Diastereoselective synthesis of hexahydro-3H-pyrrolyzin-3-ones through Pd-catalyzed carboamination

Article abstract of DOI:10.1021/jo1002032

Chemical Equation Presented The reaction of readily available (5R)-5-but-3-en-1-ylpyrrolidin-2-one with aryl bromides, chlorides, or triflates in the presence of Pd₂(dba)₃, Xphos, and Cs ₂CO₃ in 1,4-dioxane at 120^°C affords (5R,7aR)-5-aryl hexahydropyrrolizidin-3-ones in good to high yields through a diastereoselective carboamination reaction. Aryl iodides are less successful substrates than bromides and chlorides.

Full text of DOI:10.1021/jo1002032

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preparation of this class of compounds have been described
Diastereoselective Synthesis of Hexahydro-3H-
pyrrolyzin-3-ones through Pd-Catalyzed
Carboamination
in the literature.2c,d,6 However, although palladium catalysis
proved to be a powerful and versatile tool for the construc-
tion of heterocyclic rings, no examples of construction of the
hexahydropyrrolidizinone system through palladium-cata-
lyzed synthesis have been reported.
Herein we report that (5R,7aR)-5-aryl hexahydropyrroli-
zidin-3-ones 3 can be prepared through a diastereoselective
palladium-catalyzed carboamination of (5R)-5-but-3-en-1-
ylpyrrolidin-2-one 1 with aryl halides (Scheme 1).
Luana Bagnoli,† Sandro Cacchi,*,‡ Giancarlo Fabrizi,‡
Antonella Goggiamani,‡ Catalina Scarponi,† and
Marcello Tiecco†
†Dipartimento di Chimica e Tecnologia del Farmaco, Sezione
di Chimica Organica, Universitaꢀ di Perugia, 06123 Perugia,
Italy, and ‡Dipartimento di Chimica e Tecnologie del
Farmaco, La Sapienza, Universitaꢀ di Roma, P. le A. Moro 5,
00185 Rome, Italy
SCHEME 1. Synthesis of (5R,7aR)-5-Aryl Hexahydropyrroli-
zidin-3-ones 3 from (5R)-5-But-3-en-1-ylpyrrolidin-2-one 1 and
Aryl Halides
sandro.cacchi@uniroma1.it
Received February 11, 2010
Compound 1 was readily prepared as described pre-
viously7 from the commercially available (5R)-5-(hydroxy-
methyl)pyrrolidin-2-one through its conversion into the
corresponding tosyl derivative followed by a nucleophilic
substitution step with allylmagnesium bromide.
We initiated our study by examining the influence of
ligands, bases, and solvents for the reaction of 1 with 4-
bromobiphenyl 2a in the presence of 2.5 mol % of Pd2(dba)3
at 120 °C. The results of the optimization studies are sum-
marized in Table 1. After an initial screen of ligands
(Xantphos, Xphos, Sphos;8 0.05 equiv), bases (NaOBu-t,
Cs2CO3; 1.5 equiv), and solvents (toluene, 1,4-dioxane; 4 mL)
The reaction of readily available (5R)-5-but-3-en-1-ylpyr-
rolidin-2-one with aryl bromides, chlorides, or triflates in
the presence of Pd2(dba)3, Xphos, and Cs2CO3 in 1,4-
dioxane at 120 °C affords (5R,7aR)-5-aryl hexahydropyr-
rolizidin-3-ones in good to high yields through a diaster-
eoselective carboamination reaction. Aryl iodides are less
successful substrates than bromides and chlorides.
The hexahydropyrrolizine motif is abundant in many
biologically active compounds.1 For example, hexahydro-
pyrrolizine derivatives have been shown to possess interesting
properties as glycosidase inhibitors,2 nonopiate antinociceptive
agents,3 histaminic H1 and H3 antagonists,4 and antibacterial
agents.5 Because of this, several synthetic approaches to the
(6) (a) Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem. 1991, 56,
1393. (b) Murray, A.; Proctor, G. R. Tetrahedron Lett. 1995, 36, 291.
(c) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802. (d) Bowman,
W. R.; Broadhurst, M. J.; Coghlan, D. R.; Lewis, K. A. Tetrahedron Lett.
1997, 38, 6301. (e) Park, S. H.; Kang, H. J.; Ko, S.; Park, S.; Chang, S.
Tetrahedron: Asymmetry 2001, 12, 2621. (f) Coldham, J.; Hufton, R.; Price,
K. N.; Rathmell, R. E.; Snowden, D. J.; Vennal, G. P. Synthesis 2001, 1523.
(1) For recent reviews, see: (a) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J Tetrahedron: Asymmetry 2000, 11, 1645. (b) Watson, A. A.;
Fleet, G: W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001,
56, 265.
ꢀ
(g) Roche, C.; Kadlecikova, K.; Veyron, A.; Delair, P.; Philouze, C.; Greene,
A. E. J. Org. Chem. 2005, 70, 8352. (h) Smith, A. B. III; Kim, D. S. J. Org.
Chem. 2006, 71, 2547. (i) Quiroz, T.; Corona, D.; Covarruvias, A.; Avila-Zarraga,
J. G.; Romero-Ortega, M. Tetrahedron Lett. 2007, 48, 1571 and references cited
(2) For selected references, see: (a) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu,
H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet,
G. W. J. Tetrahedron Asymmetry 2000, 11, 1. (b) Yamashita, T; Yasuda, K.;
Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano,
N. J. Nat. Prod. 2002, 65, 1875. (c) Kato, A.; Kano, E.; Adachi, I.; Molyneux,
R. J.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.;
Ikeda, K.; Asano, N. Tetrahedron: Asymmetry 2003, 14, 325. (d) Cardona,
F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44,
2315. (e) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71,
1614.
(3) Carson, J. R.; Carmosin, R. J.; Vaught, J. L.; Gardocki, J. F.;
Costanzo, M. J.; Raffa, R. B.; Almond, H. R. J. Med. Chem. 1992, 35, 2855.
(4) Apodaca, R.; Carruthers, N. I.; Carson, J. R.; Chai, W.; Kwok, A. K.;
Li, X.; Lovenberg, T. W.; Rudolph, D. A.; Shah, C. R. WO 2001-US29624
20010921; Chem. Abstr. 2001, 136, 263105.
ꢀ
therein. (j) Quinet, C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Marko, I. E.
ꢀ
Tetrahedron 2008, 64, 1077. (k) Quinet, C.; Ates, A.; Marko, I. E. Tetrahedron
Lett. 2008, 49, 5032. (l) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby,
C. L.; Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615. (m) Zimmer, R.; Collas,
M.; Czerwonka, R.; Hain, U.; Reissig, H.-U. Synthesis 2008, 237.
(7) Compound 1 has been converted into an approximately 70:30 diaster-
eoisomeric separable mixture of 5-[(phenylseleno)methyl]hexahydro-3H-
pyrrolizin-3-ones through 5-exo-trig electrophilic selenocyclization with
N-(phenylseleno)phthalimide: (a) Tiecco, M.; Testaferri, L.; Bagnoli, L.;
Scarponi, C. Tetrahedron: Asymmetry 2008, 19, 2411. See also: (b) Occhiato,
E. G.; Brandi, C.; Ferrari, A.; Guarna, A. J. Org. Chem. 2005, 70, 4542.
(8) Davephos = 2-(20-N,N-dimethylaminobiphenyl)dicyclohexylphosphine;
Sphos = 2-(20,60-dimethoxybiphenyl)dicyclohexylphosphine; Xantphos = 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene; Xphos = 2-(20,40,60-triisopropyl-
biphenyl)dicyclohexylphosphine.
(5) Nash, R. J.; Wolferstan, P.; Fleet, G. W. J.; Van Ameijde, J.; Horne,
G. WO 2004-GB4624 20041103; Chem. Abstr. 2004, 142, 487686.
2134 J. Org. Chem. 2010, 75, 2134–2137
Published on Web 02/19/2010
DOI: 10.1021/jo1002032
r
2010 American Chemical Society

Bagnoli et al.
JOCNote
TABLE 1. Optimization Studiesa
TABLE 2. Synthesis of 5-Aryl Hexahydropyrrolizidin-3-ones 3a
yield (%)
of 3a
entry
ligand
base
solvent
time (h)
1
2
3
4
5
6
7
8
9
Xantphos NaOBu-t toluene
24
21
24
21
8
Xphos
Xphos
Sphos
Xphos
Xphos
Xphos
Xphos
NaOBu-t toluene
Cs2CO3 1,4-dioxane
NaOBu-t 1,4-dioxane
34
34
24
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
1,4-dioxane
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
55b
53c
34c
53c
23c
60c,d
51c,d
65b,d
8
6
21
20
4
22
3
Davephos Cs2CO3
10
12
13
Xphos
Xphos
Xphos
Cs2CO3
K3PO4
Cs2CO3
aUnless otherwise stated, reactions were carried out at 120 °C in a 0.075 M
solution, under an argon atmosphere, using 1 equiv of 2a, 1.5 equiv of 1,
1.2 equiv of base, 0.025 equiv of Pd2(dba)3, 0.05 equiv of ligand. bIn a
0.03 M solution. cIn a 0.02 M solution. dWith 0.1 equiv of Xphos.
(Table 1, entries 1-4), we found that the use of Xphos and
Cs2CO3, in 10 mL of 1,4-dioxane produced 3a diastereoselec-
tively after 8 h in 55% yield (Table 1, entry 5). Further dilution
of the reaction mixture (15 mL) did not give better results
(Table 1, entries 6-9), whereas an increase of the Xphos to Pd
ratio (2:1) enhanced the yield of 3a to 60% (Table 1, entry 10).
The best result (65% yield) was obtained by using 0.1 equiv of
Xphos in 10 mL of 1,4-dioxane (Table 1, entry 13). The main
side products observed were 4a and 5a (Ar = 4-PhC6H4).
The cis fusion of the bicyclic system was established on the
basis of the chemical shift values of the proton and the
carbon-13 at the 7a position7,9 and the relative configuration
of the C(5) was assigned by NOESY experiments.10 The
configuration of the C(7a) was stable under reaction condi-
tions. This was established by HPLC analysis on a chiral
column Chiracel OD-H, which showed that 3c, the product
obtained via the reaction of 4-chloroanisole with (5R)-5-but-
3-en-1-ylpyrrolidin-2-one (76% yield, see Table 2, entry 7), is
enantiomerically pure and that the reaction of 4-chloroani-
sole with (5S)-5-but-3-en-1-ylpyrrolidin-2-one ent-1 affords
stereoselectively ent-3c (75% yield). Combining these data,
we assigned the (5R,7aR) configuration to the stereogenic
centers of 3a and 3c. The stereochemistry of all the other
5-aryl hexahydropyrrolizidin-3-ones prepared (vide infra)
has been assigned on the basis of these data.
aReactions were carried out at 120 °C in 10 mL of 1,4-dioxane, under
an argon atmosphere, in a 0.03 M solution, using 1 equiv of 2, 1.2 equiv
of 1, 1.5 equiv of Cs2CO3, 0.025 equiv of Pd2(dba)3, 0.1 equiv of Xphos.
c
b6b was isolated in 10% yield. 6b was isolated in 15% yield. d6b was
isolated in 45% yield. e6f (Ar = 2-MeC6H4) was isolated in 40% yield.
substitution derivatives as shown by the increase of the yield
of 6b (Ar = 3-MeOC6H4) on going from 3-chloroanisole
(10% yield) to 3-bromoanisole (15% yield) to 3-iodoanisole
(45% yield) (Table 2, entries 4-6). Only with ortho-sub-
stituted aryl halides were the corresponding hexahydropyr-
rolizidin-3-ones isolated in moderate yields (Table 2, entries
11 and 16), most probably because of steric effects.
The mechanism of this reaction is most probably analo-
gous to that previously described for related palladium-
catalyzed carboaminations of alkenes11 (Scheme 2, path a;
Using the optimized conditions, we next explored the
scope and generality of the process (Table 2). Clean forma-
tion of 5-aryl hexahydropyrrolizidin-3-ones 3 was observed
with a variety of aryl and heteroaryl bromides, chlorides, and
triflates. The reaction tolerates a variety of substituents
including aldehyde, ketone, ether, ester, and nitro groups.
Aryl iodides are less successful substrates than bromides and
chlorides (Table 2, compare entry 6 with entries 4 and 5).
Aryl iodides are more prone to give free NH vinylic
(11) (a) For a recent review, see: Wolfe, J. P Synlett 2008, 2913. See also:
(b) Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130, 12907.
(c) Lemen, G. S.; Giampietro, N. C.; Hay, M. B.; Wolfe, J. P. J. Org. Chem.
2009, 74, 2533. (d) Nakhla, J. S.; Schultz, D. M.; Wolfe, J. P. Tetrahedron
2009, 65, 6549. (e) Leathen, M. L.; Rosen, B. R.; Wolfe, J. P. J. Org. Chem.
2009, 74, 5107.
(9) Jones, T. H.; Blum, M. S. J. Org. Chem. 1980, 45, 4778 and references
cited therein.
(10) See the Supporting Information for further details.
J. Org. Chem. Vol. 75, No. 6, 2010 2135

Bagnoli et al.
JOCNote
SCHEME 2. Proposed Mechanism for the Synthesis of (5R,7aR)-5-Aryl Hexahydropyrrolizidin-3-ones 3
SCHEME 3. Proposed Stereochemical Pathway for the For-
mation of (5R,7aR)-5-Aryl Hexahydropyrrolizidin-3-ones 3
ligands are omitted for clarity). The nitrogen displacement of
the halide in the arylpalladium complex A affords the amido
palladium adduct B that undergoes an intramolecular syn
aminopalladation to give the intermediate C. A subsequent
reductive elimination affords the desired (5R,7aR)-5-aryl
hexahydropyrrolizidin-3-one 3 and regenerates the active
palladium species.
The alternative mechanism involving an initial carbopal-
ladation step, followed by the formation of a six-membered
ring, nitrogen-containing palladacycle (via an intramolecu-
lar nucleophilic attack of the nitrogen atom to palladium)
and reductive elimination (Scheme 2, path b), appears less
likely due to the high stereoselectivity for the formation of
products. If the reactions were to occur through the forma-
tion of carbopalladation adducts, it is likely that a diaster-
eoisomeric mixture of 5-aryl hexahydropyrrolizidin-3-ones
would be observed. Similar considerations (i.e., formation of
a diastereoisomeric mixture) apply to the mechanism invol-
ving an intramolecular nucleophilic attack of the nitrogen on
the olefinic moiety activated by a σ-arylpalladium complex
generated in situ12 (Scheme 2, path c).
Aryl iodides have been found to be less successful substrates
than bromides and chlorides.
To explain the diastereoselectivity of the reaction, we
suggest that the stereochemistry-determining step is the
insertion of the alkene into the Pd-N bond of the conformer
D. As shown in Scheme 3, the conversion of 1 to the
diastereoisomeric derivative 30 would proceed via the con-
former D0. The presence of repulsive nonbonding interaction
between one of the external olefinic protons and one of the C(1)
hydrogens would disfavor the reaction via this conformer.
In conclusion, we have shown that palladium catalysis
provides an efficient tool for the construction of the hexahy-
dropyrrolizine motif. The new method allows the prepara-
tion of (5R,7aR)-5-aryl hexahydropyrrolizidin-3-ones in
good to high yields from readily available (5R)-5-but-3-en-
1-ylpyrrolidin-2-one and aryl bromides, chlorides, or tri-
flates through a diastereoselective carboamination process.
A halide effect on the reaction outcome has been observed.
Experimental Section
General Procedure. (5R,7aR)-5-(4-Phenylbenzyl)hexahydrop-
yrrolizidin-3-one (3a). Pd2(dba)3 (0.0069 g, 0.0075 mmol),
XPhos (0.0142 g, 0.015 mmol), 4-bromobiphenyl (0.070 g,
0.30 mmol), and Cs2CO3 (0.1589 g, 0.45 mmol) were stirred in
dry 1,4-dioxane (10 mL) at room temperature for 30 min, and
then (R)-5-(but-3-enyl)pyrrolidin-2-one (0.050 g, 0.360 mmol)
dissolved in 5 mL of 1,4-dioxane was added. The resulting
mixture was stirred at 120 °C for 3 h. After this time, the mixture
was concentrated under reduced pressure and the residue was
purified by chromatography (silica gel, 35 g; 20/80 v/v n-hexane/
EtOAc) to give 0.056 g (65% yield) of 3a: mp 118-119 °C;
[R]D = þ117.7 (c = 1.10, CHCl3); IR (KBr) 2936, 1675, 1407,
807 cm-1; 1H NMR (CDCl3) δ 7.62 (d, J = 7.6, 2H Hz), 7.55 (d,
J = 8.0 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.30-7.25 (m, 2H),
4.22-4.11 (m, 1H), 3.82-3.72 (m, 1H), 3.14 (dd, J1 = 4.0 Hz,
J2 = 16.0 Hz, 1H), 2.83 (dd, J1 = 4.0 Hz, J2 = 16.0 Hz, 1H),
2.82-2.74 (m, 1H), 2.47 (ddd, J1 = 1.6 Hz, J2 = 4.0 Hz, J3 =
16.0, 1H), 2.31-2.21 (m, 1H), 2.21-2.11 (m, 1H), 2.11-1.63
(12) For a seminal example of this chemistry, see: Fournet, G.; Balme, G.;
Gore, J. Tetrahedron Lett. 1989, 30, 69.
2136 J. Org. Chem. Vol. 75, No. 6, 2010

Bagnoli et al.
JOCNote
Sintesi Organica. Metodologie ed Applicazioni” (PRIN 2007)
ꢀ
supported by the Ministero dell’Universita e della Ricerca and
by the Universities of Rome (La Sapienza) and Perugia.
(m, 3H), 1.35-1.21 (m, 1H); 13C NMR (CDCl3) δ 175.0, 140.9,
139.2, 138.0, 130.2, 128.8, 127.2, 127.0, 62.0, 54.6, 39.9, 35.4,
32.7, 27.1; MS (m/z) 291 (5) Mþ, 167 (6), 124 (100), 81(16), 80
(23). Anal. Calcd for C20H21NO, C, 82.44; H, 7.26; N, 4.81.
Found: C, 82.32; H, 7.24; N, 4.79.
Supporting Information Available: Complete description
of experimental details and product characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. This work was carried out within the
framework of the National Project “Stereoselezione in
J. Org. Chem. Vol. 75, No. 6, 2010 2137