresponding dihydro-
pyridone with IBX, Hg(OAc)2, MCPBA or DDQ has been
described,17 but palladium catalysis was unsuccessful as
reported by Murahashi.18 Furthermore, this course would
not explain the complete regioselectivity of the double
bond formation. In fact, reacting 14 under the usual
conditions gave no evidence for the formation of 14a.
To further elucidate the course of the reaction, we
attempted to replace molecular oxygen in this Wacker-
like process19 by other stoichiometric oxidants. Copper
acetate has often been used as a stoichiometric oxidant
in Pd(II) catalyzed reactions. Therefore, the same reac-
tions were run using Cu(OAc)2 (2 equivalents), LiOAc (3
equivalents) as base in the presence of 10 mol % of
Pd(OAc)2 in DMF (reaction conditions c, Scheme 6).20 This
variation fundamentally changed the outcome of the
reaction. Transformation of amino alcohols 11 and 12
afforded the corresponding tetrahydropyridones 13a and
14a in good yields. Conversely, application of these
reaction conditions to amino alcohols 22 and 24 resulted
in complex mixtures from which neither the dihydro nor
the tetrahydro derivatives could be isolated.
As recently demonstrated, Pd(0) also transforms cy-
clopropanols into the corresponding R,â-unsaturated
ketones.3b Consequently, Pd2(dba)3 in CH3CN at 50 °C
was applied according to the literature (reaction condition
d, Scheme 6). Again, the saturated derivatives 13a, 14a,
and 27a13 (eqs 1-3, reaction condition d, Scheme 6) were
obtained predominantly, if not exclusively. The reaction
of amino alcohol 24 furnished a complex mixture with
compound 30 as the main product (50% yield), as already
observed with the thermal rearrangement of isoxazoli-
dine 23 (vide supra). Compound 26, with the primary
amine group, failed to give any product under these
conditions.
Based on our findings, we propose a mechanistic
explanation for this novel Pd(II) catalyzed domino ring
opening/cyclization/oxidation of γ-aminocyclopropanols.
This hypothesis is strongly supported by a recent pub-
lication about the aerobic alcohol oxidation catalyzed by
Pd(OAc)2/pyridine,21 including one example of an oxida-
tive ring-cleavage of a tert-cyclobutanol to an â,γ-
unsaturated ketone.4
This transformation is proposed to proceed through the
formation of a Pd alcoholate species 33 which, upon
elimination of a pyridine molecule, affords a coordina-
tively unsaturated species 34 that undergoes the â-hy-
dride elimination providing the carbonyl compound and
the reduced Pd species, that is subsequently reoxidated
by molecular oxygen (Scheme 9).
Pyridine appears to play a key role in stabilizing the
Pd(II) species and facilitates the reoxidation step after
the reductive elimination. Although a full characteriza-
tion of the reactive species has not been possible so far,
also other authors postulated a Pd alcoholate species as
key intermediate in the oxidative ring cleavage of tertiary
cyclobutanols4 and cyclopropanols.3 A similar mechanism
might be expected when applied to amino cyclopropanols,
even if the primary or secondary amino functionality
could participate in the complexation of the Pd nucleus
(Scheme 10). In fact, when lowering the nucleophilicity
of the amino nitrogen by a carbamate protective group,
as demonstrated with 31 (Scheme 8), accordingly the
corresponding R,â-unsaturated ketone 32 was obtained.
A
1H NMR analysis of the behavior of Pd(OAc)2/Py
complex upon the addition of increasing amount of amino
alcohol 11 revealed the presence of more than one species
in solution. The spectra were recorded in C6D6 at room
temperature with a 4.5 × 10-2 M concentration of
Pd(OAc)2 in the presence of an excess of Py (10 equiv).
In this conditions a precipitate of the Pd(OAc)2/py com-
plex was formed, which completely dissolves upon addi-
tion of two equivalents of the amino alcohol 11. The
singlet at 2.00 ppm, related to the two acetate group
bonded to Pd,21 decreased upon addition of 11, but
disappeared only after the addition of 2 equivalents of
amino alcohol 11 to afford two separate singlets at 2.1
and at 1.9 ppm. A still intact cyclopropane ring at room
temperature could be detected from only slightly modified
signals at 1.5 to 0.5 ppm. The solution remained stable
at least for 2 days, after which a black precipitate of
colloidal Pd(0) was formed. The observation of more than
one Pd complex may indicate a dynamic equilibrium in
which the initial pyridine ligands are exchanged with the
secondary amino group of the amino alcohol (Scheme 10).
Consequently, we propose a mechanism, postulating a
key Pd alcoholate intermediate, analogous to those
reported by Stahl et al.21 and Okumoto et al.3b
(17) O-Iodoxybenzoic acid: Nicolau, K. C.; Montagnon, T.; Baran,
P. S.; Angew. Chem., Int. Ed. 2002, 41, 993-996. Hg(OAc)2: Zhao, Z.;
Dalvie, D.; Naiman, N.; Castagnoli, K.; Castagnoli, N., Jr. J. Med.
Chem. 1992, 35, 4473-4478. m-Chloroperbenzoic acid: Kuehne, M.
E.; Muth, R. S. J. Org. Chem. 1991, 56, 2701-2712. DDQ: Pfaendler,
H. R.; Jenni, W. Heterocycles 1999, 50, 867-874.
(18) Murahashi, S.-I.; Mitsue, Y.; Tsumiyama, T. Bull. Chem. Soc.
Jpn. 1987, 60, 3285-3288.
(19) Tsuji, J. Palladium Reagents and Catalysts; John Wiley and
Sons: Chichester, 1995; Chapter 3.
(20) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001,
3, 3313-3316.
(21) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc.
2004, 126, 11268-11278
J. Org. Chem, Vol. 70, No. 14, 2005 5639

Revuelta et al.
SCHEME 10
strategy will aim for the synthetic exploitation of the
structurally diverse dihydropyridones thus made acces-
sible.
Experimental Section
Compounds 18, 21, 23, and 25 were synthesized following
the reported procedures. See refs 11 and 14.
Cycloaddition of 3,4-Dihydroisoquinoline 2-Oxide to
Methylenecyclopropane. Methylenecyclopropane (486 mg,
9.0 mmol) was added to a solution of 3,4-dihydroisoquinoline
2-oxide 15 (440 mg, 3.0 mmol) in toluene (4 mL), and the
mixture was heated in a sealed vial at 60 °C for 2 d. The
solvent was then removed under reduce pressure and the crude
products were purified by chromatography on silica gel (elu-
ent: AcOEt/petroleum ether ) 1:10) to obtain 16 as a pale-
yellow oil (356 mg, yield 59%) and 17 as a yellow oil (48 mg,
yield 8%).
1′,5′,6′,10′b-Tetrahydrospiro[cyclopropane-1,2′-[2H]isox-
azolo[3,2-a]isoquinoline] (16): Rf ) 0.35 (AcOEt/petroleum
ether 1:10); 1H NMR δ 7.30-7.10 (m, 4H), 4.90 (t, J ) 8.5,
1H), 3.42 (dd, J ) 10.3, 4.4 Hz, 1H), 3.24 (dt, J ) 10.3, 4.4 Hz,
1H), 3.10 (ddd, J ) 16.1, 10.3, 4.4 Hz, 1H), 2.90 (dt, J ) 16.1,
4.4 Hz, 1H), 2.81 (dd, J ) 12.1, 8.4 Hz, 1H), 2.47 (dd, J ) 12.1,
8.8 Hz, 1H), 1.13-0.94 (m, 2H), 0.81-0.64 (m, 2H); 13C NMR
135.7 (s), 132.6 (s), 127.6 (d), 126.6 (d), 125.8 (d), 125.6 (d),
63.3 (d), 62.3 (s), 40.1 (t), 42.4 (t), 27.6 (t), 12.1 (t), 8.1 (t); MS
(EI) m/z 201(18), 172 (49), 146 (41), 143 (53), 130 (100), 118
(29), 115 (78), 103 (44), 75 (15), 56 (35), 52 (27); IR (CDCl3)
3081, 2858, 1607, 1583, 1492, 1455, 1013 cm-1. Anal. Calcd
for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.61; H,
7.52; N, 6.95.
6′,10′b-Dihydrospiro[cyclopropane-1,1′(5′H)-[2H]isox-
azolo[3,2-a]isoquinoline] (17): Rf ) 0.13 (AcOEt/petroleum
ether, 1:10); 1H NMR δ 7.27-7.18 (m, 3H), 6.84 (m, 1H), 4.58
(s, 1H), 4.12 (system AB, 2H), 3.44-3.40 (m, 1H), 3.30-3.24
(m, 2H), 2.90-2.80 (m, 1H), 0.79-0.76 (m, 2H), 0.44 (m, 1H),
0.40 (m, 1H); 13C NMR 131.2 (s), 134.4 (s), 127.7 (d), 126.4 (d),
125.3 (d), 125.2 (d), 73.7 (t), 65.0 (d), 47.7 (t), 28.6 (t), 27.9 (s),
10.7 (t), 3.6 (t); MS (EI) m/z 201 (28), 184 (33), 180 (36), 148
(52), 145 (38), 131 (60), 127 (42), 87 (55), 85 (94), 82 (100), 58
(79), 52 (51); IR (CDCl3) 3072, 2874, 1495, 1455, 1119, 1022
cm-1. Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.54; H, 7.57; N, 6.90.
General Procedures for the Reduction of Isoxazo-
lidines. Method A. Pd(OH)2/C (20% in mass) was added to a
solution of the isoxazolidine (0.33 mmol) in MeOH (7 mL). The
reaction mixture was stirred under hydrogen at room tem-
perature until the TLC showed consumption of the starting
material. Palladium salts were then removed by filtering
through a pad of Celite, and the solvent was then removed
under reduce pressure. Method B. A 100 mL Schlenck flask
charged with the isoxazolidine (0.5 mmol) was added, under
nitrogen atmosphere, with 17.5 mL of a commercial 0.1 M THF
solution of SmI2 (3.5 equiv) at room temperature. The resulting
blue solution was stirred for 2 h. A 1 M solution of NH4OH in
MeOH (8.5 mL) was added and left under stirring for 20 min.
Finally, 17 mL of water was added, and the resulting solution
was brought to pH 9 by addition of a 1 M solution of NaOH in
water. The mixture was then saturated with Na2S2O3 and
extracted with diethyl ether (3 × 15 mL). The organic phase
was then dried with Na2SO4, filtered, and concentrated to
afford the crude product.
Once that the R,â-unsaturated ketone A (Scheme 10)
has been formed, subsequent aza-Michael addition of the
amino group would lead to palladium enolate B, which
is in equilibrium with the carbopalladated intermediate
C. Ultimately a reductive elimination affords the dihy-
dropyridone. It has been demonstrated that the aerobic
oxidation can be accomplished in the absence of Py, but
with a large excess of the acetate anions,21 and so it might
be argued that an excess of Cu(OAc)2 could also promote
oxidative ring cleavage. However, our experiments indi-
cate that excessive Cu(II) forms a Cu enolate which
competes with the Pd enolate B. Hydrolysis of the former,
in contrast to reductive elimination of the latter, simply
affords tetrahydropyridones at the end of the sequence.
With regard to the role of Pd2(dba)3, the outcome of
the reactions (Scheme 6, reaction conditions d)) is in
accordance with the inability to form enolates and with
the expected reactivity of the intermediate R,â-unsatur-
ated ketone.
In conclusion, we developed a new domino process to
structurally diverse dihydropyridones by exploiting a
combination of the synthetically versatile 1,3-dipolar
cycloaddition of nitrones to methylenecyclopropane, an
optimized reductive N-O bond cleavage, and subsequent
Pd-catalyzed cyclization. In particular, this methodology
allows regiospecific introduction of the enaminone double
bond on the less substituted side of the dihydropyridone,
thus complementing other common methods.22 On the
other hand, while the use of Pd(0) or Pd(II)/Cu(II) species
does not yet represent a practical alternative to the
thermal rearrangement of isoxazolidine-5-spirocyclopro-
panes, it appears mechanistically interesting to be able
to control the oxidation level of the products by a simple
change of the catalyst. The future developments of this
The crudes are sufficiently pure to be used directly for the
following step. A short pad filtration over silica gel of an
analytical sample affords the pure products for elemental
analysis.
1-(1,2,3,4-Tetrahydroisoquinolin-1-ylmethyl)cyclopro-
panol (11): yellow solid; method A 67% yield, method B 70%
yield; Rf ) 0.17 (CH2Cl2/CH3OH, 15:1 + 0.6% NH4OH); mp )
1
85-86 °C; H NMR δ 7.31-7.15 (m, 2H), 7.09-6.98 (m, 2H),
(22) Kuethe, J. T.; Comins, D. L. J. Org. Chem. 2004, 69, 2863-
2866 and references therein.
4.40 (dd, J ) 11.4, 2.6 Hz, 1H), 3.36-3.12 (m, 2H), 2.83 (dd, J
5640 J. Org. Chem., Vol. 70, No. 14, 2005

Metal-Mediated Synthesis of Dihydropyridones
) 7.0, 4.8 Hz, 2H), 2.54 (dd, J ) 14.6, 11.4 Hz, 1H), 1.43 (dd,
J ) 14.6, 2.6 Hz, 1H), 0.89-0.77 (m, 2H), 0.58-0.46 (m, 2H);
13C NMR 134.4 (s, 2C), 129.4 (d), 126.4 (d), 126.3 (d), 126.0
(d), 56.6 (s), 55.9 (d), 41.9 (t), 38.2 (t), 29.0 (t), 13.2 (t), 12.9 (t);
MS (EI) m/z 203(8), 197 (41), 184 (50), 170 (42), 167 (60), 158
(50), 143 (54), 130 (100), 115 (88), 103 (68), 57 (41); IR (CDCl3)
3650, 3300-3200, 3083-2949, 1489, 1433, 1305 cm-1. Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C,
76.95; H, 8.36; N, 6.80.
1-[2-(Methylamino)-2-phenylethyl]cyclopropanol (12):
method A 70% yield; method B 80% yield; Rf ) 0.18 (AcOEt/
MeOH, 10:1); 1H NMR δ 7.42-7.22 (m, 5H), 3.88 (dd, J ) 10.5,
2.9 Hz, 1H), 2.38 (dd, J ) 14.2, 10.5 Hz, 1H), 2.32 (s, 3H),
1.35 (dd, J ) 14.2, 2.9 Hz, 1H), 0.84-0.72 (m, 2H), 0.52-0.27
(m, 2H); 13C NMR 141.0 (s), 127.9 (s), 126.6 (d), 125.8 (d), 64.5
(d), 55.6 (s), 43.4 (t), 32.8 (q), 12.7 (t), 12.1(t); MS (EI) m/z 191
(0.5) 160 (2), 120 (100), 104 (22); IR (CDCl3) 3650, 3500-3200,
3085, 2803, 1600, 1493, 1299, 1008 cm-1. Anal. Calcd for
C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.70; H, 8.81;
N, 7.15.
Since the two regioisomeric isoxazolidine-5- and 4-spiro-
cyclopropane are not easily separated, the reduction step can
be performed on the crude mixture obtained from the cycload-
dition.11 From this reduction, the amino alcohol derived from
the 4-spirocyclopropane derivative was also isolated.
{1-[(Methylamino)(phenyl)methyl]cyclopropyl}meth-
anol (20): white solid; method A 8% yield; Rf ) 0.14 (AcOEt/
CH3OH, 10:1); mp ) 97-98 °C; 1H NMR δ 7.52-7.20 (m, 5H),
5.80 (bs, 2H), 3.84 (part A system AB, J ) 11.7 Hz, 1H), 3.54
(s, 1H), 3.08 (part B system AB, J ) 11.7 Hz, 1H), 2.49 (s,
3H), 0.86-0.53 (m, 3H), 0.46-0.25 (m, 1H); 13C NMR 136.8
(s), 128.7 (d), 128.1 (s), 127.4 (d), 71.8 (d), 68.0 (t), 34.3 (q),
25.6 (s), 12.1 (t), 7.9 (t); MS (EI) m/z 191 (1), 160 (2), 120 (100),
104 (3); IR (CDCl3) 3648, 3400-3150, 2800, 1600, 1450, 1255,
1120 cm-1. Anal. Calcd for C12H17NO‚H2O: C, 68.87; H, 9.15;
N, 6.69. Found: C, 68.75; H, 8.95; N, 6.87.
(42), 100 (70), 74 (50), 57 (100); IR (CDCl3) ν 3552, 3025, 2245,
1737, 1643, 1594, 1494, 1320, 1260. Anal. Calcd for C8H15-
NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.36; H, 8.88; N,
8.05.
Ethyl
N-[(Benzyloxy)carbonyl]-3-(1-hydroxycyclo-
propyl)alaninate (31). To a well-stirred solution of 26 (130
mg, 0.75 mmol) in acetone (4 mL) and water (1 mL) were added
NaHCO3 (63 mg, 0.75 mmol) and CbzCl (190 mg, 1.12 mmol).
The resulting solution was stirred under N2 for 3 h. at 0 °C
and concentrated. The solid residue was washed with CH2Cl2
and the resulting solution concentrated. The residue was
purified by FCC to obtain pure 31 (225 mg, 98%) as a yellow
oil: Rf ) 0.4 (CH2Cl2/CH3OH, 97:3); 1H NMR δ 7.43-7.22 (m,
5H), 5.64 (d, J ) 2.2 Hz, 1H), 5.17 (AB system, 2H), 4.65 (ddd,
J ) 8.5, 3.2, 2.2 Hz, 1H), 4.22 (q, J ) 7.5 Hz, 2H), 2.43 (dd, J
) 8.5, 3.2 Hz, 1H), 1.35 (m, 1H), 1.33 (t, J ) 7.5 Hz, 3H), 0.83-
0.75 (m, 1H), 0.53-0.47 (m, 1H), 0.43-0.38 (m, 2H); 13C NMR
172.4 (s), 156.4 (s), 136.1 (s), 128.5 (d), 128.3 (d), 127.5 (d),
67.3 (t), 61.8 (t), 60.9 (s), 52.0(d), 41.7 (t), 14.2 (q), 12.6 (t),
11.6 (t); MS (EI) m/z 307 (1), 91 (100), 65 (12), 57 (12), 55 (12);
IR (CDCl3) 3428, 2984, 2960, 2249, 1784, 1704, 1513, 1455,
1380, 1346, 1297, 1215, 1185. Anal. Calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56. Found: C, 62.36; H, 6.82; N, 4.50.
General Procedure for the Synthesis of Dihydro-
pyridones. A suspension of the â-aminocyclopropanol (0.5
mmol), Pd(II) catalyst (0.05 mmol), base (1.0 mmol) in toluene
(5 mL) was stirred and heated at 80 °C for 3 h in a reactor
with pressure of O2 (5 atm.). The suspension was then filtered
and concentrated and the residue purified by flash chroma-
tography.
1,6,7,11b-Tetrahydro-2H-pyrido[2,1-a]isoquinolin-2-
one (13): yellow oil; Rf ) 0.18 (AcOEt/petroleum ether, 5:1);
1H NMR δ 7.20-7.00 (m, 5H), 5.10 (d, J ) 7.3 Hz, 1H), 4.79
(dd, J ) 15.7, 4.0 Hz, 1H), 3.69-3.53 (m, 1H), 5.46 (td, J )
11.7, 3.3 Hz, 1H), 3.19 (td, J ) 15.7, 5.1 Hz, 1H), 3.06-2.98
(m, 2H), 2.86 (dd, J ) 15.7, 3.3 Hz, 1H); 13C NMR 196.9 (s),
154.1 (d), 129.0 (d), 127.1 (d), 127.0 (d), 125.6 (d), 98.5 (d), 56.6
(d), 49.6 (t), 44.0 (t), 30.3 (t); MS (EI) m/z 122 (43), 170 (47),
147 (15), 118 (28), 90 (20) 83 (100); IR (CDCl3) 3075, 3028,
2852, 1635, 1593, 1574, 1452, 1377, 1196 cm-1. Anal. Calcd
for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.20; H,
6.72; N, 7.10.
1-{[(3S)-3-tert-Butoxypyrrolidin-2-yl]methyl}cyclo-
propanol (22): pale yellow oil; method B, 90% yield; Rf ) 0.15
(AcOEt/CH3OH, 2:1 + 0.2% NH4OH). [R]20 ) +6.3 (CH2Cl2,
D
1
0.5); H NMR δ 4.05 (bs, 2H), 3.76 (dt, J ) 6.6, 3.6 Hz, 1H),
3.25 (dt, J ) 10.2, 3.6 Hz, 1H), 3.07 (ddd, J ) 11.7, 6.6, 5.6
Hz, 1H), 2.93 (ddd, J ) 11.7, 8.0, 5.6 Hz, 1H), 2.04 (tt, J )
8.0, 6.6 Hz, 1H), 1.84 (dd, J ) 13.2, 10.2 Hz, 1H), 1.63 (ddt, J
) 13.0, 5.6, 3.6 Hz, 1H), 1.22 (m, 1H), 1.13 (m, 9H), 0.69-0.58
(m, 2H), 0.35-0.29 (m, 2H); 13C NMR 73.6 (d), 68.8 (s), 65.9
(d), 55.7 (s), 44.1 (t), 37.9 (t), 34.6 (t), 28.5 (q, 3C), 12.9 (t),
12.5 (t); MS (EI) m/z (213 (3), 192 (17), 174 (19), 156 (15), 86
(17), 82 (10), 57 (100); IR (CDCl3) 3669, 3300-3200, 3083,
2976, 1630, 1462, 1434, 1364. Anal. Calcd for C12H23NO2: C,
67.57; H, 10.87; N, 6.57. Found: C, 67.66; H, 10.48; N, 6.29.
1-Methyl-2-phenyl-2,3-dihydropyridin-4(1H)-one (14):
1
orange oil; Rf ) 0.13 (AcOEt); H NMR δ 7.48-7.26 (m, 5H),
7.13 (d, J ) 7.3 Hz, 1H), 5.04 (d, J ) 7.3 Hz, 1H), 4.51 (dd, J
) 9.5, 7.3 Hz, 1H), 2.87 (dd, J ) 16.8, 7.3 Hz, 1H), 2.72 (dd, J
) 16.8, 9.5 Hz, 1H), 2.87 (s, 3H); 13C NMR 190.5 (s), 155.2 (d),
138.7 (s), 129.0 (d), 128.3 (d), 126.9 (d), 98.4 (d), 63.7 (d), 43.8
(q), 41.4 (t); MS (EI) m/z 187 (49), 159 (10), 144 (10), 104 (100),
82 (31), 77 (32), 55 (19); IR (CDCl3) 3068, 2810, 1633, 1592,
1582, 1455, 1421 cm-1. Anal. Calcd for C12H13NO: C, 76.98;
H, 7.00; N, 7.48. Found: C, 76.69; H, 7.29; N, 7.45.
1-{4-(Methylamino)-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydroquinolin-3-yl}cyclopropanol (24): colorless oil;
1
method B 95% yield; Rf ) 0.1 (CH2Cl2/CH3OH, 2:1); H NMR
(1S,8aR)-1-tert-Butoxy-2,3,8,8a-tetrahydroindolizin-
δ 7.96 (d, J ) 8.4 Hz, 1H), 7.50 (d, J ) 8.4 Hz, 2H), 7.37-7.27
(m, 1H), 7.23 (d, J ) 8.4 Hz, 1H), 7.15-7.07 (m, 1H), 7.07-
6.97 (m, 2H), 4.01-3.89 (m, 2H), 3.50 (d, J ) 3.0 Hz, 1H), 2.37
(s, 3H), 2.04 (s, 3H), 1.13 (ddd, J ) 12.1, 7.1, 3.0 Hz, 1H), 0.83-
0.68 (m, 2H), 0.40-0.22 (m, 2H); 13C NMR 144.0 (s), 135.3 (s),
134.5 (s), 131.1 (s), 129.7 (d), 128.8 (d), 128.7 (d), 127.0 (d),
125.5 (d), 124.4 (d), 60.9 (s), 56.7 (d), 44.4 (q), 43.6 (q), 34.1
(d), 21.5 (t), 13.2 (t), 11.9 (t); MS (EI) m/z 373 (2), 289 (11),
239 (13), 217 (20), 208 (8), 198 (9), 196 (100), 167 (10); IR
(CDCl3) 3688, 3547, 2980, 2950, 1599, 1486, 1171 cm-1. Anal.
Calcd for C20H24N2O2S: C, 64.49; H, 6.49; N, 7.52. Found: C,
64.30; H, 6.38; N, 7.75.
7(1H)-one (27): colorless oil; Rf ) 0.4 (CH2Cl2/CH3OH, 1:1 +
1
NH4OH 0.5%); [R]20 ) -28.3 (CH2Cl2, 0.5); H NMR δ 7.07
D
(d, J ) 7.0 Hz, 1H), 4.93 (d, J ) 7.0 Hz, 1H), 3.96 (q, J ) 7.3
Hz, 1H), 3.50 (m, 3H), 2.55 (dd, J ) 16.2, 5.1 Hz, 1H), 2.31 (t,
J ) 16.2 Hz, 1H), 2.25 (m, 1H), 1.90 (m, 1H), 1.18 (s, 9H); 13
C
NMR 191.8 (s), 150.2 (d), 97.6 (d), 76.6 (d), 74.0 (s), 62.1 (d),
47.3 (t), 39.5 (t), 33.3 (t), 28.4 (q); MS (EI) m/z 209 (24), 153
(11), 152 (72), 136 (12), 119 (19), 108 (100), 96 (11), 80 (11), 57
(41). IR (CDCl3) 2977, 2879, 2242, 1632, 1576, 1478, 1459,
1411, 1392, 1363, 1347 cm-1. Anal. Calcd for C12H19NO2: C,
68.87; H, 9.15; N, 6.69. Found: C, 68.57; H, 9.53; N, 6.42.
(4aRS,10bRS)-1-Methyl-6-[(4-methylphenyl)sulfonyl]-
4a,5,6,10b-tetrahydrobenzo[h]-1,6-naphthyridin-4(1H)-
one (28): yellow oil; Rf ) 0.16 (AcOEt/petroleum ether, 5:1);
1H NMR δ 7.79 (d, J ) 8.0 Hz, 1H), 7.61 (d, J ) 8.4 Hz, 1H),
7.40-7.30 (m, 1H), 7.26 (d, J ) 8.0 Hz, 1H), 7.18-7.08 (m,
1H), 7.05-6.97 (m, 3H), 6.28 (d, J ) 7.4 Hz, 1H), 4.92 (d, J )
7.4 Hz, 1H), 4.13-4.08 (m, 2H), 3.88 (dd, J ) 12.8, 8.0 Hz,
1H), 2.81 (td, J ) 12.8, 5.2 Hz, 1H), 2.63 (s, 3H), 2.41 (s, 3H);
Ethyl 3-(1-hydroxycyclopropyl)alaninate (26): colorless
oil; method A 100% yield; Rf ) 0.20 (AcOEt/petroleum ether,
1
1:5); H NMR δ 4.14 (q, J ) 7.1 Hz, 2H), 3.93-3.76 (m, 3H),
2.02 (dd, J ) 14.0, 9.6 Hz, 1H), 1.69 (dd, J ) 14.4, 3.3 Hz,
1H), 1.23 (t, J ) 7.1 Hz, 3H), 0.79-0.61 (m, 2H), 0.49-0.31
(m, 2H); 13C NMR 174.7 (s), 61.7 (t), 55.1 (s), 54.0 (d), 40.2 (t),
14.1 (q), 13.5 (t), 12.6 (t);. MS m/e (rel intensity) 174 (25), 102
J. Org. Chem, Vol. 70, No. 14, 2005 5641

Revuelta et al.
13C NMR: 189.7 (s), 153.0 (d), 143.9 (s), 137.4 (s), 136.1 (s),
129.7 (d, 2C), 129.4 (d), 128.1 (d), 127.2 (d, 2C), 125.4 (s), 124.7
(d), 124.5(d), 98.0 (d), 58.7 (d), 44.6 (q), 43.5 (t), 41.2 (d), 21.5
(q); MS (EI) m/z 368 (10), 213 (8), 215 (100), 195 (13), 156 (12),
130 (70), 128 (22), 91 (24), 85 (15), 84 (21), 83 (46), 77 (14), 65
(15); IR (CDCl3) 3100, 2926, 1642, 1583, 1488, 1420, 1326, 1168
cm-1. Anal. Calcd for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60.
Found: C, 65.35; H, 5.30; N, 7.65.
(0.05 mmol), Cu(OAc)2 (1.0 mmol), and LiOAc (1.5 mmol) in
DMF (5 Ml) was stirred and heated at 100 °C for 3 h. The
suspension was then filtered and concentrated and the residue
purified by flash column chromatography.
General Procedure for the Synthesis of Tetrahydro-
pyridones Using Pd(dba)2. A solution of the â-aminocyclo-
propanol (0.5 mmol) and Pd(dba)2 (0.05 mmol) in anhydrous
CH3CN was heated at 50 °C for 20 h. The solution was
concentrated and purified by flash column chromatography.
1,3,4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-
2-one (13a): white solid; Rf ) 0.33 (AcOt/petroleum ether, 5:1);
mp ) 92 °C; 1H NMR δ 7.23-7.03 (m, 4H), 3.59 (dd, J ) 11.5,
4.4 Hz, 1H), 3.39-3.29 (m, 10H); 13C NMR 208.6 (s), 136.7 (s),
134.0 (s), 129.0 (d), 126.6 (d), 126.2 (d), 124.8 (d), 61.2 (t), 54.8
(d), 50.4 (t), 47.3 (t), 41.1 (t), 29.7 (t); MS (EI) m/z 201 (59),
158 (29), 130 (65), 115 (18), 104 (10), 86 (35), 83 (100); IR
(CDCl3) 3053, 3020, 2952, 2930, 1708 cm-1. Anal. Calcd for
C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.19; H, 7.43;
N, 6.61.
Ethyl 4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate
1
(29): colorless oil; Rf ) 0.20 (AcOEt/petroleum ether, 1:5); H
NMR δ 7.23 (d, J ) 7.3 Hz, 1H), 5.09 (d, J ) 7.3 Hz, 1H), 4.38
(dd, J ) 6.6, 1.5 Hz, 1H), 4.27 (q, J ) 7.3 Hz, 2H), 2.80-2.72
(m, 2H), 1.29 (t, J ) 7.3 Hz, 3H); 13C NMR 199.3 (s), 172.4 (s),
153.5 (d), 99.1 (d), 61.3 (t), 58.0 (d), 40.0 (t), 14.1 (q); MS (EI)
m/z 169 (24), 97 (12), 96 (100), 86 (12), 84 (16), 68 (27), 55
(26); IR (CDCl3) 3436, 2928, 2245, 1737, 1643, 1594, 1494,
1392, 1374, 1260 cm-1. Anal. Calcd for C8H11NO3: C, 56.80;
H, 6.55; N, 8.28. Found: C, 56.97; H, 6.43; N, 8.25.
Ethyl
2-{[(benzyloxy)carbonyl]amino}-4-oxohex-5-
enoate (32): yellow oil; Rf ) 0.70 (AcOEt/petroleum ether, 3:7);
1H NMR δ 7.42-7.25 (m, 5H), 6.28 (m, 2H), 5.92 (dd, J ) 8.8,
2.2 Hz, 1H), 5.8 (sd, J ) 8.0 Hz, 1H), 5.11 (s, AB system, 2H),
4.62 (dt, J ) 8.8, 4.2 Hz, 1H), 4.19 (q, J ) 7.3 Hz, 2H), 3.38
(system ABX, part A), 3.15 (system ABX, part B), 1.23 (t, J )
7.3 Hz, 3H); 13C NMR 207.9 (s), 171.1 (s), 151.4 (s), 136.5 (d),
129.6 (s), 128.6 (s), 128.5 (t), 128.3 (d), 128.0 (s), 67.0 (t), 61.9
(t), 49.8 (d), 41.5 (t), 14.2 (q); MS (EI) m/z 304 (M - 1) (0.2),
199 (2.25), 107 (4), 91 (100) 65 (16); IR (CDCl3) 3435, 2984,
2961, 2257, 1785, 1720, 1682, 1615, 1507, 1465, 1296, 1209,
1035 cm-1. Anal. Calcd for C8H11NO3: C, 56.80; H, 6.55; N,
8.28. Found: C, 56.37; H, 6.64; N, 8.53.
14a: see ref 11.
27a: see ref 13.
Acknowledgment. We are grateful to Ente Cassa
di Risparmio di Firenze, Firenze, Italy, for granting a
400-MHz NMR spectrometer to the Department of
Organic Chemistry. Mrs. Brunella Innocenti and Mr.
Maurizio Passaponti are acknowledged for technical
assistance.
Supporting Information Available: General experimen-
tal methods and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
General Procedure for the Synthesis of Tetrahydro-
pyridones Using Cu(OAc)2 as Stoichiometric Oxidant.
A suspension of the â-aminocyclopropanol (0.5 mmol), Pd(OAc)2
JO050640Q
5642 J. Org. Chem., Vol. 70, No. 14, 2005