Recoverable resin-supported pyridylamide ligand for microwave-accelerated molybdenum-catalyzed asymmetric allylic alkylations: Enantioselective synthesis of baclofen

Article abstract of DOI:10.1021/ol034605m

(Matrix presented) The syntheses of a series of 4-monosubstituted pyridylamides and a resin-supported pyridylamide are described. The ligands were evaluated in the microwave-accelerated molybdenum-catalyzed asymmetric allylic alkylation. The reaction affo

Full text of DOI:10.1021/ol034605m

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2275-2278
Recoverable Resin-Supported
Pyridylamide Ligand for
Microwave-Accelerated
Molybdenum-Catalyzed Asymmetric
Allylic Alkylations: Enantioselective
Synthesis of Baclofen
Oscar Belda, Stina Lundgren, and Christina Moberg*
Department of Chemistry, Organic Chemistry, KTH, SE-100 44 Stockholm, Sweden
kimo@kth.se
Received April 8, 2003
ABSTRACT
The syntheses of a series of 4-monosubstituted pyridylamides and a resin-supported pyridylamide are described. The ligands were evaluated
in the microwave-accelerated molybdenum-catalyzed asymmetric allylic alkylation. The reaction afforded the product in high yield and with
high regio- and enantioselectivity. The heterogeneous ligand could be reused several times with no change in the reaction outcome. The
asymmetric allylic alkylation was employed as the key step in the enantioselective synthesis of (R)-baclofen.
The development of immobilized catalysts has been a
growing area during the past years.1 Due to the increased
demand for robust, reliable, and economic synthetic methods
to prepare chiral compounds, heterogeneous asymmetric
catalysis has been a field of interest for many research
laboratories. Thus, solid-supported chiral ligands have been
synthesized and used for a number of classes of asymmetric
catalytic organic transformations including oxidations, reduc-
tions, and C-C bond formations among others.2 Some
advantages of using solid-supported ligands are the ease of
removing the ligand after reaction and the possibility to reuse
the recovered ligand without loss of performance.3
Since the discovery by Trost and Hachiya4 that pyridyl-
amide 1a (Figure 1) served as an efficient ligand for the
molybdenum-catalyzed asymmetric allylic alkylation, some
effort has been made to gain a deeper understanding of the
operating reaction mechanism,5 and new classes of ligands
have been synthesized and employed successfully.6 We
(3) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999.
(1) Chiral Catalyst Immobilization and Recycling; De Vos, D. E.,
Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Weinheim, 2000.
(2) For reviews see: (a) Clapham, B.; Reger, T. S.; Janda, K. D.
Tetrahedron 2001, 57, 4637. (b) Leadbeater, N. E.; Marco, M. Chem. ReV.
2002, 102, 3217. (c) McNamara, C. A.; Dixon, M. J.; Bradley, M Chem.
ReV. 2002, 102, 3275. (d) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem.
ReV. 2002, 102, 3385.
(4) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104.
(5) (a) Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider,
P. J. J. Org. Chem. 2002, 67, 2762. (b) Trost, B. M.; Dogra, K.; Hachiya,
I.; Emura, T.; Hughes, D. L.; Krska, S.; Reamer, R. A.; Palucki, M.; Yasuda,
N.; Reider, P. J. Angew. Chem., Int. Ed. 2002, 41, 1929. (c) Krska, S. W.;
Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Sun, Y.; Trost, B. M. J. Am.
Chem. Soc. 2002, 124, 12656.
10.1021/ol034605m CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/05/2003

prepared. Our previous investigations showed that pyridy-
lamides substituted in the 4-position of the pyridine rings
could be conveniently prepared from the bis(4-chloropyri-
dine) derivative by nucleophilic aromatic substitution.8b
Pyridylamides containing two different aromatic nuclei have
been made before by stepwise formation of the monoamide
and then further reaction to form the diamide.5c However,
this procedure affords mixtures of compounds if the reaction
conditions are not carefully controlled. We observed that
when slowly adding a 0.05 M solution of picolinic acid
activated with carbonyl diimidazole (CDI) to a 0.05 M solu-
tion of (1R,2R)-1,2-diaminocyclohexane, the monoamide was
formed almost exclusively. Further reaction with activated
4-chloropicolinic acid gave the desired monosubstituted pre-
cursor 1b in 46% yield after chromatography (Scheme 1).
Figure 1. Parent bis-pyridylamide.
developed a convenient and robust procedure for the reaction
of cinnamyl methyl carbonate with sodium dimethyl mal-
onate using Mo(CO)6, ligand 1a, and N,O-bis(trimethylsilyl)-
acetamide (BSA) under air that afforded the product with
high regio- and enantioselectivity.7 We were also interested
in the influence of the electronic and steric properties of the
ligand on the outcome of the reaction and synthesized several
substituted pyridylamides and evaluated them as ligands for
the allylation reaction with different model substrates.8 Our
results showed that electron-donating groups in the 4-position
of the pyridine rings of the ligand improved the regioselec-
tivity in favor of the branched product.
Scheme 1. Synthesis of the Monofunctionalized Ligand 1b
Previously in our group, we have made resin-supported
pyridyloxazolines9 and bis(oxazolines)10 for use in the
complementary palladium-catalyzed allylic alkylation reac-
tion. Herein, we report the preparation and use of a recyclable
polymer-supported pyridylamide for the microwave-acceler-
ated molybdenum-catalyzed allylic allylation.
For the immobilization of pyridylamide 1a, methods
involving the reaction of a derivative of 1a substituted either
in the diamine part of the molecule or in a pyridine ring
with a suitably functionalized solid support were considered.
The former method, which may retain the C2 symmetry of
the molecule, was recently utilized for the heterogenization
of the Trost diphosphane.11 However, the attachment via a
pyridine ring allows for a higher flexibility, and the func-
tionalization can at the same time be employed for tuning
of the electronic properties of the ligand. In addition, it has
recently been demonstrated that 2-fold symmetry is not a
requirement for high selectivity in the catalytic reaction under
study.5b,6d
With 1b in hand, we prepared a series of monosubstituted
ligands by treatment of 1b with a suitable nucleophile under
microwave heating to give the corresponding derivative (1c-
e) in high yields (Scheme 2).
To study the behavior of ligands containing only one sub-
stituted pyridine ring, some monofunctionalized ligands were
Scheme 2. Synthesis of Monofunctionalized Ligands by
Nucleophilic Aromatic Substitution of 1b
(6) (a) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141. (b) Glorius, F.;
Neuburger, M.; Pfaltz, A. HelV. Chim. Acta 2001, 84, 3178. (c) Malkov,
A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Rusell, D. R.;
Mansfield, D. J.; Valko, M.; Kocˇovsky´, P. Organometallics 2001, 20, 673.
(d) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocˇovsky´, P. Tetrahedron Lett.
2001, 42, 509.
(7) Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A.
Angew. Chem., Int. Ed. 2000, 39, 3596.
(8) (a) Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg,
A.; Moberg, C. J. Org. Chem. 2000, 65, 5868. (b) Belda, O.; Moberg, C.
Synthesis 2002, 1601.
(9) Hallman, K.; Macedo, E.; Nordstro¨m, K.; Moberg, C. Tetrahedron:
Asymmetry 1999, 10, 4037.
(10) Hallman, K.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 1475.
(11) (a) Song, C. E.; Yang, J. W.; Roh, E. J.; Lee, S.; Ahn, J. H. Angew.
Chem., Int. Ed. 2002, 41, 3852. (b) Trost, B. M.; Pan, Z.; Zambrano, J.;
Kujat, C. Angew. Chem., Int. Ed. 2002, 41, 4691.
2276
Org. Lett., Vol. 5, No. 13, 2003

was very slow when ligand 1e, having a free primary amino
group, was used. Even after 12 min at 160 °C, only small
amounts of product were detected by GC-MS, and the
branched-to-linear ratio and % ee could not be determined
accurately. When using polymer-supported ligand 1f, the
reaction was also slower, presumably because of the het-
erogeneous nature of the catalyst. However, when the
reaction was run with double concentration of the reagents
(1.54 M for the nucleophile and 1.42 M for 2), no starting
material could be detected after 30 min and the product
exhibited a branched-to-linear ratio of 35:1 and an enantio-
meric excess of 97%. Furthermore, the resin-supported ligand
could be recovered by filtration from the reaction mixture
and reused as ligand, after washing with different solvents
and vacuum-drying, for at least seven times with no
significant change in the reaction outcome.
The molybdenum-catalyzed allylic alkylation has high
synthetic potential.5a,12 We wanted to apply our convenient
procedure for the allylation reaction in the synthesis of (R)-
baclofen (8). The racemic form of 8 is used as a muscle
relaxant (antispasmodic) lipophilic derivative of γ-aminobu-
tyric acid (GABA). Pharmacological studies have shown that
the (R)-enantiomer is the therapeutically useful agonist of
the GABAB receptor.13 Therefore, several efforts have been
made to prepare enantiomerically pure 8.14 Allylic carbonate
5 was easily prepared by the addition of vinylmagnesium
chloride to 4-chlorobenzaldehyde and subsequent treatment
with methyl chloroformate.15 Alkylation with malonate
afforded 616 (Table 2) in good yield and enantioselectivity
Scheme 3. Preparation of the Solid-Supported Ligand 1f
Furthermore, the primary amino group in ligand 1e could
be utilized as an attachment point to a carboxylic acid
functionalized resin by simple amide formation. Thus,
reaction of the ligand with a TentaGel HL-COOH resin in
the presence of DCC and DMAP in dichloromethane for 24
h at room temperature gave the desired immobilized ligand
in 84% yield based on elemental analysis (Scheme 3).
The ligands were evaluated in the allylation reaction of
dimethyl malonate with 3-phenylprop-2-enyl methyl carbon-
ate (2) (Table 1). Catalysts showing high regio- and
Table 1. Results of the Catalytic Reaction Using Ligands
1b-f
Table 2. Preparation of Intermediate (R)-6
entry ligand T (°C) t (min) yield of 3a (%) 3/4b % eec
1
2
3
4
1a
1b
1c
1d
1e
1f
160
160
160
160
160
160
160
160
6
6
6
80
89
90
89
traces
90b
95b
82
19:1
74:1
98:1
75:1
98
97
97
99
6
5
12
20
25
30
6d
7d
8d
35:1
35:1
35:1
97
97
97
1f
1fe
THF PhMe
T
t
yielda
a Isolated yield. b Determined by GC-MS. c Determined by chiral HPLC.
d Concentration of the reagents was doubled. e The ligand could be reused
at least seven times without change in the reaction outcome.
entry ligand
(mL) (mL) (°C) (min) (%)
b/lb % eec
1
2
3
4
(S,S)-1a
(S,S)-1f
(S,S)-1f
2
0
160
160
160
160
6
30
30
30
78
26:1
27:1
24:1
25:1
96
48
76
89
1
0
95b
98b
76
0.5
0.5
0.9
enantioselectivity were produced when the monosubstituted
bispyridylamides 1b-d were used. Very high regioselectivity
(98:1) was observed when the 4-methoxy-monosubstituted
ligand (1c) was used, while the 4-chloro-substituted ligand
(1b) afforded the product in nearly the same branched-to-
linear ratio as the 4-pyrrolidine substituted ligand (1d) (74:1
and 75:1, respectively). These ligands 1b-d also afforded
the branched product with high selectivity (97% ee for 1b
and 1c and 99% ee for 1d). On the other hand, the reaction
(S,S)-1fd 0.1
a Isolated yield. b Determined by GC-MS. c Determined by chiral HPLC.
d The ligand could be reused at least seven times without change in the
reaction outcome.
(96% ee when using ligand 1a). The polymer-supported
ligand 1f also afforded the product in good yield, but with
drastically lower enantioselectivity, probably as a result of
Org. Lett., Vol. 5, No. 13, 2003
2277

and cleavage of the ozonide with Me2S produced the
corresponding aldehyde18 that was immediately treated with
NH4OAc and NaBH3CN19 at room temperature for 12 h.
Then addition of 2 N NaOH to the reaction mixture at room
temperature afforded 8 (Scheme 4), after workup and
formation of the hydrochloric salt in 22% yield overall (from
7).
Scheme 4. Synthesis of (R)-Baclofen from 6
In summary, we have synthesized new monosubstituted
pyridylamide ligands and developed a new resin-supported
pyridylamide ligand for the microwave-accelerated molyb-
denum-catalyzed allylic alkylation reaction. The ligands were
evaluated in the reaction and yielded the product in high
yields and with high selectivity. The resin-supported ligand
could easily be recovered and reused several times without
significant loss in the outcome of the reaction. A short
enantioselective synthesis of (R)-baclofen was achieved using
the allylation reaction as the key step.
a memory effect.5a As shown by Hughes et al.5a for the parent
ligand, running the reaction in toluene minimized the memory
effect, and in our case the enantioselectivity increased to 89%
ee when the reaction was run in that solvent.
Decarboxylation of the geminal diester (Scheme 4) was
achieved when a solution of 6 and NaCl in DMSO/water
was heated in the microwave cavity for 20 min.17 Oxidation
of the double bond in 7 with ozone at -78 °C for 10 min
Acknowledgment. This work was supported by the
Swedish Foundation for Strategic Research. We thank Dr.
Wolfgang Fro¨stl (Novartis Pharma AG) and Rolf R. Bader
for a generous donation of a sample of (R)-baclofen.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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OL034605M
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2278
Org. Lett., Vol. 5, No. 13, 2003