Domino Palladium(II)-Mediated Rearrangement-Oxidative Cyclization of β-Aminocyclopropanols

Article abstract of DOI:10.1055/s-2003-42122

β-Aminocyclopropanols were transformed, in a domino process catalyzed by Pd(II) salts, into the corresponding 2,3-dihydro-1H-pyridin-4-ones. Conversely the use of a Pd(0) derivative, Pd(dba)₂, afforded the corresponding tetrahydropyrid-4-ones. The saturated derivatives were also obtained, in better yields, using Pd(II) and Cu(OAc)₂ as stoichiometric oxidant.

Full text of DOI:10.1055/s-2003-42122

LETTER
2305
Domino Palladium(II)-Mediated Rearrangement-Oxidative Cyclization of
b-Aminocyclopropanols
C
yclizationof
t
b
-Ami
e
nocyclopro
f
panols ano Cicchi, Julia Revuelta, Alessandra Zanobini, Matteo Betti, Alberto Brandi*
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita` di Firenze and Istituto di Chimica dei Composti Organo Metallici-
ICCOM-CNR, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573572; E-mail: alberto.brandi@unifi.it
Received 9 September 2003
Dedicated to Professor Francesco De Sarlo on the occasion of his 65th birthday.
O
OH
Abstract: b-Aminocyclopropanols were transformed, in a domino
process catalyzed by Pd(II) salts, into the corresponding 2,3-dihy-
dro-1H-pyridin-4-ones. Conversely the use of a Pd(0) derivative,
Pd(dba)2, afforded the corresponding tetrahydropyrid-4-ones. The
saturated derivatives were also obtained, in better yields, using
Pd(II) and Cu(OAc)2 as stoichiometric oxidant.
R1
R2
Pd(dba)2
R1
R2
or Pd(AcO)2
4
3
R
R
O
R
O
Key words: domino reactions, palladium, Wacker reactions, het-
erocycles, catalysis
[Pd]
NH OH
NH
N
R1
R1
R1
5
6
2
Scheme 2
The reactivity of small ring derivatives has become a fun-
damental resource for organic chemists for the develop-
ment of new synthetic tools and methods.1,2 The ring
strain that characterizes these compounds is responsible
for their reactivity which is often triggered off by a simple
thermal treatment3 or induced by the action of other re-
agents.1,4 The rearrangement of 5-spirocyclopropane isox-
azolidines,5,6 extensively studied by our group,3a,7 is an
example of a useful thermal domino transformation of cy-
clopropanes leading to mono- and polycyclic tetrahydro-
pyridones (Scheme 1).
In this work we present our results on the reactivity of b-
aminocyclopropanols mediated by Pd, and the discovery
of a novel domino process mediated by Pd(II) in which the
intermediate enone undergoes nucleophilic amination
with a process closely related to the Wacker oxidation.11
One of the possible approaches to b-aminocyclo-
propanols12 is the reduction of the N–O bond in 5-spirocy-
clopropaneisoxazolidines 1 obtained through 1,3-dipolar
cycloaddition of nitrones with methylenecyclopropane.3
The N–O bond of simple isoxazolidines can be easily
reduced by several reagents.13 However, the presence of
the cyclopropyl moiety renders the final product very re-
active, apart from the possible hydrogenation of the
cyclopropane ring. The reduction of 714 (Scheme 3) with
Mo(CO)613,15 afforded a complex mixture of compounds,
as well as with Pd/C16 and H2, although this latter reduc-
tion method was already used in the presence of a cyclo-
propanol moiety.17 Also indium was tested with no
success.18 Only Pd(OH)2/C and H2 afforded the expected
amino alcohol 8 in good yield (70%) and purity. The same
reaction conditions gave the amino alcohol 10 in 67%
yield from 919 (Scheme 3). This synthesis of b-amino-
cyclopropanols appears very straightforward, quite gener-
al, and valuable, considering also that the Kulinkovich
reaction,12 the best method for the synthesis of cyclo-
propanols, has been rarely applied to b-amino acids.20
R1
N
R
R
O
R
O
∆
+
R1 N
N
R1
O
2
1
Scheme 1
Recently, cyclopropanols 3 have been reported to undergo
ring cleavage with the formation of unsaturated ketones 4
mediated by Pd(II)8 or Pd(0)9 catalysts (Scheme 2). This
transformation is synthetically useful and it is predictable
that properly substituted substrates may undergo intramo-
lecular reaction profiting from the conjugated double
bond electrophilicity. For example, b-aminocyclopro-
panol 5 might afford a tetrahydropyridone derivative 2 by
an intramolecular Michael reaction of the intermediate
a,b-unsaturated ketone 6 (Scheme 2).10
The reactivity of aminocyclopropanols under the catalysis
of Pd(OAc)2 (10 mol%) was then studied (Table 1). By
using the reaction conditions previously reported in the
literature for Pd(II) salts, pyridine as the base, atmospher-
ic O2 as stoichiometric oxidant and toluene as solvent,8
amino alcohol 8 gave exclusively the dihydropyridone 11,
whereas amino alcohol 10 gave a mixture of the unsatur-
ated compound 13 and the saturated 14 in 1:1.5 ratio,
SYNLETT 2003, No. 15, pp 2305–2308
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42122; Art ID: G23403ST
© Georg Thieme Verlag Stuttgart · New York

2306
S. Cicchi et al.
LETTER
The =CH protons a to nitrogen resonate downfield (7.13
ppm, d, J = 7.3 Hz for 11), as well as the corresponding
carbon nuclei (155.2 and 154.1 ppm for 11 and 13, respec-
tively) in the NMR spectra. Conversely, the =CH protons
b to nitrogen resonate at 5.06 (d, J = 7.3 Hz) and 5.10 ppm
(d, J = 7.3 Hz) for compounds 11 and 13, respectively.
The corresponding carbon nuclei resonate at 98.4 ppm for
both 11 and 13. The use of PdCl2 (Table 1, entries 3, 4, 9)
did not appreciably improve the overall yield and selectiv-
ity of the reaction. The only remarkable difference was the
selective formation of 13 (50% yield) using pyridine as a
base (see entry 9 and compare with entry 7). Longer reac-
tion times, 12 h, (Table 1 entries 3 and 9) were necessary
for PdCl2, compared with reaction times of 3 h for
Pd(OAc)2. To optimize the reaction conditions, other sto-
ichiometric oxidants were tested.
Pd(OH)2/C
H2
NH OH
7
70%
8
N
O
Pd(OH)2/C
H2
NH
N
O
OH
10
67%
9
Scheme 3
respectively (see Figure 1 and Table 1, entries 1 and 7).
Remarkably the selectivity of the second reaction was im-
proved on changing the base from pyridine to DIPEA af-
fording only the unsaturated derivative 13, albeit in 40%
yield (Table 1, entry 8). The unexpected structures of 11
and 13 were easily assigned on the basis of the spectro-
scopic data, since the less substituted enaminone moiety
presents a characteristic array of signals related to the
double bond.
The use of quinone oxidants led to complex reaction mix-
tures. In analogy to the Wacker oxidation, Cu(OAc)2 was
used as a stoichiometric oxidant. The reaction was per-
formed in DMF using 10% of Pd(OAc)2 and 2 equivalents
of Cu(OAc)2 together with LiOAc as the base. The new
reaction conditions changed the outcome of the reaction
completely. Amino alcohol 8 afforded exclusively the sat-
urated tetrahydropyridone 12, whereas amino alcohol 10
afforded again the mixture of 13 and 14, but in a 1:5 ratio
(Table 1, entries 5 and 10). The presence of Cu(OAc)2,
therefore, altered the catalytic cycle of Pd(OAc)2 afford-
ing new products. Finally, g-amino alcohols 8 and 10 were
treated with Pd(dba)2 as catalyst, following the reaction
conditions reported.9 Again the main products were the
saturated ones, although the yield of 12 was consistently
poorer than with the Pd(II)/Cu(II) couple (Table 1, entries
6 and 11).
N
O
N
O
11
12
N
O
N
O
13
Figure 1
14
The different results obtained raise the question about
the nature of the catalytic process able to justify the for-
mation of tetrahydropyridones, and the unexpected
Table 1 Reactivity of b-Aminocyclopropanols with Pd Catalysts
Entry
Alcohol
Catalyst (0.1 equiv) Base
Oxidant
O2
Product
Yield (%)
1
2
8
8
Pd(OAc)2
Pd(OAc)2
PdCl2
Py
11
65
10
59
10
70
30
87
40
50
75
90
DIPEA
Py
O2
11
3
8
O2
11
4
8
PdCl2
DIPEA
LiOAc
O2
11
5
8
Pd(OAc)2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2
12
6
8
12
7
10
10
10
10
10
Py
O2
13/14 (1:1.5)
13
8
DIPEA
Py
O2
9
O2
13
10
11
Pd(OAc)2
Pd(dba)2
LiOAc
Cu(OAc)2
13/14 (1:5)
13/14 (1:5)
Synlett 2003, No. 15, 2305–2308 © Thieme Stuttgart · New York

LETTER
Cyclization of b-Aminocyclopropanols
2307
dihydropyridones, as well as the influence of the copper Another possible mechanism of our process could be sug-
salts on the selectivity. Whereas the behaviour of Pd(0) is gested in analogy to the palladium(II)-catalyzed dehy-
in line with the expected reactivity, i.e. the in situ formed drosilylation of silyl enol ethers.23 In fact, Pd(II)-
a,b-unsaturated ketone undergoes the expected domino catalyzed 1,4-addition of the amine, could give rise to the
intramolecular Michael addition to form the tetrahydropy- formation of a palladium-enolate 20, or an oxo-p-allyl-
ridone, a different catalytic process of Pd(II) must be at palladium(II) complex 21,24 which gives the enaminone
work to rationalize the formation of the dihydropyridones. by HPdX elimination (Scheme 6).
R
N
O
O
R
O
PdX2
– HX
R1
Pd(II)
Base
L
R1
R1
O PdX
N
R1
R
N
R1
R
NH
R1
15
16
20
Scheme 4
R
N
H
R
R1
O
– HPdX
R1
N
O
The dehydrogenation of b-amino ketones (Scheme 4),
documented by Murahashi,21 should be excluded in our
case, because tetrahydropyridones failed to undergo dehy-
drogenation in Murahashi’s work. On the other hand, the
complete regioselectivity observed in our process, leading
to the less substituted double bond, seems very unlikely in
the case of a dehydrogenation of a formed tetrahydropyri-
done. In fact, compound 14, subjected to the same reac-
tion conditions, was not converted into 13.
L
Pd
X
21
17
Scheme 6
The different behavior when Pd(0) is used as a catalyst is
well accounted for by both mechanisms that are proposed.
Pd(0) can not undergo the Wacker oxidation, and its lower
Lewis acidic character allows the uncatalyzed aza-Micha-
el addition to occur. Copper acetate, finally, can easily
catalyze the aza-Michael addition, overwhelming the role
of Pd(II) for the much higher molar ratio, and probably
making this mechanism the only one working in that case.
R
R
O
PdII
R1 NH
HO
NH
R1
ref. 5
6
R
O
We have described a new domino process, which converts
b-aminocyclopropanols selectively into valuable dihydro-
and tetrahydropyridones. The method complements the
known thermal rearrangement of 5-spirocyclopropane-
annelated isoxazolidines and isoxazolines.7 The synthesis
of the dihydropyridones is noteworthy since it is an exam-
ple of catalytic oxidative addition of a non-aromatic
amine to an olefin.11,25 This process, due to the catalyst
poisoning activity of amines, has few precedents in the lit-
erature.26 The further application and mechanistic evalua-
tion of this process are in progress in our laboratory.
NH
PdII
R1
PdII
18
O2
R
N
Pd(0)
R1
O
R
PdII
19
R1
N
O
17
General Procedure for the Synthesis of Compounds 11 and 13:
A suspension of the b-aminocyclopropanol (0.5 mmol), Pd(II) cat-
alyst (0.05 mmol), base (1.5 mmol) and dry molecular sieves (200
mg) in toluene (5 mL) was stirred and heated at 80 °C for 3 h while
bubbling dry air through it. The suspension was then filtered, con-
centrated and the residue purified by flash column chromatography.
Scheme 5
The observed process appears to resemble the Wacker ox-
idation of a,b-unsaturated esters.10,11,22 Once the rear-
rangement to vinylketone 6 has occurred, the regenerated
Pd(II) could give the palladium-complexed alkene 18,
which rapidly evolves to 19, the precursor of enaminone
17 by b-hydride elimination (Scheme 5).
A similar process was suggested by Spencer,10 however,
in his case it led to the protonolysis of the intermediate
palladium species and formation of the saturated com-
pounds. The nature of the palladium(II) catalyst and the
absence of the stoichiometric oxidant might be responsi-
ble for the different outcome.
1-Methyl-2-phenyl-2,3-dihydro-1H-pyridin-4-one (11). Rf 0.13
(EtOAc). IR (CDCl3): 3068, 2810, 1633, 1592, 1582, 1455, 1421
cm–1. 1H NMR (CDCl3): d = 7.48–7.26 (m, 5 H), 7.13 (d, J = 7.3 Hz,
1 H), 5.06 (d, J = 7.3 Hz, 1 H), 4.51 (dd, J = 9.5, 7.3 Hz, 1 H), 2.93–
2.81 (dd, J = 16.8, 7.3 Hz, 1 H), 2.72 (dd, J = 16.8, 9.5 Hz, 1 H),
2.87 (s, 3 H). 13C NMR (CDCl3): d = 190.5 (s), 155.2 (d), 138.7 (s),
129.0 (d, 2 C), 128.3 (d), 126.9 (d, 2 C), 98.4 (d), 63.7 (d), 43.8 (q),
41.4 (t). MS: m/z = 187 (49) [M+], 159 (10), 144 (10), 104 (100), 82
(31), 77 (32), 55 (19). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00;
N, 7.48. Found: C, 76.90; H, 7.35; N, 7.56.
5,6-Dihydro-4aH-pyrido[1,2-a]quinolin-2-one (13). Rf 0.18 (Pe-
troleum ether– EtOAc, 1:5). IR (CDCl3): 3072, 3028, 2852, 1635,
1
1593, 1574, 1452, 1377, 1196 cm–1. H NMR (CDCl3): d = 7.20–
7.00 (m, 5 H), 5.10 (d, J = 7.3 Hz, 1 H), 4.79 (dd, J = 15.7, 4.0 Hz,
Synlett 2003, No. 15, 2305–2308 © Thieme Stuttgart · New York

2308
S. Cicchi et al.
LETTER
1 H), 3.69–3.53 (m, 1 H), 3.46 (td, J = 11.7, 3.3 Hz, 1 H), 3.19 (td,
J = 15.7, 5.1 Hz, 1 H), 3.06–2.90 (m, 2 H), 2.86 (dd, J = 15.7, 3.3
Hz, 1 H). 13C NMR (CDCl3): d = 196.9 (s), 154.1 (d), 139.8 (s),
136.6 (s), 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). Anal. Calcd for C13H13NO: C, 78.36;
H, 6.58; N, 7.03. Found: C, 78.50; H, 6.35; N, 7.26.
(5) Ochoa, E.; Mann, M.; Sperling, D.; Fabian, J. Eur. J. Org.
Chem. 2001, 4223.
(6) Hassner, A.; Stumer, C. Organic Synthesis Based on Name
Reactions, Tetrahedron Organic Chemistry Series, 22, 2nd
ed.; Pergamon: Oxford, UK, 2002, 42.
(7) (a) Brandi, A.; Cordero, F. M.; De Sarlo, F.; Goti, A.;
Guarna, A. Synlett 1993, 1. (b) Goti, A.; Cordero, F. M.;
Brandi, A. Top. Curr. Chem. 1996, 178, 1.
(8) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147.
(9) Okumoto, H.; Jinnai, T.; Shimizu, H.; Harada, Y.; Mishima,
H.; Suzuki, A. Synlett 2000, 629.
(10) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
(11) Tsuji, J. Palladium Reagents and Catalysts; John Wiley &
Sons: Chichester, 1995, Chap. 3.
(12) (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000,
100, 2789. (b) Gibson, D. H.; DePuy, C. H. Chem. Rev.
1974, 74, 605.
(13) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351; and references cited
therein.
General Procedure for the Synthesis of Compounds 12 and 14
using Cu(OAc)2 as Stoichiometric Oxidant:
A suspension of the b-aminocyclopropanol (0.5 mmol), Pd(AcO)2
(0.05 mmol), Cu(AcO)2 (1 mmol), LiAcO (1.5 mmol) and dry mo-
lecular sieves (200 mg) in DMF (5 mL) was stirred and heated at
100 °C for 3 h. The suspension was then filtered, concentrated and
the residue purified by flash column chromatography.
General Procedure for the Synthesis of Compounds 12 and 14
using Pd(dba)2:
A solution of the b-aminocyclopropanol (0.5 mmol) and Pd(dba)2
(0.05 mmol) in anhyd CH3CN was heated at 50 °C for 20 h. The so-
lution was concentrated and purified by flash column chromatogra-
phy.
(14) Brandi, A.; Garro, S.; Guarna, A.; Goti, A.; Cordero, F.; De
Sarlo, F. J. Org. Chem. 1988, 53, 2430.
(15) Guarna, A.; Guidi, A.; Goti, A.; Brandi, A.; De Sarlo, F.
Synthesis 1989, 175.
(16) Brueckner, C.; Reissig, H.-U. Chem. Ber. 1987, 120, 617.
(17) (a) Wessjohann, L.; Krass, N.; Yu, D.; de Meijere, A. Chem.
Ber. 1992, 125, 867. (b) Pansare, S. V.; Jain, R. P.
Tetrahedron Lett. 1999, 40, 2625.
(18) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A.
Org. Lett. 2003, 5, 1773.
1-Methyl-2-phenyl-piperidin-4-one (12). See: Brandi A., Garro
S., Guarna A., Goti A., Cordero F., De Sarlo F.; J. Org. Chem.;
1988, 53: 2430
4,4a,5,6-Tetrahydro-3H-pyrido[1,2-a]quinolin-2-one (14): Rf
(Petroleum ether–EtOAc, 1:5) = 0.33; mp = 92 °C. 1H NMR
(CDCl3): d = 7.23–7.03 (m, 4 H), 3.59 (dd, J = 11.5, 4.4 Hz, 1 H),
3.39–2.29 (m, 10 H). 13C NMR (CDCl3): d = 208.6 (s), 136.7 (s),
134.0 (s), 129.0 (d), 126.6 (d), 126.2 (d), 124.8 (d), 61.7 (t), 54.8 (d),
50.4 (t), 47.3 (t), 41.1 (t), 29.7 (t). Anal. Calcd for C13H15NO: C,
77.58; H, 7.51; N, 6.96. Found: C, 77.29; H, 7.43; N, 6.61.
(19) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025.
(20) (a) Esposito, A.; Taddei, M. J. Org. Chem. 2000, 65, 9245.
(b) Okamoto, S.; Iwakubo, M.; Kobayashi, K.; Sato, F. J.
Am. Chem. Soc. 1997, 119, 6984.
Acknowledgment
We thank the European Community, Brussells, Project INTAS-
2000-0549.
(21) Murahashi, S.-I.; Mitsue, Y.; Tsumiyama, T. Bull. Chem.
Soc. Jpn. 1987, 60, 3285.
(22) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257.
(23) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011. (b) Suzuki, H.; Yamazaki, N.; Kibayashi, C. J. Org.
Chem. 2001, 66, 1494. (c) Hogenauer, K.; Mulzer, J. J. Org.
Lett. 2001, 3, 1495. (d) Larock, R. C.; Hightower, T. R.;
Kraus, G. A.; Pat, H.; Zheng, D. Tetrahedron Lett. 1995, 36,
2423.
(24) Murahashi, S.-I.; Mitsue, Y.; Tsumiyama, T. J. Organomet.
Chem. 1973, 52, C58.
(25) Hegedus, L. S. In Organometallics in Synthesis; Schlosser,
M., Ed.; Wiley: Chichester, 2002, 1137.
References
(1) Houben–Weyl, Methods of Organic Chemistry, Carbocyclic
Three-Membered Ring Compounds, Vol. E1; de Meijere, A.,
Ed.; Thieme: Stuttgart, 1997.
(2) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
(3) (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
Rev. 2003, 103, 1213. (b) Baldwin, J. E. Chem. Rev. 2003,
103, 1197.
(4) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(26) Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem.
1992, 57, 2575.
Synlett 2003, No. 15, 2305–2308 © Thieme Stuttgart · New York