Pd-catalyzed carboamination of oxazolidin-2-ones: A stereoselective route to trans -2,5-disubstituted pyrrolidines

Article abstract of DOI:10.1021/ol1006828

Palladium-catalyzed carboamination reactions between aryl bromides and 4-(but-3-enyl)-substituted oxazolidin-2-ones are described. These transformations afford bicyclic oxazolidin-2-one derivatives that can be converted to trans-2,5-disubstituted pyrrolid

Full text of DOI:10.1021/ol1006828

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2322-2325
Pd-Catalyzed Carboamination of
Oxazolidin-2-ones: A Stereoselective
Route to trans-2,5-Disubstituted
Pyrrolidines
Georgia S. Lemen and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 N. UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
jpwolfe@umich.edu
Received March 23, 2010
ABSTRACT
Palladium-catalyzed carboamination reactions between aryl bromides and 4-(but-3-enyl)-substituted oxazolidin-2-ones are described. These
transformations afford bicyclic oxazolidin-2-one derivatives that can be converted to trans-2,5-disubstituted pyrrolidines in one step. The
starting materials are easily prepared from amino acid precursors, and products that contain up to three stereocenters are generated with
>20:1 dr.
The development of convergent, stereoselective methods for
the synthesis of trans-2,5-disubstituted pyrrolidines is of
significant importance due to the presence of this motif in
chiral auxiliaries, ligands, and catalysts.1,2 These heterocycles
are also displayed in several interesting biologically active
compounds such as the highly potent ꢀ3 andrenergic receptor
agonist 1 (Figure 1).3 In addition, polysubstituted pyrrolidines
with a trans-relationship between the C2 and C5 substituents
are found in many natural products, including the potent
glycosidase inhibitor broussonetine C (2).4
(1) For recent approaches to the synthesis of trans-2,5-disubstituted
pyrrolidines, see: (a) Enkisch, C.; Schneider, C. Eur. J. Org. Chem. 2009,
5549. (b) Davis, F. A.; Zhang, J.; Qiu, H.; Wu, Y. Org. Lett. 2008, 10,
1433. (c) Hernandez, J. N.; Ramirez, M. A.; Rodriguez, M. L.; Martin,
V. S. Org. Lett. 2008, 10, 2349. (d) Moloney, M. G.; Panchal, T.; Pike, R.
Org. Biomol. Chem. 2006, 4, 3894. (e) Davis, F. A.; Song, M.; Augustine,
A. J. Org. Chem. 2006, 71, 2779, and references therein. (f) Pichon, M.;
Figure 1
derivatives.
. Biologically active trans-2,5-disubstituted pyrrolidine
Our group has devised an efficient approach to the construc-
tion of substituted pyrrolidines via Pd-catalyzed carboamination
reactions of γ-aminoalkene derivatives.5-7 For example, treat-
Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927
.
(2) For selected recent examples of pyrrolidine-derived ligands and
catalysts see: (a) Chen, H.; Sweet, J. A.; Lam, K.-C.; Rheingold, A. L.;
McGrath, D. V. Tetrahedron: Asymmetry 2009, 20, 1672. (b) Simonini,
V.; Benaglia, M.; Pignataro, L.; Guizzetti, S.; Celentano, G. Synlett 2008,
1061. (c) Liu, Z.; Qu, H.; Gu, X.; Min, B. J.; Nyberg, J.; Hruby, V. J. Org.
Lett. 2008, 10, 4105. (d) Frisch, K.; Landa, A.; Saaby, S.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 6058. (e) Sprott, K. T.; Corey, E. J. Org.
(3) Berger, R.; Chang, L.; Edmonson, S. D.; Goble, S. D.; Harper, B.;
Kar, N. F.; Kopka, I. E.; Li, B.; Morriello, G. J.; Moyes, C. R.; Shen,
D.-M.; Wang, L.; Wendt, H.; Zhu, C. PCT Int. Appl. WO 2009/123870
A1, October 8, 2009; Chem. Abstr. 2009, 151, 448256.
Lett. 2003, 5, 2465
.
10.1021/ol1006828  2010 American Chemical Society
Published on Web 04/20/2010

ment of 3 with 4-bromoanisole and NaOtBu in the presence
of a palladium catalyst affords cis-2,5-disubstituted pyrro-
lidine 5 in 60% yield as a single diastereomer (Scheme 1).6b
the observed cis-2,5-disubstituted pyrrolidine products (e.g., 5).
Moreover, the stereochemical outcome of reactions that generate
molecules with more than two stereocenters is also dictated by
minimization of A(1,3)-strain interactions. For example, the Pd-
catalyzed carboamination of 6 yields 8 with >20:1 dr even
though the substrate C4-ether group is in a pseudoaxial
orientation in transition state 7 and suffers from a 1,3-diaxial
interaction with the C2-alkyl group.6d Thus, the conversion of
substrates such as 3 to trans-2,5-disubstituted pyrrolidines does
not appear to be feasible using this method.
Scheme 1. Formation of cis-2,5-Disubstituted Pyrrolidines
The allylic strain model shown in Scheme 1 suggests two
possible substrate modifications that could yield trans-2,5-
disubstituted pyrrolidines. The first would simply involve
use of primary amine substrates, as absence of the N-Boc
group should favor equatorial orientation of the C2-substitu-
ent and lead to preferential formation of trans-disubstituted
products.8 Unfortunately, all efforts to effect carboamination
reactions of primary aliphatic amines have thus far resulted
in substrate N-arylation, with no observed pyrrolidine forma-
tion.9 A second approach to the construction of trans-2,5-
disubstituted pyrrolidines would employ carboamination
reactions of 4-(but-3-enyl)-substituted oxazolidin-2-ones such
as 9 (Scheme 2). These substrates should undergo ring
The installation of different groups can be achieved by simply
varying the starting aryl or alkenyl bromide. Thus, many
different pyrrolidine analogues can be prepared from a single
γ-aminoalkene substrate.
Despite the utility of Pd-catalyzed carboamination reac-
tions for preparation of cis-2,5-disubstituted pyrrolidines such
as 5, the analogous synthesis of pyrrolidines with a trans-
relationship between substituents at C2 and C5 has not yet
been accomplished. However, such a transformation would
be of significant synthetic utility. For example, these car-
boamination reactions could potentially be used to optimize
properties of trans-2,5-disubstituted pyrrolidine derived
ligands, auxiliaries, catalysts, or pharmaceutical lead com-
pounds such as 1. In addition, an assortment of nitrogen-
containing sugar analogues, including the broussonetine
alkaloids, could be accessed in a straightforward manner from
a common aminoalkene precursor.
Scheme 2. Approach to trans-2,5-Disubstituted Pyrrolidines
formation via transition state 10, as other possible transition
states suffer from significant ring strain.10,11 Reaction via
transition state 10 would give rise to bicyclic products 11,
which could be hydrolyzed or reduced to yield trans-2,5-
disubstituted pyrrolidines 12 (R ) H or Me).
To probe this hypothesis, a series of oxazolidin-2-ones
bearing pendant alkenes were prepared as shown in Scheme
3. The majority of these substrates were generated through
conversion of 13 to substituted N-Boc-amino alcohols 15a-d
(Scheme 3). For example, treatment of 13 with LiBH4
afforded monosubstituted product 15a.12 Alternatively, con-
As shown in Scheme 1, transformations of 3 and related
substrates are believed to occur through transition states such
as 4, in which the C2-substituent is oriented in a pseudoaxial
position. This transition state geometry minimizes A(1,3)-strain
between the Boc group and the C2-phenyl group and leads to
(4) (a) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles 2002, 57,
1539. (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (c) Ribes, C.; Falomir, E.; Murga,
J.; Carda, M.; Marco, J. A. Tetrahedron 2009, 65, 10612. (d) Trost, B. M.;
Horne, D. B.; Woltering, M. J. Chem.sEur. J. 2006, 12, 6607.
(5) Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe,
J. P. Synlett 2008, 2913.
(8) This strategy has successfully been employed in the formation of
cis- vs trans-3,5-disubstituted pyrazolidines. See: Giampietro, N. C.; Wolfe,
J. P. J. Am. Chem. Soc. 2008, 130, 12907.
(9) In some instances tandem N-arylation/carboamination reactions of
these substrates have been achieved. However, the N-arylation precedes
the carboamination, and cis-2,5-disubstituted pyrrolidines are generated. See:
Yang, Q.; Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7, 2575.
(6) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(b) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447. (c) Ney,
J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (d) Bertrand, M. B.;
Wolfe, J. P. Org. Lett. 2006, 8, 2353. (e) Bertrand, M. B.; Neukom, J. D.;
Wolfe, J. P. J. Org. Chem. 2008, 73, 8851.
(10) During the course of these studies Cacchi described related Pd-
catalyzed carboamination reactions of aryl halides with 5-(but-3-enyl)pyr-
rolidin-2-one that afford trans-5,7a-disubstituted pyrrolizidin-3-ones. See:
Bagnoli, L.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Scarponi, C.; Tiecco,
(7) For Cu- or Au-catalyzed carboamination reactions, see: (a) Fuller,
P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477. (b) Zeng, W.; Chemler,
S. R. J. Am. Chem. Soc. 2007, 129, 12948, and references therein. (c) Zhang,
G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474. For
alkene carboamination reactions involving solvent C-H bond functional-
ization, see: (d) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael,
F. E. J. Am. Chem. Soc. 2009, 131, 9488. (e) Sibbald, P. A.; Rosewall,
C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
M. J. Org. Chem. 2010, 75, 2134
.
(11) For other ring-closing reactions of oxazolidin-2-one derivatives that
afford substituted pyrrolidines with a trans-relationship between groups on
C2 and C5, see: (a) Hirai, Y.; Terada, T.; Amemiya, Y.; Momose, T.
Tetrahedron Lett. 1992, 33, 7893. (b) Bland, D.; Chambournier, G.; Dragan,
V.; Hart, D. J. Tetrahedron 1999, 55, 8953
.
Org. Lett., Vol. 12, No. 10, 2010
2323

Scheme 3
.
Synthesis of Oxazolidin-2-one Substrates
Table 1. Optimization of Reaction Conditionsa
palladium
conversion yield
yield
sourceb c
ligand14
Dppe
Dpe-phos
S-Phos
PCy2(o-biphenyl)
RuPhos
(%)
19 (%)d 20 (%)d
,
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
27
15
70
17
92
92
96e
0
2
57
<1
8
9
3
2
3
4
3
87
[(allyl)PdCl]2 RuPhos
[(allyl)PdCl]2 RuPhos
79
81 (80)f
a Conditions: 1.0 equiv of 9, 1.2 equiv of 4-bromoanisole, 1.2 equiv of
NaOtBu, 2 mol % Pd, 4 mol % monodentate ligand/2 mol % bidentate
ligand, NaOtBu, toluene (0.25 M), 80-90 °C. Product 19 was formed with
>20:1 dr in all experiments. b Experiments with the dinuclear palladium
complex [(allyl)PdCl]2 were conducted using 1 mol % of the dimer (2 mol
% total Pd). c When Pd(OAc)2 was employed, the ligand and palladium
source were stirred at rt in toluene for 5 min prior to addition of the substrate
and other reagents. d Yields for optimization studies were determined by
1H NMR analysis of crude reaction mixtures using phenanthrene as an
internal standard. e The reaction was conducted using benzene as solvent.
f Isolated yield (average of two or more experiments).
version of 13 to Weinreb amide 14 followed by addition of
a Grignard reagent and then reduction with LiAl(OtBu)3H
afforded amino alcohols 15b-d in good yield and with >20:1
diastereoselectivity. The amino alcohols 15a-c were trans-
formed to 9 and 16a,b by treatment with NaH to effect ring
closure. The synthesis of trans-4,5-disubstituted oxazolidin-
2-ones 18a,b was accomplished through two methods.
Methyl-substituted derivative 18a was prepared via allylation
of iodide 17.13 Alternatively, treatment of amino alcohol 15d
with MsCl and iPr2NEt provided 18b in 64% yield.
In our preliminary experiments, we examined the Pd-
catalyzed carboamination of 9 with 4-bromoanisole. As
shown in Table 1, these reactions afforded mixtures of the
desired product 19 and side product 20, which results from
competing Heck arylation of the starting material. Although
Dpe-phos or dppe have proven to be useful ligands in other
Pd-catalyzed carboamination reactions,6,14 catalysts derived
from these ligands exhibited low reactivity in transformations
of 9 and failed to generate significant amounts of 19.
However, after some optimization we found that Buchwald’s
RuPhos ligand15 provided satisfactory results. Use of [(al-
lyl)PdCl]2 as precatalyst and benzene as solvent simplified
experimental setup, as premixing the ligand and metal
complex was not required.16,17 These optimized conditions
provided 19 in 80% yield upon isolation.
As shown in Table 2, the optimized conditions outlined
above allow the construction of a number of tetrahydropy-
rrolo[1,2-c]oxazol-3(1H)-one derivatives. Several different
electron-neutral or electron-rich aryl bromides proved to be
viable coupling partners. However, attempts to employ
electron-poor aryl bromides such as 4-bromobenzophenone
led to competing N-arylation of the oxazolidin-2-one starting
material. Competing N-arylation was also observed with
modestly electron-deficient aryl bromides (e.g., p-fluorobro-
mobenzene), but use of PCy2(o-biphenyl) as ligand sup-
pressed this side reaction and provided optimal results with
these substrates (entries 7, 11, and 13).
The synthesis of bicyclic products bearing three stereo-
centers was accomplished using 4,5-disubstituted oxazolidin-
2-ones as substrates. In all cases products were obtained with
>20:1 dr, and enantiomerically enriched (+)-18a and (+)-
16b were converted to the desired products without loss of
optical activity (Table 2, entries 6 and 14). Similar product
yields were obtained regardless of the oxazolidin-2-one’s
relative stereochemistry. For example, trans-disubstituted
substrate 18a and cis-disubstituted compound 16a were
coupled with 4-bromoanisole to afford 24 and 27 in 83%
and 84% yields, respectively (entries 5 and 9).
(12) Ester 13 was prepared from commercially available N-Boc-serine
methyl ester in 62% yield over two steps. See: Dunn, M. J.; Jackson,
R. F. W.; Pietruszka, J.; Turner, D. J. Org. Chem. 1995, 60, 2210.
(13) Iodide 17 was prepared from threonine methyl ester in 40% yield
over four steps.
(14) dppe ) 1,2-bis(diphenylphosphino)ethane; Dpe-Phos ) bis(2-
diphenylphosphinophenyl)ether; S-Phos ) 2-dicyclohexylphosphino-2′,
6′-dimethoxy-1,1′-biphenyl; RuPhos ) 2-dicyclohexylphosphino-2′,6′-di-
isopropoxy-1,1′-biphenyl.
(15) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(16) Relatively low yields were obtained when Pd(OAc)2 was used as
the palladium source unless the precatalyst and ligand were stirred in toluene
for 5 min prior to addition of the substrate and other reagents.
(17) Use of other solvents such as acetonitrile, tert-butanol, diglyme,
or 1,4-dioxane or palladium sources such as Pd2(dba)3 led to lower yields
and/or incomplete conversion.
The bicyclic products formed in the carboamination
reactions can easily be transformed to trans-2,5-disubstituted
pyrrolidines (Scheme 4).18 For example, hydrolysis of 27
was accomplished using NaOH/EtOH and afforded 33 in
96% yield. Alternatively, the conversion of 27 to N-methyl
pyrrolidine 34 was achieved via reduction with LiAlH4 (95%
(18) (a) Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans.
1 1996, 465. (b) Lakanen, J. R.; Pegg, A. E.; Coward, J. K. J. Med. Chem.
1995, 38, 2714.
2324
Org. Lett., Vol. 12, No. 10, 2010

Table 2. Synthesis of Bicyclic Oxazolidin-2-onesa
a Conditions: 1.0 equiv of substrate, 1.2 equiv of ArBr, 1.2 equiv of NaOtBu, 1 mol % [(allyl)PdCl]2, 4 mol % RuPhos, benzene (0.25 M), 80 °C. b Isolated yield
(average of two or more experiments). All products were formed with >20:1 dr. c The reaction was conducted with 2 mol % [(allyl)PdCl]2 and 8 mol % RuPhos.
d The reaction was conducted with 2 mol % Pd(OAc)2. e The reaction was conducted with 2.5 mol % [(allyl)PdCl]2 and 10 mol % Cy2JohnPhos.
acid derived precursors. Further studies on the application
of this method to the synthesis of natural products, ligands,
and catalysts are underway.
Scheme 4
.
Conversion of 27 to trans-2,5-Disubstituted
Pyrrolidines
Acknowledgment. The authors thank the NIH-NIGMS
(GM071650) for financial support of this work. Additional
support was provided by the Camille and Henry Dreyfus
Foundation (Camille Dreyfus Teacher Scholar Award),
GlaxoSmithKline, Eli Lilly, and Amgen. We acknowledge
Ms. Xin Zhou, a summer REU student from Peking
University, for help with preliminary experiments.
Supporting Information Available: Experimental pro-
cedures, characterization data, descriptions of stereochemical
assignments, and copies of 1H and 13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
yield). In both cases the pyrrolidine products were formed
with no loss of stereoisomeric purity.
In conclusion we have developed a concise and convergent
approach to the synthesis of trans-2,5-disubstituted pyrro-
lidines. Products bearing up to three stereocenters can be
prepared in good yields as single enantiomers from amino
OL1006828
Org. Lett., Vol. 12, No. 10, 2010
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