Enantioselective hydrogenation of arecaidine over cinchona alkaloid-modified palladium catalyst: A novel route to enantioenriched nipecotic acid derivatives

Article abstract of DOI:10.1016/j.jcat.2008.04.007

The hydrogenation of N-methyl-3,4-dehydronipecotic acid (arecaidine) over Pd/Al₂O₃ catalyst in presence of cinchona alkaloids and benzylamine additive results in the quantitative formation of N-methylnipecotic acid in good (up to 60%) optical purity. The reaction is a novel example of the efficient use of chirally modified heterogeneous metal catalysts allowing the preparation of enantioenriched N-heterocyclic carboxylic acids.

Full text of DOI:10.1016/j.jcat.2008.04.007

Journal of Catalysis 256 (2008) 349–352
Contents lists available at ScienceDirect
Journal of Catalysis
www.elsevier.com/locate/jcat
Research Note
Enantioselective hydrogenation of arecaidine over cinchona alkaloid-modified
palladium catalyst: A novel route to enantioenriched nipecotic acid derivatives
a,∗
a
a,b
György Sz o˝ ll o˝ si , Kornél Sz o˝ ri , Mihály Bartók
a
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
Department of Organic Chemistry, University of Szeged, Hungary
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydrogenation of N-methyl-3,4-dehydronipecotic acid (arecaidine) over Pd/Al O catalyst in presence
2
3
Received 5 March 2008
Revised 11 April 2008
Accepted 11 April 2008
Available online 8 May 2008
of cinchona alkaloids and benzylamine additive results in the quantitative formation of N-methylnipecotic
acid in good (up to 60%) optical purity. The reaction is a novel example of the efficient use of chirally
modified heterogeneous metal catalysts allowing the preparation of enantioenriched N-heterocyclic car-
boxylic acids.
©
2008 Elsevier Inc. All rights reserved.
Keywords:
Hydrogenation
Enantioselective
Cinchona alkaloid
Palladium catalyst
Nipecotic acid
N-heterocyclic
Carboxylic acids
1
. Introduction
cinchona alkaloids provides saturated carboxylic acids in good to
excellent optical purities [17–30]. The hydrogenation of the unsat-
urated esters results in a loss of enantiodifferentiation compared
with the corresponding free carboxylic acids [17,20,28]. Attempts
at the enantioselective hydrogenation of N-containing acids or es-
ters over modified metal catalysts have resulted in low optical pu-
rity [31–36]; only fair enantioselectivity was reported recently over
cinchona-Pd catalyst [37]. The hydrogenation of an N-heterocyclic
ester in this catalytic system also gave disappointing results; even
under harsh reaction conditions, the hydrogenation of ethyl 1,4,5,6-
tetrahydronicotinate produced 24% enantioselectivity accompanied
by low yield over cinchona-modified Pd [38]. Similarly, low enan-
tioselectivity has been obtained in the one-step hydrogenation of
ethyl nicotinate to ethyl nipecotinate over a chiral Pd complex
immobilized in the pores of mesoporous silica [39]. The hetero-
geneous enantioselective hydrogenation of C=N group has proven
even more difficult, and thus is not considered a viable alternative
for the preparation of optically enriched N-heterocyclic carboxylic
acid derivatives [40,41].
The biological activity of natural N-heterocyclic compounds is
the driving force behind efforts aimed at developing novel asym-
metric synthetic methods for the preparation of the substructures
of these pharmacologically active substances [1]. Several methods,
including asymmetric catalytic procedures, have been elaborated
for the synthesis of these optically pure building blocks [2,3].
Among these, the asymmetric catalytic hydrogenation of substi-
tuted unsaturated N-heterocycles has proven to be a convenient
method [4–6]. Due to the advantages of the heterogeneous cata-
lysts, the preparation of saturated N-heterocycles by asymmetric
hydrogenation over such catalysts also has been attempted [7].
The most successful strategies used the diastereoselective hydro-
genation of the aromatic heterocyclic compounds coupled with
optically pure auxiliaries [8,9]. The direct enantioselective hydro-
genation of the N-heterocyclic substrates over chiral heteroge-
neous catalysts should be a more convenient procedure. To date,
only a few efficient heterogeneous chirally modified catalysts have
been developed for the hydrogenation of β-keto esters, activated
ketones, 2-pyrone derivatives, and prochiral α,β-unsaturated car-
boxylic acids [10–16].
In the present study, we used a novel strategy to prepare opti-
cally enriched nipecotic acid derivatives by heterogeneous catalytic
hydrogenation over cinchona-modified Pd catalyst. Based on previ-
ous findings (e.g., hydrogenation of free carboxylic acids in higher
optical yields as the corresponding esters [17,20], sluggish hydro-
genation of the substrate containing a secondary amino group
[38]), we designed the structure of the N-heterocyclic α,β-un-
The hydrogenation of α,β-unsaturated carboxylic acids of di-
verse structures over supported Pd catalysts in the presence of
Corresponding author. Fax: +36 62 544 200.
E-mail address: szollosi@chem.u-szeged.hu (G. Sz o˝ ll o˝ si).
*
0
021-9517/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2008.04.007

350
G. Sz o˝ ll o˝ si et al. / Journal of Catalysis 256 (2008) 349–352
Scheme 1. Preparation of arecaidine (1) from arecoline hydrobromide [44].
saturated carboxylic acid to increase the enantioselectivity of hy-
drogenation in the presence of cinchona alkaloids.
Table 1
a
Enantioselective hydrogenation of 1 over CD modified Pd catalysts
2. Experimental
The 5% Pd/Al2O3 (Engelhard 40692) commercial catalyst (metal
2
−1
dispersion, 0.19–0.21; BET surface area, 185–200 m g ; average
Pd particle size, 5.8 nm) [18,42,43], arecoline hydrobromide, and
the cinchona alkaloids, solvents, and reagents (Aldrich and Fluka
products) were used as received. Arecaidine (1) was prepared as
described previously [44], as shown in Scheme 1. Hydrogenations
were performed in a glass hydrogenation apparatus or a glass-lined
stainless steel autoclave. The catalyst and solvent were loaded into
the reactor and stirred at 1000 rpm for 30 min under H2, fol-
lowed by addition of the modifier, stirring for another 5 min, and
then addition of 1 and benzylamine (BA). The reactor was flushed
with H2 and pressurized to the desired pressure, and the mix-
ture was stirred (1000 rpm) while the H2 uptake was recorded.
H2 consumption of up to 20% of the total uptake was used to
Entry
Solvent
Additiveb
Timec
Ri
ee
(%)
−
1
−1
h )
(
min)
(mmol g
cat
1d
2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
–
–
–
BA
BA
BA
BA
BA
–
10
25
30
15
35
80
50
20
115
59
33
73
36
13
33
62
38
32
67
–
18
33
39
40
40
32
30
0
e
3
4
f
5
6
7
8
9
g
h
e
H2O
110
40
20
1
0
AcOH
–
BA
10
20
i
11
DMF
calculate the initial reaction rate (R ). After the specified reac-
i
a
Reaction conditions: 50 mg Pd/Al2O3, 3 ml solvent, 0.7 mmol 1, 0.035 mmol
tion time, the catalyst was removed by filtration, the solution was
neutralized using HCl ethanolic solution, and the products were
analyzed by gas chromatograph (Agilent Techn. 6890N GC–5973
MSD and HP 5890 ser II GC–FID) with a Cyclosil-B (30 m ×
CD, 0.1 MPa H2, stirring 1000 rpm, 295 ± 2 K.
b
c
d
e
f
Additive: 0.7 mmol BA.
Reaction time needed for complete conversion.
Reaction without modifier.
Using 0.35 mmol CD.
0.2 mm, J&W Scientific) chiral capillary column. Analysis of sam-
Over catalyst pretreated in flow of H2 at 523 K.
Reaction carried out at 274 ± 2 K.
ples transformed in methyl esters using CH2N2 ethereal solution
gave identical results to those for the free carboxylic acid samples.
The N-methylnipecotic acid (2) enantiomers were identified after
transformation in methyl esters and comparison of retention time
with that of a sample prepared from commercial (S)-nipecotic
acid by reaction with methyliodide. The enantioselectivity was ex-
pressed as enantiomeric excess (ee), calculated as
g
h
i
Over 5% Pd/TiO2 catalyst prepared by precipitation.
N,N-dimethylformamide with 2.5 vol% water content.
even under low H2 pressure (see Table 1). In the presence of
5 mol% cinchonidine (CD; CD/Pdsurf molar ratio about 7.5) in
MeOH, the Ri decreased by half compared with the racemic re-
action; however, even in the presence of the modifier, 1 was hy-
drogenated in less than 30 min. Low ee in favor of the (R)-2
enantiomer was obtained, which was increased by using 50 mol%
CD. The addition of achiral organic base to the reaction mixture
is known to have a beneficial effect on the ee in the hydrogena-
tion of α,β-unsaturated carboxylic acids of various structures [21,
24–30,36,37]. Using benzylamine (BA) as an additive in the hydro-
genation of 1 resulted in a significant increase in ee, accompanied
by an increase in Ri, similar to that observed in the hydrogenation
of α-phenylcinnamic acid and its methoxy-substituted derivatives
[21,25,26]. The reaction was free of external diffusion control, as
verified by using various catalyst amounts and stirring velocities
(data not shown). Thus, we can conjecture that BA may act simi-
larly as in the hydrogenation of α-phenylcinnamic acid, increasing
the desorption rate of the strongly adsorbed N-containing satu-
rated acid interacting with the modifier on the Pd surface. This
interpretation requires confirmation by further studies; however.
Similar ee values were obtained over the catalyst prereduced in a
flow of H2 at 523 K and also in the reaction carried out at 274 K,
whereas Ri was significantly decreased in both reactions. No in-
creases in ee were achieved by changing the catalyst to 5% Pd/TiO2
or by hydrogenation in other solvents, as shown in Table 1.
ꢀ
ꢁ
ꢂ
ꢁ
ꢂꢀ
ꢃꢁ
ꢂ
ꢁ
ꢂꢄ
ꢀ
ꢀ
ee (%) = (R) − 2 − (S) − 2 × 100/ (R) − 2 + (S) − 2
.
3
. Results and discussion
According to earlier results on the enantioselective hydrogena-
tion of prochiral α,β-unsaturated carboxylic acids and esters [17,
0], the presence of a free carboxylic acid group leads to increased
2
enantioselectivity. In addition, a secondary amine group in the β
position has a detrimental effect, likely due to its competition with
the quinuclidine N of the modifier in the interaction with the car-
boxyl group and also its deactivation effect, as demonstrated by
the hydrogenation of ethyl 1,4,5,6-tetrahydronicotinate [38]. The
possible intermolecular and intramolecular side reactions of this
group also may contribute, as indicated by the difficulty preparing
1,4,5,6-tetrahydronicotinic acid. Thus, changing the position of the
C=C double bond and N-alkylation of the secondary amino group
was expected to have a beneficial effect on the rate and selectivity
of hydrogenation. Based on the foregoing considerations, we inves-
tigated the hydrogenation of N-methyl-1,2,5,6-tetrahydronicotinic
acid (1) prepared by hydrolysis of commercially available arecoline
(see Scheme 1).
The hydrogenation of 1 resulted in selective formation of N-
methyl nipecotic acid (2), rapidly reaching complete conversion
Further increases in both Ri and ee were attained by increasing
the H2 pressure (see Table 2); however, unlike in the hydrogena-

G. Sz o˝ ll o˝ si et al. / Journal of Catalysis 256 (2008) 349–352
351
Scheme 2. Preparation [48] and attempts on enantioselective hydrogenation of guvacine (3) over cinchona modified Pd catalyst.
ꢀ
Table 2
containing compound [37]. Methoxy substituent on the C6 of the
quinoline moiety decreased the ee substantially in both series of
H2 pressure and modifier structure effect on the enantioselective hydrogenation of
a
1
over cinchona modified Pd/Al2O3 catalyst
8
9
cinchona alkaloids, however, in this pair, also the (R)C –(S)C cin-
chona (quinidine) gave a higher ee value than quinine.
Finally, the strategy used in this work seems to give good re-
sults for the preparation of optically enriched N-methyl nipecotic
acid by enantioselective heterogeneous catalytic hydrogenation of
the corresponding α,β-unsaturated acid. An essential feature of
the substrate design is the use of a compound bearing tertiary N.
The importance of this factor was verified by attempting the hy-
drogenation of guvacine (3) prepared according to Scheme 2 [48].
No hydrogenation products were detected under H2 pressure of 0.1
or 5 MPa over either CD- or CN-modified Pd/Al2O3 after 3 h of re-
action, thus confirming our rationale.
Timeb
(min)
Entry
Modifier
pH2
Ri
ee (%)
−
1
−1
)
(Conf.)c
(
MPa)
(mmol g
h
cat
In conclusion, in the present study we have extended the ap-
plicability of the cinchona alkaloid-modified Pd catalyst on the
enantioselective hydrogenation of a tetrahydronicotinic acid deriva-
tive through careful choice of the structural elements of the sub-
strate. The proper position of the C=C group, the presence of a
free carboxylic acid group, and alkylation of the N are the key
features that together result in the enantioselective formation of
the saturated product. This is the first reported example of hy-
drogenation of an N-heterocyclic α,β-unsaturated carboxylic acid
over a chirally modified supported noble metal catalyst with sat-
isfactory optical purity. Obviously, gaining more insight into the
influence of the reaction parameters on the rate and enantioselec-
tivity of the reaction and elucidating the structure of the surface
intermediate responsible for enantioselection require further de-
tailed kinetic, spectroscopic, and theoretical studies, which will
be the subject of our future investigations. As it stands, however,
the pharmaceutical importance of the chiral piperidine derivatives
makes this approach an interesting and novel preparation proce-
dure, the further development of which may eventually result in
practical applications.
1
2
3
CD
CD
CD
CD
CD
CD
CD
QN
CN
CN
QD
0.1
1
2
2
3
5
10
2
2
2
15
8
5
5
5
5
5
10
5
5
73
129
180
171
256
316
39 (R)
43 (R)
47 (R)
50 (R)
45 (R)
44 (R)
37 (R)
5 (R)
d
4
5
6
7
8
9
e
n.d.
156
177
169
183
50 (S)
60 (S)
16 ( S)
1
0d
11
2
5
a
Reaction conditions: 50 mg Pd/Al2O3, 3 ml MeOH, 0.7 mmol 1, 0.035 mmol
modifier, 0.7 mmol BA, stirring 1000 rpm, 295 ± 2 K.
b
Reaction time needed for complete conversion.
Configuration of the excess enantiomer.
Using 0.07 mmol CD.
n.d.—not determined.
c
d
e
tion of prochiral α,β-unsaturated aliphatic carboxylic acids [18]
and α-acetamidoacrylic acid [37], here the ee achieved maximal
value under 2 MPa H2 pressure, resembling the recently reported
behavior in the hydrogenation of itaconic acid [28]. The ee was
further increased up to 50% by increasing the amount of CD to
10 mol% (with respect to 1). The high amount of CD used to ob-
Acknowledgments
tain the best ee indicates that a relatively high concentration of
dissolved CD-acid salt (either dimer or monomer acid) is needed
to obtaining good ee in this system, as is typically the case in the
hydrogenation of α,β-unsaturated aliphatic carboxylic acids [45].
We assume that this may be related to the adsorption strengths of
CD, 1, and CD-1 salt and also to the possible reactions between the
dissolved CD-1 salt and the adsorbed modifier, similar to a previ-
ous proposal [46].
Financial support was provided by the Hungarian National Sci-
ence Fundation (OTKA grants T 048764 and K 72065). G.S. thanks
the Hungarian Academy of Sciences for the award of a Bolyai János
Research grant.
References
Interestingly, the use of cinchonine (CN) resulted in higher ee
values compared with CD, along with inversion of the ee sense
corresponding to the opposite configuration of the C and C9 chiral
centers of the modifier. Thus, (S)-2 was obtained at up to 60% opti-
cal purity using 10 mol% CN. This observation is rather surprising;
generally, the use of CN instead of CD results in significantly lower
ee in the hydrogenation of prochiral α,β-unsaturated carboxylic
acids over Pd catalysts [28,45,47]. Similar behavior was observed
only in the hydrogenation of α-acetamidoacrylic acid, another N-
[1] J.J. Li, D.S. Johnson, D.R. Sliskovic, B.D. Roth, Contemporary Drug Synthesis, Wi-
ley, Hoboken, NJ, 2004.
[2] H.U. Blaser, E. Schmidt (Eds.), Asymmetric Catalysis on Industrial Scale: Chal-
8
lenges, Approaches and Solutions, Wiley–VCH, Weinheim, 2004.
[3] M.G.P. Buffat, Tetrahedron 60 (2004) 1701.
[4] T. Ohkuma, M. Kitamura, R. Noyori, in: I. Ojima (Ed.), Catalytic Asymmetric
Synthesis, second ed., Wiley, New York, 2000, chap. 1, p. 1.
[
5] H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv. Synth.
Catal. 345 (2003) 103.
[6] A. Lei, M. Chen, M. He, X. Zhang, Eur. J. Org. Chem. (2006) 4343.
[7] M. Heitbaum, F. Glorius, I. Escher, Angew. Chem. Int. Ed. 45 (2006) 4732.

352
G. Sz o˝ ll o˝ si et al. / Journal of Catalysis 256 (2008) 349–352
[
[
8] P. Kukula, R. Prins, Top. Catal. 25 (2003) 29.
9] M. Besson, C. Pinel, Top. Catal. 25 (2003) 43.
[31] A. Tungler, Á. Fürcht, Zs.P. Karancsi, G. Tóth, T. Máthé, L. Heged u˝ s, Á. Sándi,
J. Mol. Catal. A Chem. 139 (1999) 239.
[
10] P.B. Wells, R.P.K. Wells, in: D.E. De Vos, I.F.J. Vankelecom, P.A. Jacobs (Eds.), Chi-
[32] R. Hernández Valdés, L. Puzer, M. Gomes Jr., C.E.S.J. Marques, D.A.G. Aranda,
M.L. Bastos, A.L. Gemal, O.A.C. Antunes, Catal. Commun. 5 (2004) 631.
[33] N.J. Colston, R.P.K. Wells, P.B. Wells, G.J. Hutchings, Catal. Lett. 103 (2005) 117.
ral Catalyst Immobilization and Recycling, Wiley–VCH, Weinheim, 2000, p. 123.
[
[
11] M. Studer, H.-U. Blaser, C. Exner, Adv. Synth. Catal. 345 (2003) 45.
12] D.Y. Murzin, P. Mäki-Arvela, E. Toukoniitty, T. Salmi, Catal. Rev. Sci. Eng. 47
2005) 175.
[
[
[
34] N.J. Coulston, R.P.K. Wells, P.B. Wells, G.J. Hutchings, Catal. Today 114 (2006)
(
353.
[
[
[
[
13] M. Bartók, Curr. Org. Chem. 10 (2006) 1533.
35] N.J. Coulston, E.L. Jeffery, R.P.K. Wells, P. McMorn, P.B. Wells, D.J. Willock, G.J.
Hutchings, J. Catal. 243 (2006) 360.
36] M. Gomes Jr., R. Hernández-Valdés, C.E.S.J. Marques, M.L. Bastos, D.A.G. Aranda,
O.A.C. Antunes, React. Kinet. Catal. Lett. 87 (2006) 19.
14] T. Osawa, T. Harada, O. Takayasu, Curr. Org. Chem. 10 (2006) 1513.
15] T. Mallat, E. Orglmeister, A. Baiker, Chem. Rev. 107 (2007) 4863.
16] Gy. Sz o˝ ll o˝ si, Magy. Kem. Foly. 113 (2007) 146.
[
17] T.J. Hall, P. Johnston, W.A.H. Vermeer, S.R. Watson, P.B. Wells, Stud. Surf. Sci.
[
37] Gy. Sz o˝ ll o˝ si, E. Szabó, M. Bartók, Adv. Synth. Catal. 349 (2007) 405.
38] H.-U. Blaser, H. Hönig, M. Studer, C. Wedemeyer-Exl, J. Mol. Catal. A Chem. 139
1999) 253.
Catal. 101 (1996) 221.
18] K. Borszeky, T. Mallat, A. Baiker, Catal. Lett. 41 (1996) 199.
19] Y. Nitta, Chem. Lett. (1996) 897.
[
[
[
[
[
[
(
39] S.A. Raynor, J.M. Thomas, R. Raja, B.F.G. Johnson, R.G. Bell, M.D. Mantle, Chem.
Commun. (2000) 1925.
40] K. Borszeky, T. Mallat, R. Aeschiman, W.B. Schweizer, A. Baiker, J. Catal. 161
[20] K. Borszeky, T. Mallat, A. Baiker, Tetrahedron: Asymmetry 8 (1997) 3745.
[21] Y. Nitta, Chem. Lett. (1999) 635.
[22] M. Maris, W.-R. Huck, T. Mallat, A. Baiker, J. Catal. 219 (2003) 52.
(1996) 451.
[
23] Gy. Sz o˝ ll o˝ si, S. Niwa, T. Hanaoka, F. Mizukami, J. Mol. Catal. A Chem. 230 (2005)
41] Gy. Sz o˝ ll o˝ si, I. Kun, M. Bartók, Chirality 13 (2001) 619.
9
1.
24] Gy. Sz o˝ ll o˝ si, T. Hanaoka, S. Niwa, F. Mizukami, M. Bartók, J. Catal. 231 (2005)
80.
25] T. Sugimura, J. Watanabe, T. Okuyama, Y. Nitta, Tetrahedron: Asymmetry 16
2005) 1573.
26] Y. Nitta, J. Watanabe, T. Okuyama, T. Sugimura, J. Catal. 236 (2005) 164.
27] T. Sugimura, J. Watanabe, T. Uchida, Y. Nitta, T. Okuyama, Catal. Lett. 112 (2006)
7.
[
[
42] K. Borszeky, T. Bürgi, Z. Zhaohui, T. Mallat, A. Baiker, J. Catal. 187 (1999) 160.
43] M. Casagrande, S. Franceschini, M. Lenarda, O. Piccolo, A. Vaccari, J. Mol. Catal.
A Chem. 246 (2006) 263.
[
[
[
4
[44] Z. Guo, X. Zheng, W. Thompson, M. Dugdale, R. Gollamudi, Bioorg. Med.
(
Chem. 8 (2000) 1041.
[
[45] I. Kun, B. Török, K. Felföldi, M. Bartók, Appl. Catal. A Gen. 203 (2000) 71.
[46] A. Solladié-Cavallo, F. Hoernel, M. Schmitt, F. Garin, J. Mol. Catal. A Chem. 195
(2003) 181.
[47] Y. Nitta, A. Shibata, Chem. Lett. (1998) 161.
[48] R.A. Olofson, J.T. Martz, J.-P. Senet, M. Piteau, T. Malfroot, J. Org. Chem. 49
(1984) 2081.
2
[
28] Gy. Sz o˝ ll o˝ si, K. Balázsik, M. Bartók, Appl. Catal. A Gen. 319 (2007) 193.
[
29] B. Hermán, Gy. Sz o˝ ll o˝ si, F. Fülöp, M. Bartók, Appl. Catal. A Gen. 331 (2007) 39.
[
30] Gy. Sz o˝ ll o˝ si, T. Varga, K. Felföldi, Sz. Cserényi, M. Bartók, Catal. Commun. 9
(2008) 421.