Diastereoselective hydrogenation of substituted quinolines to enantiomerically pure decahydroquinolines

Article abstract of DOI:10.1002/adsc.200900763

The stereoselective hydrogenation of auxiliary-substituted quinolines was used to build up saturated and partially saturated heterocycles. In a first step, the formation and diastereoselective hydrogenation of 2-oxazolidinone- substituted quinolines to 5,6,7,8-tetrahydroquinolines is reported. In this unprecedented process, stereocenters on the carbocyclic quinoline ring were formed with a dr of up to 89:11. Platinum oxide as a catalyst and trifluoroacetic acid as a solvent were found to be optimal for high levels of chemo- and stereoselectivity in this step. In a second hydrogenation step, the completely saturated decahydroquinolines with 4 newly formed stereocenters were obtained with enantioselectivities of up to 99%. Rhodium on carbon as a catalyst and acetic acid as a solvent gave the best results for this hydrogenation and allowed a traceless cleavage of the chiral auxiliary. Thus, this new method allows an efficient stereoselective synthesis of valuable 5,6,7,8-tetrahydro- and decahydroquinoline products.

Full text of DOI:10.1002/adsc.200900763

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DOI: 10.1002/adsc.200900763
Diastereoselective Hydrogenation of Substituted Quinolines to
Enantiomerically Pure Decahydroquinolines
Maja Heitbaum,a Roland Frçhlich,a and Frank Gloriusa,*
a
Organisch-Chemisches Institut der Westfꢀlischen Wilhelms-Universitꢀt Mꢁnster, Corrensstraße 40, 48149 Mꢁnster,
Germany
Fax : (+49)-251-83-39-772; e-mail: glorius@uni-muenster.de
Received: November 30, 2009; Revised: December 31, 2009; Published online: February 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900763.
Abstract: The stereoselective hydrogenation of aux-
iliary-substituted quinolines was used to build up
saturated and partially saturated heterocycles. In a
first step, the formation and diastereoselective hy-
drogenation of 2-oxazolidinone-substituted quino-
lines to 5,6,7,8-tetrahydroquinolines is reported. In
this unprecedented process, stereocenters on the
carbocyclic quinoline ring were formed with a dr of
up to 89:11. Platinum oxide as a catalyst and tri-
fluoroacetic acid as a solvent were found to be opti-
mal for high levels of chemo- and stereoselectivity
in this step. In a second hydrogenation step, the
completely saturated decahydroquinolines with 4
newly formed stereocenters were obtained with
enantioselectivities of up to 99%. Rhodium on
carbon as a catalyst and acetic acid as a solvent
gave the best results for this hydrogenation and al-
lowed a traceless cleavage of the chiral auxiliary.
Thus, this new method allows an efficient stereose-
lective synthesis of valuable 5,6,7,8-tetrahydro- and
decahydroquinoline products.
et al. developed a highly selective Ir-catalyzed homo-
geneous hydrogenation of pyridine ylides,[3d] Zhang
and Lei used a sequential combination of heterogene-
ous and homogeneous hydrogenation,[3c] Rueping
et al. reported an organocatalytic approach employing
chiral Brønsted acids, using a Hantzsch ester as the
reducing agent.[3b] Whereas all these methods employ
chiral, enantiomerically pure catalysts, Glorius et al.
developed an efficient hydrogenation of chiral oxazo-
lidinone-substituted pyridines using achiral heteroge-
nous hydrogenation catalysts like Pd(OH)2/C.[3e,f] In
this latter reaction, the auxiliary was cleaved under
the reaction conditions and fully saturated piperidines
with up to 4 newly formed stereocenters and high ees
(85–98%) were obtained. Significantly more methods
have been reported for the asymmetric (partial) hy-
drogenation of quinolines. Since the aromatic stabili-
zation of the second aromatic ring in bicyclic aromat-
ics is somewhat lower, hydrogenation of the annulat-
ed ring is significantly facilitated. Most of these meth-
ods employ homogeneous iridium, rhodium or ruthe-
Keywords: asymmetric synthesis; chiral auxiliaries;
decahydroquinolines; heterocycles; hydrogenation
Enantiomerically pure saturated or partially saturated nium complexes of chiral ligands[4a–n] together with
heterocyclic compounds are important building blocks molecular hydrogen or, alternatively, chiral Brønsted
and fragments of many biologically active compounds acids as organocatalysts[4o,p] in transfer hydrogenations
like coniine, the poisonous alkaloid of hemlock, or (Scheme 1).[2]
the multiply substituted Lycopodium alkaloids.[1] The
However, despite these advances in the area of
asymmetric hydrogenation of heteroaromatic sub- asymmetric hydrogenation of (hetero)aromatics,
strates presents an attractive strategy for their prepa- many challenges remain. For example, the asymmetric
ration and the last years have seen many significant hydrogenation of benzene rings is still an unsolved,
contributions to this field.[2] For example, several dif- though important task. Consequently, whereas the
ferent approaches have been reported for the asym- asymmetric hydrogenation of substituted quinolines
metric hydrogenation of pyridines: e.g., Charette to 1,2,3,4-tetrahydroquinolines with a newly formed
Adv. Synth. Catal. 2010, 352, 357 – 362
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357

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Scheme 1. Asymmetric homogeneous hydrogenation of quinolines.
stereocenter in the 2-position has been reported sev- available anilines through the corresponding aceto-
eral times,[4] the asymmetric hydrogenation of quino-
lines to 5,6,7,8-tetrahydroquinolines or to enantiomer-
ACHTUNGTRENNUNG
ically pure decahydroquinolines with stereocenters in drogenation to 5,6,7,8-tetrahydroquinolines as well as
the cyclohexane ring fragment has not been described the hydrogenation to the fully saturated decahydro-
to the best of our knowledge. Herein we report the quinolines. Our study commenced with the partial hy-
first (asymmetric) hydrogenation of auxiliary-substi- drogenation of 4,8-dimethyl-2-oxazolidinone-substi-
tuted quinolines to selectively form chiral 5,6,7,8-tet- tuted quinoline 1a. It was unclear whether the highly
rahydroquinolines. Furthermore, the successive hydro- regioselective hydrogenation of the carbocyclic ring
genation leading to enantiomerically pure decahydro- of the quinolines would be possible, but some litera-
quinolines with a total of 4 stereocenters, 3 of them in ture reports were promising.[7] Screening of different
the cyclohexane ring fragment is described reaction parameters revealed the catalyst and espe-
(Scheme 1).
cially the solvent to be critical factors for the selectivi-
We reasoned that an auxiliary-based approach ty of the hydrogenation of the benzene ring. Gratify-
could lead to high levels of stereoselectivity in build- ingly, Adamꢃs catalyst (PtO2) and the solvent tri-
ing up stereocenters on the benzene ring[2d,e] of the fluoroacetic acid (TFA) were found to be optimal to
quinoline system. The hydrogenation of 2-oxazolidi- provide high levels of reactivity and selectivity for the
none-substituted quinolines seemed attractive. In desired hydrogenation to the 5,6,7,8-tetrahydroquino-
acidic media, a hydrogen bond should result in a rigid line 2a (Table 1).[6] After 20 h reaction time under
structure, in which the top face would be shielded by these reaction conditions with a hydrogen pressure of
the R1 substituent of the chiral auxiliary (Scheme 2). 20 bar, complete and selective conversion to the de-
The bottom face would be accessible for adsorption sired 5,6,7,8-tetrahydroquinolines in a diastereomeric
to the heterogeneous catalyst and would thus receive ratio of 89:11 was observed (entry 3). When the less
the hydrogen atoms, resulting in the stereoselective acidic AcOH was used as a solvent the chemoselectiv-
formation of a new stereocenter.[3f] The required sub- ity of the reaction was decreased and partial hydroge-
strates 1 were prepared starting from commercially nation of the pyridine ring occurred (not shown).[6]
Furthermore, an H2 pressure of 5 bar was still found
to be sufficient for complete conversion and the selec-
tivity of the reaction was not affected by different H2
pressures between 1 and 70 bar (entries 1–4). Amaz-
ingly, and unlike in many other applications of oxazo-
lidinones,[8] the isopropyl group proved to be the best
substituent on the chiral auxiliary for obtaining high
selectivities in this transformation. Benzyl- and tert-
butyl-substituted oxazolidinones were significantly
less selective (entries 5–7). This is attractive, since the
i-Pr-substituted auxiliary is stable under the hydroge-
nation conditions (unlike the benzyl derivative) and
can be synthesized from the naturally occurring and
cheap amino acid l-valine.
Scheme 2. Asymmetric heterogeneous hydrogenation of pyr-
idines – mode of action of the chiral auxiliary.[3f]
Scheme 3. Retrosynthesis of the substrates.[6]
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Adv. Synth. Catal. 2010, 352, 357 – 362

Diastereoselective Hydrogenation of Substituted Quinolines to Enantiomerically Pure Decahydroquinolines
Table 1. Influence of hydrogen pressure and the substituent
tiomers – could not be separated by using GC or
HPLC with columns containing achiral phases; on
NMR no baseline resolution was achieved. Only by
using a column with a chiral stationary phase could a
separation be achieved. The results show a decrease
of selectivity the more bonds are located between the
newly formed stereocenters and the chiral auxiliary
(entry 1: 5 bonds, entry 3: 7 bonds). In all cases one
main diastereomer (2) formed preferentially.
of the chiral auxiliary.[a]
To analyze the stereochemistry of the products, the
minor diastereomer 3a was isolated in pure form and
crystallized. Its structure, and consequently also the
one of the major diastereomer 2a, was unequivocally
proven by single crystal X-ray analysis (Figure 1).[9]
The methyl-substituted tetrahydroquinolines 2 were
further hydrogenated to the decahydroquinolines.
Gratifyingly, traceless cleavage[10] of the chiral auxili-
ary occurred in the course of the reaction. Optimiza-
tion of the reaction conditions showed Rh/C as a cata-
lyst, acetic acid as solvent at 150 bar and elevated
temperatures to be optimal. The results are shown in
Table 3.
Entry
Substrate
Pressure [bar]
dr 2:3[b]
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1b
1c
1
5
89:11[c]
89:11
89:11
89:11
82:18[d]
79:21
84:16
20
70
5
20
20
[a]
General procedure: 1 (40 mg), PtO2 (8 mg, 20 wt%), and
TFA (1 mL) were stirred in an autoclave under a hydro-
gen atmosphere at room temperature for 20 h. In each
case, unless otherwise mentioned, clean reactions and
full conversion was obtained.
dr determined by GC.
Incomplete conversion.
54 h reaction time.
The decahydroquinolines could be isolated as the
corresponding hydrochlorides in 72–99% yield. As ex-
pected, the hydrogenation is highly cis-selective and
the diastereomeric ratio of the products depends on
the dr of the starting material. The ee of the major
[b]
[c]
[d]
Differently substituted quinolines 1 were hydrogen- diastereomer was found to be very high in each case
ated under the optimized conditions (Table 2). The (97–99% ee), whereas the ee of the minor diastereo-
determination of the diastereomeric ratio was slightly mer was only moderate. One reason for the latter ob-
more complicated for products 2/3d and 2/3e. The two servation might be the influence of the initially
stereocenters are separated by 6 or 7 bonds and the formed stereocenter in the 6-, 7- or 8-position
diastereomers – obviously behaving more like enan- (matched/mismatched case). However, the directing
Table 2. Hydrogenation of differently methyl-substituted quinolines.[a]
Entry
Substrate
Isolated Yield[b]
dr 2:3
1
2
3
4
1a
1d
1e
1f
95%
91%
99%
94%
89:11[c]
86:14[d]
81:19[d]
78:10:5:7[d]
[a]
General procedure: substrate (300 mg), PtO2 (60 mg, 20 wt%) and TFA (3 mL) were stirred in an autoclave under a hy-
drogen atmosphere (20 bar) at room temperature for 20 h.
After purification by column chromatography.
Determined by GC.
Determined by HPLC using a Chiralcel AD-H column.
[b]
[c]
[d]
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power of the chiral auxiliary is still stronger than the
one of the methyl group and the stereochemical out-
come of the reaction can be explained by Horeauꢃs
principle[11] as shown in Scheme 4.
To prove the relative and absolute stereochemistry,
one of the products, 4a, was crystallized and examined
by single crystal structural analysis. The structure of
decahydroquinoline·HCl 4a is shown in Figure 2.[9]
In conclusion, we have demonstrated a new and, ar-
guably, the first strategy for the stereoselective forma-
tion of chiral 5,6,7,8-tetrahydro- and decahydroquino-
lines with newly formed stereocenters in the cyclohex-
ane ring. Remarkably, in these cases the chiral auxili-
ary can influence the formation of a new stereocenter
over a wide distance, namely 5 to 7 bonds away from
its own stereocenter. Whereas the known hydrogena-
tion methods are limited to the formation of 1,2,3,4-
tetrahydroquinolines mostly with a stereocenter in the
2-position only, our method was demonstrated to
Figure 1. Crystal structure of the minor diastereomer 3a.
Table 3. Second hydrogenation step to decahydroquinolines.
Entry
Substrate
dr
Product
dr 4:5[b,c]
ee[d]
Isolated yield of the
hydrochlorides 4 and 5
1
89:11
87:13
99% (4a); 72% (5a)
81%[e]
99%
2
3
>97:3
85:15
79:21
>99% (4a)
88:12
81:19
97% (4d); 48% (5d)
97% (4e); 68% (5e)
72%[f]
86%
4
[a]
General procedure: substrate (200 mg), catalyst (20–25 wt%) and acetic acid (3 mL) were stirred in an autoclave under a
hydrogen pressure (150 bar) at 608C for 60–84 h.
Diastereomeric ratio of the crude product was determined by GC analysis.
Other diastereomers <5%.
ee determined by chiral GC.
48% yield, if only major diastereomer 4 was isolated.
Only the major diastereomer 4 was isolated.
[b]
[c]
[d]
[e]
[f]
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Adv. Synth. Catal. 2010, 352, 357 – 362

Diastereoselective Hydrogenation of Substituted Quinolines to Enantiomerically Pure Decahydroquinolines
under a hydrogen atmosphere (20 bar) at room temperature
for 20 h. After releasing the hydrogen pressure, the reaction
mixture was filtered through celite to remove the catalyst.
The filtrate was concentrated under reduced pressure. The
residue was taken up with MTBE (30 mL) and the organic
layer was washed with saturated aqueous Na2CO3 solution.
The aqueous layer was extracted with MTBE (2ꢄ30 mL)
and the combined organic layers were dried over Na2SO4
and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography or re-
crystallization.
General Procedure for the Hydrogenation of 5,6,7,8-
Tetrahydroquinolines to Decahydroquinolines
A mixture of 5,6,7,8-tetrahydroquinoline (200 mg), Rh/C
(40 mg, containing 5 wt% Rh) and acetic acid (3 mL) was
stirred in an autoclave under a hydrogen atmosphere
(150 bar) at 608C for 60 to 84 h. After releasing the hydro-
gen pressure, the reaction mixture was filtered through
celite. 3 mL of HCl in MeOH (c=1 mol/L) were added to
the filtrate. The filtrate was concentrated under reduced
pressure. The crude product was taken up with a small
amount of CH2Cl2, washed with saturated aqueous Na2CO3
solution, dried over Na2SO4 and purified by flash chroma-
tography (CH2Cl2/MeOH, 10:1!5:1, height: 5 cm). Before
the solvent was removed, an excess of HCl was added to
convert the volatile products into non-volatile hydrochloride
derivatives.
Scheme 4. Plausible explanation for the selectivities ob-
tained in the hydrogenation to decahydroquinolines.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie (fellowship for M.H.) for
generous financial support. In addition, the research of F.G.
has been supported by the Alfried Krupp Prize for Young
University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation. Donations of precious chemicals by
Merck KGaA and Heraeus are also gratefully acknowledged.
Figure 2. Single crystal structure of decahydroquinoline 4a.
work for building up stereocenters in the 5-, 6-, 7- and
8-positions of the tetrahydroquinoline ring system.
Furthermore, the auxiliary can be cleaved traceless-
ly[10] in a second hydrogenation step, resulting in the
formation of the corresponding decahydroquinolines
with up to 99% ee, containing up to 4 stereocenters.
The development of efficient hydrogenation methods
for the asymmetric formation of heterocyclic com-
pounds is ongoing in our laboratories.
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Adv. Synth. Catal. 2010, 352, 357 – 362
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b=11.5870(6),
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[10] Cleavage of a chiral auxiliary often leaves behind an
ꢀ
undesired functional group, whereas in this case, a C
H bond is formed on the parent molecule: “traceless
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used in the context of traceless linkers: S. Brꢀse, S.
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ꢀ
[5] Anilines are readily available starting materials. For C
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Adv. Synth. Catal. 2010, 352, 357 – 362